Artículos de revistas sobre el tema "Ospedali Riuniti di Bergamo"

Abstract Leukocytes contribute to the pathogenesis of thrombosis in essential thrombocythemia (ET) through recently discovered mechanisms of activation and interaction with platelets and endothelial cells. To evaluate whether an increased leukocyte count was associated with thrombosis and whether this effect can be modulated by therapy, we analyzed the clinical course of 439 patients with ET followed at the Ospedali Riuniti di Bergamo. The strength of the association was measured at diagnosis or before thrombotic events by multivariable analyses carried out using data at baseline as well as time-varying covariates. The results showed that (1) an increased leukocyte count at diagnosis was associated with thrombosis during follow-up (“baseline analysis,” relative risk [RR] 2.3, 95% confidence interval [CI] 1.4-3.9, P = .001); (2) hydroxyurea (HU) lowered leukocytosis and reduced the strength of the association between leukocytosis and thrombosis (“time-dependent analysis,” RR 1.6, 95% CI 0.9-2.0, not significant [NS]); (3) the association of leukocytosis and thrombosis was more evident in untreated low-risk patients (RR 2.7, 95% CI 1.2-6.4, P = .01) compared with HU-treated high-risk patients (RR 1.6, 95% CI 0.8-3.2, NS); and (4) the presence of JAK2 V617F was not identified as a risk factor for thrombosis during follow-up despite a significant association between the mutation and leukocytosis. We suggest validation of these findings in prospective clinical studies.

Abstract Introduction Since the landmark study of Omura et al. (Blood 1980;55:199), validating cranial irradiation as an adjunct to intrathecal (IT) methotrexate, no other randomized trial of CNS prophylaxis was performed in adult ALL. Although the risk of CNS relapse is now only 1-4%, irradiation contributes to cumulative CNS toxicity together with high-dose methotrexate/cytarabine (HD-M/A), or is logistically difficult, so that developing an effective radiation-free CNS prophylaxis remains an important clinical task. IT DepoCyte® (ITD) might be advantageous, the slow release of liposome-associated cytarabine allowing therapeutic concentrations in the cerebrospinal fluid for 14+ days. An open trial reported prohibitive CNS toxicity from ITD in 6/31 patients (Jabbour et al. Blood 2007;109:3214), but ITD to ITD and HD-M/A to ITD intervals were short (14 and 10 days, respectively) and no patient suffered from CNS relapse. Methods In a phase II randomized trial (ClinicalTrials.gov NCT-00795756) we evaluated toxicity and feasibility (as primary study endpoint) of ITD 50 mg in comparison with IT triple therapy (ITT: methotrexate 12,5 mg, cytarabine 50 mg, prednisone 40 mg). Stratification was by cell lineage and risk class. ITT was given on d1 of courses 1,2,4,6,8; d15 of courses 1,2,8; and d1 of maintenance cycles 2-5 (12x). ITD was given on d1 of courses 1,2,4,6,8; d15 of courses 1,8 (T-ALL only); and d1 of maintenance cycle 2 (6-8x). The shortest ITD to ITD interval was 14 days in T-ALL (courses 1-2 [3x] and 8 [2x]), otherwise it was 21 days between ITD and any prior/subsequent ITD and HD course. ALL therapy consisted of eight induction-consolidation courses followed by risk/minimal residual disease-oriented maintenance or stem cell transplantation (SCT). In HD courses 3,7 (M/A) and 5 (M/Asparaginase) M dosage was 2.5 g/m2 (Ph- B-ALL) and 5 g/m2 (T-ALL) up to 55 years, and A 2 g/m2. Imatinib was used with de-intensified chemotherapy in Ph+ ALL; selected high-risk subsets received early SCT. Results Between 2007-12 201 total patients were enrolled and 141 randomized to ITT (n=73) or ITD (n=68). Median age was 42 years (range 18-68) and risk subsets (ITT/ITD) were SR-B 27.4%/29.4%; HR-B Ph- 26%/25%, Ph+ 23.3%/22.1%, SR-T 5.5%/5.9%, HR-T 17.8%/17.7%. Complete remission was 89% (n=65)/89.7% (n=61). Rates of actual v planned IT injections during induction-consolidation cycles 1-8, after removal of study losses (resistance, early death, SCT, toxicity and relapse), were ITT 374/415 (90.1%) v ITD 219/245 (89.3%) (P=0.76). Although toxicity/medical reasons caused 5 ITD patients to discontinue permanently the study v none in ITT arm (P=0.02), toxicity-driven omissions of IT therapy were marginally increased in ITD arm (29/415 [6.9%] v 24/245 [9.8%]; P=0.20). Neurologic toxicity occurred in 20 (27.4%) ITT v 36 (53%) ITD patients, respectively (P=0.002). According to NCI CTC grading (G), neurotoxicity episodes were GI 7 v 10 (P=0.36), GII 13 v 32 (P=0.003), GIII 4 v 12 (P=0.04), GIV 1 v 5 (P=0.12). GIII-IV neurotoxicity developed