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Rationale: Prone positioning reduces mortality in patients with severe acute respiratory distress syndrome (ARDS). To date, no evidence supports the use of prone positioning (PP) during venovenous extracorporeal oxygenation (ECMO). Objectives: The aim of the study was to assess the feasibility, safety, and effect on oxygenation and lung mechanics of PP during ECMO. As a secondary exploratory aim, we assessed the association between PP and hospital mortality. Methods: We performed a multicenter retrospective cohort study in six Italian ECMO centers, including patients managed with PP during ECMO support (prone group; four centers) and patients managed in the supine position (control group; two centers). Physiological variables were analyzed at four time points (supine before PP, start of PP, end of PP, and supine after PP). The association between PP and hospital mortality was assessed by multivariate analysis and propensity score–matching. Results: A total of 240 patients were included, with 107 in the prone group and 133 in the supine group. The median duration of the 326 pronation cycles was 15 (12–18) hours. Minor reversible complications were reported in 6% of PP maneuvers. PP improved oxygenation and reduced intrapulmonary shunt. Unadjusted hospital mortality was lower in the prone group (34 vs. 50%; P = 0.017). After adjusting for covariates, PP remained significantly associated with a reduction of hospital mortality (odds ratio, 0.50; 95% confidence interval, 0.29–0.87). Sixty-six propensity score–matched patients were identified in each group. In this matched sample, patients who underwent pronation had higher ECMO duration (16 vs. 10 d; P = 0.0344) but lower hospital mortality (30% vs. 53%; P = 0.0241). Conclusions: PP during ECMO improved oxygenation and was associated with a reduction of hospital mortality.

Background: Patients with COVID-19 can develop acute respiratory distress syndrome (ARDS), which is associated with high mortality. The aim of this study was to examine the functional and morphological features of COVID-19-associated ARDS and to compare these with the characteristics of ARDS unrelated to COVID-19. Methods: This prospective observational study was done at seven hospitals in Italy. We enrolled consecutive, mechanically ventilated patients with laboratory-confirmed COVID-19 and who met Berlin criteria for ARDS, who were admitted to the intensive care unit (ICU) between March 9 and March 22, 2020. All patients were sedated, paralysed, and ventilated in volume-control mode with standard ICU ventilators. Static respiratory system compliance, the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air, ventilatory ratio (a surrogate of dead space), and D-dimer concentrations were measured within 24 h of ICU admission. Lung CT scans and CT angiograms were done when clinically indicated. A dataset for ARDS unrelated to COVID-19 was created from previous ARDS studies. Survival to day 28 was assessed. Findings: Between March 9 and March 22, 2020, 301 patients with COVID-19 met the Berlin criteria for ARDS at participating hospitals. Median static compliance was 41 mL/cm H2O (33–52), which was 28% higher than in the cohort of patients with ARDS unrelated to COVID-19 (32 mL/cm H2O [25–43]; p

IntroductionThe use of routine antithrombotic prophylaxis is not recommended for advanced cancer patients receiving chemotherapy. The effect of bevacizumab-containing therapy on the risk of thromboembolic events remains controversial in ovarian cancer patients. We report on the incidence of thromboembolic events and the prevalence of antithrombotic therapy in patients enrolled in the single arm, phase IV, MITO-16A/MaNGO-OV2A trial.MethodsIn this trial, potential prognostic factors for patients with previously untreated ovarian cancer receiving a combination of platinum-based chemotherapy and bevacizumab were explored and the final analysis has already been reported. In this secondary analysis, the occurrence of thromboembolic events and the use of antithrombotic therapy were described according to the clinical characteristics of the patients. The prognostic role of thromboembolic events for progression-free and overall survival were also evaluated.ResultsFrom October 2012 to November 2014, 398 eligible patients were enrolled. 76 patients (19.1%) were receiving some type of anticoagulant or anti-aggregant treatment at baseline. Overall, 24 thromboembolic events were reported (cumulative incidence of 6.0%). The occurrence of thromboembolic events was not associated with baseline patient characteristics and was not modified by the use of antithrombotic prophylaxis (HR 0.60, 95% CI 0.18 to 2.0). Occurrence of thromboembolic events was not associated with progression-free survival (HR 1.34, 95% CI 0.83 to 2.15) or overall survival (HR 0.78, 95% CI 0.37 to 1.61).ConclusionsIn our study, a 6.0% rate of thromboembolic events was reported during treatment with bevacizumab plus chemotherapy. Thromboembolic events were not associated with the clinical characteristics of the patients or with the use of antithrombotic prophylaxis, nor did they significantly affect the long-term prognosis.Trial registration numberNCT01706120