in 5/73 (6.8%) ITT patients v 10/52 (19.2%) and 5/16 (31.2%) B- and T-ALL ITD patients, respectively (P= 0.01), correlating in T-ALL with the second/third q14d ITD at courses 1,2,8 (4/5 patients, 5/6 episodes). Apart from reversible headache/radicular pain, the most serious toxicity occurred in 3 (4.1%) ITT patients (seizures 1; leukoencephalopathy 1; loss of consciousness 1) v 5 (7.3%) ITD patients (loss of consciousness 4, 1 with seizures; cerebral oedema/pseudotumor cerebri 1) (P=0.48). Four-year overall and disease-free survival were 54% and 52.2% v 58.9% and 47.7% in ITT and ITD arms, respectively, and relapse rate was 32.3% v 24.6% (all P=NS). In ITT arm there were 2 (3%) CNS and 2 (3%) combined CNS/marrow relapses. In ITD arm only one poorly compliant subject not given any HD course had an isolated CNS relapse (1.6%); no other patient had a CNS recurrence. Conclusion A radiation-free CNS prophylaxis with six spaced ITD in conjunction with HD-M/A may be feasible and at least as effective as other regimens. Excluding reversible headache/radiculitis, serious CNS toxicity was not significantly increased compared with ITT regimen, although some patients were forced to discontinue IT prophylaxis. The occasionally severe CNS toxicity prompts the investigation of a lower ITD dosage (25 mg), also to limit GI-II side effects, and the tighter schedule used in T-ALL should be abandoned because too toxic. Disclosures: Bassan: Mundipharma Oncology; Sigma-Tau; Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Liposome-encapsulated cytarabine (DepoCyte®) used in a prospective phase II randomized trial of CNS prophylaxis in ALL. Masciulli:Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo Osseo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Università degli Studi di Firenze: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding. Gallamini:Millenium: Consultancy. Marfisi:Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency: Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore-Roma: Research Funding; Università degli Studi di Firenze: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding. Marchioli:Associazione Italiana Linfomi (AIL): Research Funding; Celgene: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Sigma-Tau: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Genzyme Olanda: Research Funding; AMGEN S.p.A.: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; Ospedali Riuniti di Bergamo: Research Funding; Novartis: Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding; Università degli Studi di Firenze: Research Funding. Rambaldi:Italfarmaco: Honoraria; Sanofi: Honoraria; Novartis: Honoraria.

Abstract Abstract 305 Introduction: Non-Hodgkin's lymphoma (NHL) are malignant tumors usually sensitive to chemotherapy; this results in prolonged survival and possibly disease eradication in a large proportion of patients. However, despite the general improvement in treatment options, a variable number of patients still shows a refractory disease, i.e. poor or absent response to induction therapy. Prediction and management of refractory disease is a major issue in the biological and clinical research programs for NHL. The present study was undertaken to evaluate on a large series of NHL patients, managed at two Italian centers over the last three decades: i. the actual rate of refractory patients; ii. the main factors associated with refractory disease; iii. the long-term outcome of refractory vs. responsive patients. Patients and Methods: Data have been collected on a series of 3,952 NHL patients, referred and treated at the University Hematology of Torino (S. Giovanni B. and Mauriziano Hospitals) (864 cases) and at the Hematology Division of Ospedali Riuniti di Bergamo (3,088 cases), between 1984 and 2012. There were 1,819 (46%) female patients, 2,056 (52%) were aged less than 60 yrs, B-cell NHL were 3,633 (92%), with 318 (8%) patients diagnosed as T-NHL; main histological subtypes included: 1,809 (45.8%) Diffuse Large Cell Lymphoma (DLCL), 758 (19.2%) follicular lymphoma (FL), 210 (5.3%) mantle-cell lymphoma, the remaining 1,175 (29.7) had other histologies. According to Ann Arbor staging, 2,369 (62%) patients presented with advanced stage disease and 914 out of 2,174 evaluable patients (42%) had an intermediate-high IPI score. Overall, 1,430 out of 3,187 (44.9%) received conventional chemo-radiotherapy supplemented with rituximab. The criteria to identify refractory patients were: stable or progressive disease (fully refractory) or transient response with disease progression within 6 months (early relapse), following first-line chemotherapy. Results: Among 2,543 broadly analysed patients, treated during the last 28 yrs, 649 (25.5%) were classified as refractory, including 14% fully refractory and 11.5% with early relapse or disease progression. The overall incidence of refractory disease was similar in the two Centers, 24.1% in Torino and 26.3% in Bergamo. The rate of refractoriness was as high as 46.9% in the small T-cell subgroup, while the overall incidence was 23.6% for B-cell NHL (p<0.001), with refractory patients more frequently observed among DLCL (26.0%) than in FL (15.1%) (p<0.001). Besides T-cell histology, the following factors had the highest association (p<0.001) with treatment response: i. intermediate-high risk IPI presentation, with 38.5% refractory patients, compared to 16.7% for 0–2 IPI scores; ii. female gender, with a markedly lower incidence (22%) of refractoriness compared to males (28.4%); iii. rituximab addition, that cut the incidence of refractoriness to 19.2% compared to 28.8% for patients treated without rituximab. These factors maintained their independent predictive values in multivariate regression analysis. At a median follow-up of 5.4 yrs., 1,607 (61%) out of 2,543 patients are alive, 11.8% of them were refractory to their first line treatment. Indeed, among 649 refractory patients, 189 (29%) are presently alive, compared to 1,418 alive (75%) among 1,894 responsive patients. Lastly, the overall survival (OS) was significantly poorer for fully refractory (median survival: 1.1 yrs) compared to early relapse patients (2.09 yrs) (p<0.001); both these refractory subgroups had a definitely poorer OS compared to responsive patients, whose median survival was 22.2 yrs (see Figure 1). Conclusions: i. Overall, in this large series of NHL patients who received induction therapy both in the pre- and post-Rituximab era, approximately one fourth displays full refractoriness or early relapse/progression; ii. the introduction of rituximab has markedly reduced the risk of refractory disease, whose incidence is now around 19%; iii. a markedly higher rate of refractory disease is observed with T-subtypes compared to B-cell NHL; iv. intermediate-high IPI score is associated to refractoriness, while female gender significantly reduces the risk of refractory disease; iv. patients responsive to first-line therapy have a very prolonged life expectancy, with a median survival around 22 yrs, whereas the median survival for refractory patients does not exceed 2 yrs. Disclosures: Tarella: Hoffmann-La Roche: Consultancy, Honoraria. Rambaldi:Hoffmann-La Roche: Consultancy, Honoraria.

Abstract Philadelphia-negative Myeloproliferative Neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Myelofibrosis, both Primary (PMF) and secondary to PV or ET (PPV-MF and PET-MF). A MPN is frequently the underlying cause of splanchnic vein thrombosis (SVT), accounting for 31.5% of portal vein thrombosis (PVT) and 40.9% of Budd Chiari syndrome (BCS). In patients (pts) with MPN and SVT, splenomegaly can arise as the consequence of the hematological disease and/or blood flow abnormalities consequent to the thrombosis itself. Splenomegaly and the compensatory enlarged splanchnic vessels are responsible for several complications including esophageal and gastric varices. Splenomegaly may cause abdominal discomfort; furthermore pts may present symptomatic burden due to the MPN. Current treatment strategies for MPN pts with SVT include anticoagulants and cytoreductive therapy (ie hydroxyurea, interferon) that have little influence in the control of splenomegaly and symptoms and do not improve flow abnormalities. Ruxolitinib, a JAK1/2 inhibitor, was highly effective in reducing spleen volume and improving symptoms in patients with MF and PV in phase II and III studies. We hypothesized that the decrease of the enlarged spleen determined by Ruxolitinib could result in a reduction of the local pressure in splanchnic vessels, producing both symptomatic improvement of splenomegaly-related symptoms and of splanchnic circulation. We designed an investigator-initiated multicentre phase 2 study of Ruxolitinib in pts with splenomegaly due to an underlying MPN associated with SVT. The drug was provided free of charge by Novartis, that had no role in trial design nor in data analysis. The primary study objective was to evaluate the proportion of subjects achieving ≥ 50% reduction in spleen length from left costal margin (LCM) measured by palpation at any time from baseline to week 24 (w24) and at w24, or a ≥ 35% reduction in spleen volume by MRI or CT at week 24. The secondary objectives