Background Sigh is a cyclic brief recruitment maneuver: previous physiologic studies showed that its use could be an interesting addition to pressure support ventilation to improve lung elastance, decrease regional heterogeneity, and increase release of surfactant. Research Question Is the clinical application of sigh during pressure support ventilation (PSV) feasible? Study Design and Methods We conducted a multicenter noninferiority randomized clinical trial on adult intubated patients with acute hypoxemic respiratory failure or ARDS undergoing PSV. Patients were randomized to the no-sigh group and treated by PSV alone, or to the sigh group, treated by PSV plus sigh (increase in airway pressure to 30 cm H2O for 3 s once per minute) until day 28 or death or successful spontaneous breathing trial. The primary end point of the study was feasibility, assessed as noninferiority (5% tolerance) in the proportion of patients failing assisted ventilation. Secondary outcomes included safety, physiologic parameters in the first week from randomization, 28-day mortality, and ventilator-free days. Results Two-hundred and fifty-eight patients (31% women; median age, 65 [54-75] years) were enrolled. In the sigh group, 23% of patients failed to remain on assisted ventilation vs 30% in the no-sigh group (absolute difference, –7%; 95% CI, –18% to 4%; P = .015 for noninferiority). Adverse events occurred in 12% vs 13% in the sigh vs no-sigh group (P = .852). Oxygenation was improved whereas tidal volume, respiratory rate, and corrected minute ventilation were lower over the first 7 days from randomization in the sigh vs no-sigh group. There was no significant difference in terms of mortality (16% vs 21%; P = .337) and ventilator-free days (22 [7-26] vs 22 [3-25] days; P = .300) for the sigh vs no-sigh group. Interpretation Among hypoxemic intubated ICU patients, application of sigh was feasible and without increased risk. Trial Registry ClinicalTrials.gov ; No.: NCT03201263 ; URL: www.clinicaltrials.gov

It is known that lymphocytopenia is one of the most negative biomarkers in cancer patients, being an expression of cancer-related immunosuppression. Today it is known that, despite its complexity, the antitumor immunity is mainly mediated by dendritic cell-T lymphocyte system and suppressed by the macrophage-regulatory T lymphocyte system. Then, lymphocyte-to-monocyte ratio (LMR) has been proven to represent a more appropriate prognostic clinical index than the simple lyphocytopenia alone. Because of the fundamental role of lymphocytes in mediating tumor cell destruction, the correction of cancer-related lymphocytopenia could influence the clinical history of the neoplastic disease. At present, the only cytokine able to induce a clear in vivo lymphocytosisis IL-2. However, it has been demonstrated that the immune system is physiologically under a neuroendocrine control, and that the pineal hormone MLT may stimulate T lymphocyte proliferation and activation. On these bases, we have evaluated the effect of highdose MLT therapy in metastatic solid tumor patients with persistent lymphocytopenia and abnormally low values of LMR. The study included 14 patients, and the results were compared to those found in a control group of 20 lymphocytopenic untreatable metastatic cancer patients treated with the only best supportive care alone. Patients received MLT at a dose of 100 mg/day orally in the evening for 3 consecutive months. Lymphocyte mean count increases on MLT therapy, and the values observed after two months of therapy were significantly higher than the pretreatment ones, with a normalization of lymphocyte number in 4/14 (29%) patients, whereas no spontaneous lymphocyte rise occurred in the control group. On the other hand, monocyte count rapidly diminished on MLT therapy, and LMR mean values observed after only one month of treatment was significantly higher than that found prior to therapy, whereas it significantly decreases in controls. This preliminary study shows that high-dose MLT may improve the immune status of cancer patients, and be effective in the treatment of disseminated cancer-related lymphocytopenia.