included: evaluation of safety of Ruxolitinib in MPN-associated SVT; assessment of splanchnic circulation through Doppler analysis, measurement of hyperdynamic arterial circulation by echocardiography and stiffness of hepatic/splenic parenchyma by fibroscan; status of esophageal varices at w24 compared to baseline. Quality of Life assessment was performed using MPN-SAF questionnaire. Exploratory objectives include evaluations of changes in JAK2V617F or MPLW515 allelic burden, association of baseline mutations with response to treatment, changes in cytokine and microRNAs profiles, quantification of circulating endothelial cells. At the time of abstract submission 7 out of 21 pts have been enrolled, of which 5 completed the 24 weeks of treatment; two additional pts are in screening phase. Three pts had PMF, two ET, one PV and one PPV-MF, associated to spleno-porto-mesenteric thrombosis (5 pts) and Budd Chiari syndrome (2 pts). All pts were under oral anticoagulation therapy. Initial dose of Ruxolitinib was 10 mg BID for PV, 25 mg BID for ET, 15 mg BID for MF pts with baseline platelet count of 100 to 200x109/L and 20 mg BID for those with baseline platelet count >200x109/L. A palpable splenomegaly greater than 5 cm below LCM was a criterion for enrollment; the 5 patients who completed the 24 weeks of treatment had a median splenomegaly of 8 cm below LCM at baseline, and obtained a median reduction of 69% measured by palpation at week 24, associated with a significant reduction in abdominal discomfort as measured by MPN-SAF questionnaire (median score at screening 5 vs 1.5 at week 24). The total symptom score calculated by using BFI and MPN-SAF was reduced from 50 at screening to 35 at week 24. Instrumental evaluations of splanchnic and systemic circulation showed that 3 pts obtained a reduction of the spleen stiffness from a median value of 66 to 49.6 kilopascals (KPa), 2 pts had a reduction of the liver stiffness from a median value of 23.85 to 18.2 KPa and 1 pt a reduction of the cardiac output from 5.871 to 4.6 L/min. Evaluation of esophageal varices at week 24 showed stabilization with neither worsening nor need of banding. Ruxolitinib was well tolerated, with no SAE reported; one pt developed anemia G2 and one G3 leading to dose reduction. Other adverse events include G1 asthenia and G≤2 AST/ALT increase in 3 pts, one case of Herpes Zoster and one case of abdominal pain both G1. Updated results will be presented at the meeting. Disclosures: Marchioli: Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding; Università degli Studi di Firenze: Research Funding. Vannucchi:NOVARTIS: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Introduction: The role of EBUS-TBNA in the diagnosis and staging of lung cancer is well established. EBUS-TBNA can be performed using different aspiration techniques. The most common aspiration technique is known as “suction”. One alternative to the suction technique is the slow-pull capillary aspiration. To the best of our knowledge, no studies have assessed the diagnostic yield of slow-pull capillary EBUS-TBNA in PD-L1 amplification assessment in NSCLC. Herein, we conducted a single-centre retrospective study to establish the diagnostic yield of slow-pull capillary EBUS-TBNA in terms of PD-L1 in patients with NSCLC and hilar/mediastinal lymphadenopathies subsequent to NSCLC. Materials and Methods: Patients with hilar and/or mediastinal lymph node (LN) NSCLC metastasis, diagnosed by EBUS-TBNA between January 2021 and April 2022 at Pulmonology Unit of “Ospedali Riuniti di Ancona” (Ancona, Italy) were enrolled. We evaluated patient characteristics, including demographic information, CT scan/ FDG-PET features and final histological diagnoses, including PD-L1 assessment. Results: A total of 174 patients underwent EBUS-TBNA for diagnosis of hilar/mediastinal lymphadenopathies between January 2021 and April 2022 in the Interventional Pulmonology Unit of the “Ospedali Riuniti di Ancona”. Slow-pull capillary aspiration was adopted in 60 patients (34.5%), and in 30/60 patients (50.0%) NSCLC was diagnosed. EBUS-TBNA with slow-pull capillary aspiration provided adequate sampling for molecular biology and PD-L1 testing in 96.7% of patients (29/30); in 15/29 (51.7%) samples with more than 1000 viable cells/HPF were identified, whereas in 14/29 (48.3%) samples contained 101–1000 viable cells/HPF. Conclusion: These retrospective study shows that slow-pull capillary aspiration carries an excellent diagnostic accuracy, almost equal to that one reported in literature, supporting its use in EBUS-TBNA for PD-L1 testing in NSCLC.

RIASSUNTOScopo — Lo studio QUALYOP si prefigge tre obiettivi: 1) descrivere la situazione dei 12 ex ospedali psichiatrici lombardi in relazione a caratteristiche strutturali e organizzative e all'andamento di ammisioni/dimissioni e decessi dei pazienti ricoverati; 2) descrivere la qualita di strutture, organizzazione e attivita dei reparti; 3) descrivere le caratteristiche socio-demografiche, cliniche e le potenzialita riabilitative della popolazione ricoverata. I dati presentati in questo articolo si riferiscono ai primi due obiettivi. Disegno - Studio descrittivo-valutativo. Gli ospedali sono stati vistitati nell'arco di sei mesi (luglio-novembre 1994) da un gruppo di ricercatori-rilevatori in una data concordata con i rispettivi direttori. Sono state utilizzate quattro fonti di informazione e documentazione: scheda ospedale, scheda reparto, scheda paziente, documentazione fotografica delle strutture. Setting - I 12 ex-ospedali psichiatrici pubblici della Regione Lombardia in funzione alia data della rilevazione (Bergamo, Brescia, Castiglione delle Stiviere, Codogno, Como, Cremona, Limbiate, Mantova, Milano, Sondrio, Varese, Voghera). Principali misure utilizzate - È stato utilizzato un gruppo di indicatori che forniva informazioni sulle strutture, sull'organizzazione della vita di reparto e sulle attività svolte. I giudizi di qualita sono stato espressi in relazione a criteri espicitati a priori. I reparti sono stati quindi raggruppati in tre tipologie a seconda del livello di adeguatezza delle strutture, dell'organizzazione e delle attività. Risultati - I 12 ospedali psichiatrici pubblici della Lombardia risultano costituiti da 63 reparti che accolgono complessivamente 2752 ricoverati. La situazione risulta estremamente eterogenea nei diversi ospedali che si differenziano per affollamento dei reparti, rapporto operatori-pazienti, decremento negli anni della popolazione ricoverata e numero di nuove ammissioni. La valutazione della qualita strutturale, organizzativa e delle attivita evidenzia che il 70% dei reparti e inadeguato o gravemente inadeguato dal punto di vista strutturale, mentre più del 70% è inadeguato o gravemente inadeguato dal punto di vista organizzativo e delle attività che vi si svolgono. Conclusioni - Lo studio dimostra la fattibilita di valutazioni di programmi di sanita pubblica utilizzando criteri non riferiti a dati di efficacia ma formulati a partire da valori etici, senso comune, eventi non ammissibili, risultati di studi quasi-sperimentali ed esperienza. I dati cosi raccolti permettono di concludere che le politiche di superamento dell'ospedale psichiatrico sono estremamente carenti nella maggior parte dei casi e che la ricoversione esclusivamente strutturale degli immobili, in molti casi assolutamente necessaria, non è tuttavia sufficiente a garantire un reale superamento. Molto più urgente sembra essere la necessita di formare e motivare il personale di assistenza e amministrativo.

Objective Evaluate outcomes of the lengthening temporalis myoplasty in facial reanimations. Study Design Case series with planned data collection. Setting Ospedali Riuniti, Bergamo, and AOUC Careggi, Florence, Italy. Subjects and Methods From 2011 to 2016, 11 patients underwent lengthening temporalis myoplasty; demographic data were collected for each. Pre- and postoperative photographs and videos were recorded and used to measure the smile angle and the excursion of the oral commissure, according to the SMILE system (Scaled Measurements of Improvement in Lip Excursion). All patients were tested with the Facial Disability Index, and they also completed a questionnaire about the adherence to physiotherapy indications. Results All patients demonstrated a significant improvement in functional parameters and in quality of life. On the reanimated side, the mean z-line and a-value, measured when smiling, significantly improved in all patients: from 22.6 mm (95% CI, 20.23-25.05) before surgery to 30.9 mm (95% CI, 27.82-33.99) after surgery ( P < .001) and from 100.5° (95% CI, 93.96°-107.13°) to 111.6° (95% CI, 105.63°-117.64°; P < .001), respectively. The mean postoperative dynamic gain, passing from rest to a full smile at the reanimated side, was 3.1 mm (95% CI, 1.30-4.88) for the z-line and 3.3° (95% CI, 1.26°-5.29°) for the a-value. The Facial Disability Index score increased from a preoperative mean of 33.4 points (95% CI, 28.25-38.66) to 49.9 points (95% CI, 47.21-52.60) postoperatively ( P < .001). Conclusions The lengthening temporalis myoplasty can be successfully used for smile reanimation, with satisfying functional and quality-of-life outcomes.