The future of laboratory analyses would require the identification of clinical parameters involving the main integrative biological functions including neuroendocrine, immune and cardiovascular systems, and capable of predicting the evidence of metabolic alterations and the possible occurrence of systemic diseases. According to the clinical data available up to now, the status of health may be identified by the following five major biomarkers, consisting of normal circadian rhythm of cortisol and the pineal hormone melatonin, normal blood concentrations of fatty acid amide hydrolase (FAAH), whose increase is associated with an endocannabinoid system deficiency, normal lymphocyte-to-monocyte ratio (LMR) values, normal blood levels of TGF-beta, the main immunosuppressive anti-inflammatory endogenous molecule, and normal values of ANP-to-ET-1 ratio. Since the evidence of alterations involving these five parameters may predispose to the onset of more severe metabolic disorders or systemic disease, the clinical evaluation of these five biomarkers could constitute the routinary laboratory analyses for realizing a real Preventive Medicine.

Background/aim The aim of the study was to assess the clinical outcome of patients with malignant transformation of an ovarian mature teratoma. Patients and methods This study was conducted on 23 patients who underwent primary surgery at three Italian Gynecological Centers. Histologically, nine (39.1%) patients had squamous cell carcinoma, five (21.7%) had a thyroid carcinoma, six (26.1%) had a carcinoid, one (4.3%) patient had papillary renal carcinoma, one (4.3%) had medulloblastoma and one (4.3%) had intestinal-type mucinous adenocarcinoma. Results All six patients with stage I squamous cell carcinoma had no evidence of disease (NED) after a median time of 141 months. Of the three patients with stage IIb-IIIc squamous cell carcinoma, two had NED after 119 and 154 months, and one died of the disease 9 months after diagnosis. All five women with stage I thyroid carcinoma had NED after a median of 60 months. Of the six patients with stage I carcinoid, five had NED after a median of 168 months, whereas one died due to carcinoid heart disease. The three patients with stage I renal carcinoma, medulloblastoma and mucinous adenocarcinoma had NED after 24, 141 and 149 months, respectively. Conclusion The clinical outcome of early-stage malignancies associated with mature ovarian teratomas is excellent following treatment.

Background: Even if borderline ovarian tumours (BOTs) in young women treated with fertility-sparing treatment (FST) have an excellent outcome, the type of surgery might affect relapse and fertility. We investigated the effect of surgical approach (open surgery vs. laparoscopy) and type of surgery (salpingo-oophorectomy [SO] vs. cystectomy [Cy]) on oncologic and fertility outcomes in patients with BOT. Patients and methods: Patients with BOT treated at San Gerardo Hospital, Monza, with FST in 1978–2013 period were included. Cox models, stratified by decade of surgery, were used to investigate the association between time to first recurrence or conception and clinical factors. Results: Among 535 patients included, 271 underwent unilateral SO and 264 underwent Cy. Median follow-up was 13.5 years. Ten-year (10-yr) recurrence rate was 23% (95% confidence interval [CI]: 18–29%) for SO and 31% (95% CI: 24–38%) for Cy group (P = 0.10) in patients with unilateral tumour, whereas it was 62% (95% CI: 44–79%) and 72% (95% CI: 59–84%), respectively, (P = 0.35) in patients with bilateral tumour. Multivariable analysis showed no association between recurrence and surgical approach (P = 0.44), type of surgery (P = 0.06) and a negative association with advanced stage (hazard ratio [HR] = 3.18; 95% CI: 2.11–4.78; P < 0.001) and bilateral tumours (HR = 2.48; 95% CI: 1.78–3.47; P < 0.001). Among 252 patients (47.1%) with pregnancy desire, multivariable analysis showed no association between conception success and the type of surgery, surgical approach, histology and tumour laterality. Fertility after surgery was positively associated with prior pregnancy (HR = 1.68; 95% CI: 1.17–2.41; P = 0.005) and negatively associated with the number of surgical procedures (HR = 0.62; 95% CI: 0.53–0.73; P < 0.001). Conclusions: The type of surgical procedures did not influence recurrence rate or fertility. However, additional surgical procedures decreased the fertility potential. These data can support clinicians in tailoring the best strategy for FST in young patients with BOT

The recent proposal of cancer immunotherapy with anti-checkpoint inhibitor monoclonal antibodies, as well as the previous immunotherapy with IL-2, would require an interpretation of cancer chemotherapy not only in terms of therapeutic strategy carried out to destroy cancer cells, but also as an approach potentially able to influence and modulate the cytokine network in an attempt to correct cancer-related cytokine alterations responsible for tumor progression itself. This statement is justified by the fact that the efficacy of cancer immunotherapy is depending at least in part on the cytokine secretions of patients. Despite the great number of cancer-related cytokine alterations, the main alterations provided by a physiopathological and prognostic significance would consisting of low blood levels of IL-2 and IL-12 in association with abnormally high concentrations of IL-1, IL-6, TNF-alpha, IL-10 and TGF-beta. The effects of chemotherapy on cytokine secretions have appeared to depend on the type of agent, as well as on its dosage and schedule of administrarion. At present, the main effects of chemotherapy provided by a potential clinical application would be represented by the stimulatory action of adriamycin on IL-2 secretion, the inhibitory effect of cisplatin on IL-6 secretion, the stimulatory effect of gemcitabine on IL-12 production, and the inhibitory action of both cyclophosphamide and gemcitabine on regulatory T cell system. Then, the future chemo-immunotherapeuticregimenswouldhavenot to be elaborated not only on the bases of empiristic criteria and on the cytotoxic effects of che various chemotherapeutic agents, but also by taking into consideration their specific activity on the secretion of those cytokines, whose anomalous production has to be corrected and neutralized.

Objectives Supplementation of antithrombin might decrease the amount of heparin needed to achieve a given anticoagulation target during extracorporeal membrane oxygenation. However, exogenous antithrombin itself may increase the risk of bleeding. We conceived a study to evaluate the effect of antithrombin supplementation in adult patients requiring venovenous extracorporeal membrane oxygenation for respiratory failure on heparin dose, adequacy of anticoagulation, and safety. Design Prospective randomized controlled trial. Setting ICUs of two Italian referral extracorporeal membrane oxygenation centers. Patients Adult patients requiring venovenous extracorporeal membrane oxygenation for severe respiratory failure and unfractionated heparin for systemic anticoagulation. Interventions Before extracorporeal membrane oxygenation start, patients were randomized to either receive antithrombin concentrate to maintain a plasmatic level 80-120% (treatment) or not (control) during the extracorporeal membrane oxygenation course. Measurements and main results The primary outcome was the total amount of heparin required to maintain activated partial thromboplastin time ratio 1.5-2. Secondary outcomes were anti-factor Xa, the incidence of hemorrhagic and thrombotic events, and the amount of blood products transfused. Twenty-four patients in the treatment group and 24 in the control group were included in the intention-to-treat analysis. Antithrombin was 109.5% (93.0-123.0%) in the treatment group and 84.0% (68.5-98.0%) in the control group (p = 0.001). Supplementation of antithrombin did not decrease heparin dose (13.5 international units/kg/hr [9.6-17.9 international units/kg/hr] vs 15.1 international units/kg/hr [10.7-18.3 international units/kg/hr] in the treatment and control group, respectively; p = 0.33) and anti-Factor Xa levels (0.4 international units/mL [0.3-0.5 international units/mL] vs 0.3 international units/mL [0.2-0.5 international units/mL] in the treatment group and control group respectively; p = 0.65). Bleeding, blood product transfusions, and thrombosis were not different in the two groups. Conclusions Antithrombin supplementation may not decrease heparin requirement nor diminish the incidence of bleeding and/or thrombosis in adult patients on venovenous extracorporeal membrane oxygenation.