Abstract Background. Although, the recent introduction of Rituximab in combination with chemotherapy has improved outcome of patients with indolent lymphomas, in particular FL, these diseases are still considered incurable and the majority of patients still have a fatal course. Enzastaurin, an acyclic bisindolylmaleimide, is a potent and selective competitive inhibitor of protein kinase C beta, which has been shown to inhibit cell proliferation and angiogenesis in human cancer cell lines. The purpose of the present study was to test enzastaurin for its effects on proliferation and survival of B-cell lines established from NHL patients. Methods. The WSU-NHL and Karpas 422 were kindly provided Dr M Introna ( Division of Haematology, Ospedali Riuniti, Bergamo, Italy); the RL was purchased by DSMZ. All three lines are carrying the t(14; 18) and Karpas 422 is EBV+. We decided to conduct all the experiments under the optimal culture conditions with 10% FCS to avoid subjecting the cells to further stress stimuli. IC50 values were calculated from curves based on enzastaurin concentration ranging from 1 to 10μM using MTT assay and cell viability assessment by Trypan Blue exclusion. Cell apoptosis was assessed by flow cytometer after staining with Annexin V-FITC and propidium iodide. The effects of enzastaurin on caspases activation as well as on AKT phosphorilation were evaluated by Western blotting. We also investigated the interaction of enzastaurin with chlorambucil and fludarabine. Results using MTT assay were expressed as fraction of cells killed by the individual drug or the combination in the drug-treated versus untreated cells. The interaction between drugs was analyzed by isobologram analysis using the StaCorp8.2 software program based upon the Chou-Talalay method to determine if the combinations were additive or synergistic. Results. We found that enzastaurin alone inhibits the proliferation of B-cell lymphomas cell lines at IC50 values ranging from 5 to 7.5 μM after 48 h and from 2.5 to 3.2 μM after 72 h. Induction of apoptosis by enzastaurin evaluated on WSU-NHL and RL, by flow cytometry analysis of membrane permeability, showed that enzastaurin induces an increase in the percentage of apoptotic cells compared with untreated controls in a time-dependent fashion. Furthermore, enzastaurin induces the appearance of the cleaved caspase-3 fragment in the same cell lines in a time dependent fashion. Activation of the apoptotic pathway was confirmed by cleavage of the PARP enzyme. The apoptosis is partially prevented by the ZVAD–fmk broad caspase inhibitor. Phosphorilation status analysis of AKT up to 72h of treatment showed a decrease of AKT phosphorilation starting from 48h after treatment. We tested the effect of enzastaurin combined with chlorambucil and fludarabine,drugs that are active against B-cell lymphoma and we demonstrated that these agents enhanced the cytotoxicity triggered by enzastaurin in a dose-dependent fashion. A clear synergistic interaction (CI=0.87) appeared using low concentrations of the drugs and increased (CI=0.1) at high concentrations. Conclusions. Our data suggest that in B lymphoma cell lines carrying t(14; 18), enzastaurin elicits its antitumor effect suppressing AKT phosphorilation, inducing apoptosis and inhibiting proliferation. Furthermore, enzastaurin synergizes with chlorambucil and fludarabine. These results support the potential use of enzastaurin in patients with NHL, and in particular provide a rationale for combination with chlorambucil and fludarabine.

752 Background: Glucose and other metabolites (lactates and glutamine) in the tumor microenvironment (TME) may alter the activity of the immune system cells. Cancer cells consume glucose and its decrease in the TME affects the function of tumour-infiltrating lymphocytes (TILs). Moreover, tumor-infiltrated immunosuppressive cells and vascular endothelial cells also deplete nutrients, in the TME, enhancing an immunosuppressive environment. On the basis of the results coming from our previous works regarding lymphocytes to monocytes ratio (LMr) and diabetes, suggesting a role for each of them as predictors of better outcomes, in this study we evaluate both of them in order to establish a possible role of them as outcomes predictive factors. Methods: Data from 228 patients (pts) were collected retrospectively from 2016 to 2021: 175 from the Medical Oncology Unit of University Hospital of Cagliari; 53 from the Medical Oncology Unit, AOU Ospedali Riuniti di Ancona. All pts had stage IV disease and received gemcitabine plus nab-paclitaxel 1st line chemotherapy. Statistical analysis was performed with the MedCalc package. We aimed to evaluate the correlation between treated DM2 and lymphocytes to monocytes ratio (LMr) ≥ 4 with outcomes. Survival distribution was assessed by Kaplan-Meier curves. Multivariate analysis was performed taking into consideration the following prognostic factors: sex, ECOG-PS, LMr, NLr, LDH, Ca19.9, and metastatic sites. Results: Median age was 68 (±9), 123/228 (54%) were male, 94/232 (40,6%) were affected by DM2 (insulin or metfomin-treated) and 138 (59,4%) pts were not affected by DM2. 52/228 (23%) pts had a LMr ≥ 4, 176/228 (77%) pts had a LMr < 4. In multivariate analysis, DM2 and LM ratio ≥ 4 were found to be independent factors associated with higher overall survival. Therefore, we divided the pts into 3 groups: co-presence DM2 and LM ≥ 4 (DM+LM+); absence of DM2 and LM ≥ 4 (DM-LM-); presence of DM2 or LM ≥ 4 (DM+LM- or DM-LM+). DM+LM+ demonstrated statistically significantly higher median OS than DM+LM-/DM-LM+ and DM-LM- (not reached versus 21 versus 9 months, respectively, p < 0.0001). Furthermore, DM+LM+ showed a statistically significant better median PFS than DM+LM-/DM-LM+ and DM-LM- (11 versus 9 versus 6 months, respectively, p = 0,0036). Conclusions: Results showed a correlation between pts with DM2/LMr ≥ 4 and better outcomes. This may suggest the presence of a link between glucose metabolism and lymphocytes activation. Antidiabetic medications could promote the inhibition of Warburg effect in tumor cells, and, consequently, provide a better glucose intake to extracellular microenvironment, and immune cells, including T lymphocytes. This process leads to a higher activity of T-cells and a better treatment response. Further studies are warranted.

IntroductionIn the last decades, many haemostatic substances included oxidized cellulose topically applied have been used during surgery and their use have become a common practice. Oxidized cellulose (OC) is one of the most used haemostatic substances. However, different studies have shown the persistence of OC deposits after surgical procedures that may simulate recurrent malignancies and abscesses. We present a case series of patients with enlarged on CT and PET-FDG positive lymphadenopathies due to foreign body inflammatory reaction to OC after lung surgery for pulmonary malignancies.MethodsRetrospective chart review of patients from 2021 to 2022 who underwent EBUS-TBNA for the characterization of hilar and/or mediastinal lymphadenopathies and a histopathological diagnosis of foreign body inflammatory reaction to OC.ResultsEight patients were referred to “Ospedali Riuniti di Ancona” (n = 7) and “Ospedale San Martino” (Genoa) (n = 1) Interventional Pulmonology Units for the characterization of hilar and/or mediastinal lymphadenopathies. All the evaluated patients underwent surgical procedures for lung cancers within the previous 12 months. EBUS-TBNA was performed in all the patients to rule out nodal metastasis. The cyto-pathological evaluation revealed amorphous acellular eosinofilic material surrounded by inflammatory reaction. As no other apparent causes might explain this finding and considering the temporal relationship between the lymphadenopathy and the lung surgery, foreign body inflammatory reaction to OC is the most likely cause of the phenomenon.ConclusionIn patients who underwent surgery for lung cancer, especially within few months, the development of lymph node foreign body reaction due to surgical material retention should always be considered.