Background: Squamous cell carcinoma of the vulva is a rare malignancy that affects elderly women. About one-third of vulvar cancers are diagnosed in an advanced stage, requiring extensive surgery. Neoadjuvant chemotherapy (NACT) has been introduced to reduce local tumor burden. In this retrospective study, we analyze the efficacy and toxicity of NACT followed by radical surgery. Methods: Patients with locally advanced vulvar cancer (LAVC) treated at our institution with neoadjuvant platinum and paclitaxel-based chemotherapy ± ifosfamide followed by surgery at our institution were retrospectively identified. Results: Fourteen patients (93%) completed NACT with tolerable toxicities (G3–G4 toxicity: 30%). Thirteen patients (87%) underwent surgery. The overall clinical response rate on vulvar disease was 66% (20% complete response, 46% partial response), confirmed by histopathologic analysis, while on inguinal lymph nodes it was 69% (23% complete response, 46% partial response). At the pathologic examination, all patients had negative surgical margins. Three out of 9 patients (33%) with lesions infiltrating the urethral meatus and 4 patients out of 7 (57%) with anal involvement did not require urethral amputation or colostomy, respectively, after NACT. No severe postoperative complications were described. Overall survival at 5 years was 60%, and median overall survival was 76 months. Conclusion: NACT followed by surgery in locally advanced vulvar cancer is well tolerated and allows surgical modulation.

Introduction Heart failure (HF) constitutes a growing public health problem in aging societies: when pharmacological therapies fail, HF can be sustained intensively if patients are eligible for either orthotopic heart transplantation (OHT) or mechanical ventricular assistance, otherwise additional treatments could be inappropriate. In December 2017 Italian Legislator brought in the provisions regarding the end-of-life choices, including indications for withdrawing and withholding life-sustaining therapies. The aim of our study was to provide an overview of the daily practice of our center with regard to terminally ill HF patients. Methods and results In April 2019 the 7 intensivist cardiologists and 21 nurses of a tertiary ICCU were asked in, to complete a questionnaire relating to a hypothetical terminally ill HF patient for whom the decision to withdraw active treatment had been made. To assess current practice, we also identified patients who died in the previous 12 months. Out of 29 deceased patients, 18 were identified as terminally ill HF, with no indications for therapy upgrading. We observed a striking disparity between belief and practice. Conclusions Our survey showed that the care of terminally ill HF patients in our ICCU was characterized by aggressive use of medical therapy and invasive technology. The wide disparity between belief and practice could be in part a consequence of lack of professional training, with regard to law, ethics and communication techniques.

Contains fulltext : 232064.pdf (Publisher’s version ) (Open Access) PURPOSE: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL). METHODS AND MATERIALS: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed. RESULTS: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population. CONCLUSIONS: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.

Fil: Lissoni, Paolo. Instituto de Medicina Biológica; Italia Fil: Brivio, Fernando. Instituto de Medicina Biológica; Italia Fil: Fumagalli, Luca. Surgical Division; Italia Fil: Rovelli, Franco. Instituto de Medicina Biológica; Italia Fil: Colciago, Massimo. Instituto Nacional de Descanso y Atención al Adulto Mayor; Italia Fil: Messina, Giusy. Instituto de Medicina Biológica; Italia Fil: Monzon, Alejandra. Instituto de Medicina Biológica; Italia Fil: Pelizzoni, Francesco. Instituto de Medicina Biológica; Italia Fil: Lissoni, Arianna. Instituto de Medicina Biológica; Italia Fil: Porro, Giorgio. Instituto de Medicina Biológica; Italia Fil: Di Fede, Giuseppe. Instituto de Medicina Biológica; Italia Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas; Argentina Abstract: Recent advances in the area of the psycho-neuroendocrine-immunology have demonstrated that the inflammatory and immune reactions depend not only on immune factors, but also, they are under an intricate neuroendocrine regulation. In turn, the activity of the nervous and endocrine systems is affected by immune-inflammatory signals. Although most hormones and neuromodulators can potentially influence the immune function, main immunomodulatory properties seem to be exerted by opioid and cannabinoid systems. Brain opioid and cannabinoid systems are endocrinologically connected to the adrenal, and to the pineal gland, respectively. In addition, the neurohypophysis is also important for the neuroimmunomodulation through the release of vasopressin and oxytocin. Experimental evidence supports the conclusion that two fundamental functional circuits occur, including a brain opioid system-vasopressin-adrenal axis, characterized by a prevalent immunosuppressive activity, and a brain cannabinoid-oxytocin-pineal axis, which exerts an immunostimulatory role. The latter is relevant mainly for anticancer immunity. The opioid-adrenal functional axis is active in stress and depressive conditions, while the cannabinoid-pineal axis has been proven to be involved in pleasure perception and spiritual expansion of mind. The findings could explain the predisposition to severe systemic diseases played by stress and depression, and on the other hand the protective action of pleasure and spirituality in the onset of important pathologies. The clinical and therapeutic applications of these concepts may constitute a landmark for future Medicine.