Abstract Objectives Current evidence on TAVI has been generated exclusively by cardiology studies and no operative data from cardiac surgeons are available. Here we describe the development of our TAVI program and report the results of transfemoral TAVI done by cardiac surgeons on their own. Methods This study included all the TAVI procedures on native valve performed at Cardiac Surgery Unit, Ospedali Riuniti di Ancona, during the period October 2018 – July 2022. Relevant prospectively collected preoperative, intraprocedural and postoperative data were retrieved from the Institutional database. Results A total of 413 patients were included in the study. Mean patients’ age was 82 years and among them 44% (180/413) were male. STS score was 3.1% (2.2 – 4.4). Eighty patients underwent transapical TAVI and 333 patients had a transfemoral approach. We progressively moved from trans-apical TAVI towards trans-femoral procedures that are now routinely performed on conscious sedation and using a fully percutaneous approach. After trans-femoral TAVI, 30-day mortality rate was 1%, cerebral stroke occurred in 2% of the cases, permanent pacemaker implantation was necessary in 23% of the patients and in 6% of the cases there was a moderate/severe degree of aortic regurgitation. There was no association between operators performing TAVI and 30-day mortality. Conclusions The acquisition of catheter-based skills and an adequate training allowed cardiac surgeons to perform on their own awake and fully percutaneous trans-femoral TAVI with similar results when compared with major randomized clinical trials and registries’ experiences.

Abstract Background Takotsubo syndrome (TTS) is an acute and reversible left ventricular dysfunction, whose pathophysiological mechanisms are not completely known. There are evidence suggesting a possible link between neurological disease and TTS. Aim of the study was to evaluate incidence and prognostic value of cognitive neurological disorders among TTS patients. Methods 379 consecutive patients were enrolled in a prospective multicenter registry. History, clinical features, echocardiographic parameters, in-hospital complications and long-term follow up events of all patients were recorded. Cognitive neurological disorders included Alzheimer disease, old age dementia and cognitive impairment for other causes. Results Prevalence of cognitive neurological disorders among TTS patients was 5.5% (num=21). Among this subset of patients 48% (num=10) had Alzheimer syndrome, 24% (num=5) old age dementia and 28% (num=6) cognitive impairment for other causes. Compared to the control group, these patients were older (81±5 vs 71±12, p=0.01) and predominantly men (24% vs 9%, p=0.01). No differences in term of cardiovascular risk factors and left ventricular ejection fraction at admission and discharge were found among the two groups. TTS patients with cognitive neurological disorders experienced higher rate of in-hospital complications (62% vs 28% p=0.01), that were mainly driven by higher rate of pulmonary edema (14% vs 9% p=0.01), cardiogenic shock (29% vs 8%, p=0.01), death (24% vs 4% p=0.01), ischemic stroke (10% vs 4% p=0.01) and left ventricular thrombi (10% vs 3%, p=0.01). At long term follow up patients with cognitive neurological disorders when compared to those without, experienced higher rate of mayor cardiovascular events (48% vs 16%, p=0.01), cardiovascular re-hospitalization (14% vs 10%, p=0.01) and death (43% vs 9%, p=0.01). Conclusion TTS patients with cognitive neurological disorders had an increased risk of in and out of hospital mayor cardiac adverse events and mortality at short and long-term follow-up. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Ospedali Riuniti di Foggia-Università di Foggia

Abstract Background Several studies have shown that Takotsubo syndrome (TTS) secondary to neurological disorders is associated with higher rate of in-hospital complications. Imaging brain studies found that atrophy or damage of some regions and their altered connectivity with other brain regions are typical features of TTS patients. Aim of the study To evaluate rates of in hospital and long-term follow up events in TTS patients with history or acute cerebrovascular events (CVE). Methods 395 consecutive patients were enrolled in a multicenter prospective registry. History, clinical data, echocardiographic parameters and in-hospital and long-term follow up events of all patients were evaluated. Results Prevalence of CVE among TTS patients was 9.4% (N=37). Compared to the control group, these patients were older (80±7 vs 71±12 years, p=0.01) and predominantly men (24% vs 9%, p=0.01). No differences in terms of cardiovascular risk factors and left ventricular ejection fraction at admission and discharge were found between the two groups. The prevalence of physical stressors was higher in the CVE group (67% vs 44% p=0.01). The incidence of in-hospital adverse events was higher in the CVE group (70% vs 29%), mainly driven by higher rates of cardiogenic shock (19 vs 8%, p=0.01) and in-hospital death (19 vs 4%, p=0.01). At long-term follow-up, patients in the CVE group had higher mortality rates (38% vs 20%, p=0.01). Patients presenting with acute CVE, 10 out of 37 patients (27%), when compared with chronic CVE had higher in-hospital mortality rates (40% vs 11%, p=0.01). Conclusion TTS patients with history or CVE had higher rates of in-hospital events and death at long-term follow-up. Acute CVEs in the setting of TTS are associated with a worse prognosis. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Ospedali Riuniti di Foggia. Università di Foggia