Background/aim The role of neoadjuvant chemotherapy (NACT) is under investigation in locally advanced cervical cancer (LACC). Patients and methods A total of 49 patients with FIGO stage IB1-IIB cervical cancer who underwent two different regimens of weekly dose-dense NACT were included. The objective was to evaluate clinical/pathological response and toxicity profile. Results A clinical complete response and partial response were obtained in 43 patients with a clinical overall response rate of 88%. Among the 42 surgically treated patients, 7 (17%) and 35 (83%) achieved a pathological overall optimal response and a suboptimal pathological response, respectively. G3-G4 neutropenia occurred in 16% of patients, whereas no cases of G3 thrombocytopenia, G3 anemia and febrile neutropenia were observed. Conclusion Dose-dense NACT is safe, has acceptable toxicity, and obtains good clinical response, but is less effective in terms of pathological overall optimal response rates compared to other regimens.

Oral cancer (OC) is an uncommon malignancy in Western countries, being one of the most common cancers in some high-risk areas of the world. It is a largely preventable cancer, since most of the different risk factors identified, such as tobacco use, alcohol consumption, and betel nut chewing, are behaviors that increase the likelihood of the disease. Given its high mortality, early diagnosis is of utmost importance. Prevention and the anticipation of diagnosis begin with identification of potentially malignant lesions of the oral mucosa and with local conditions promoting chronic inflammation. Therefore, every lesion must be recognized promptly and treated adequately. The clinical recognition and evaluation of oral mucosal lesions can detect up to 99% of oral cancers/premalignancies. As stated by the World Health Organization, any suspicious lesion that does not subside within two weeks from detection and removal of local causes of irritation must be biopsied. Surgical biopsy remains the gold standard for diagnosis of oral cancer. Adjunctive tools have been developed and studied to help clinicians in the diagnostic pathway, such as toluidine blue vital staining and autofluorescence imaging. In the near future other methods, i.e., identification of salivary markers of progression may help in reducing mortality due to oral cancer.

Objective advanced stage clear cell ovarian cancer (CCOC) carries a higher risk of relapse and death compared to other histological subtypes. The prognosis of early-stage CCOC is controversial. Methods Early-stage high-grade OC patients from two Italian oncologic centers were included. Patients with early-stage CCOC were compared with those with high-grade endometrioid (HGE) and serous (HGS) OC in terms of relapse-free interval (RFI), cancer-specific survival (CSS) and post relapse cancer-specific survival (prCSS). The Cox proportional hazard model and the restricted mean survival time were used. Results Between 1981 and 2012, 134 patients with CC, 152 with HGE and 160 with HGS were treated at two referral centers. Median follow-up was 11.5 years. Ten years RFI rates were 80.6%, 72.1%, 60.6%, and CSS rates were 84.3%, 82.6%, 81.7% respectively. Adjuvant chemotherapy significantly improved RFI (aHR 0.61, 95%CI 0.40 to 0.91, P = 0.015). In the multivariable analysis HGS histotype was associated with a shorter RFI compared to CC, (Hazard Ratio [HR]: 1.81; 95%CI: 1.12–2.93; P = 0.016), whereas CSS was not statistically different. prCSS was longer in HGS compared to CCOC (HR, 0.36; 95% CI, 0.17–0.74; P = 0.006). According to the stage, IA/IB/IC1 HGSOC had a shorter RFI (HR, 2.13; 95% CI, 1.14–3.99; P = 0.018) compared to IA/IB/IC1 CCOC, but similar CSS. For prCSS, CC compared to HGS conferred a worse prognosis regardless of the initial stage. Conclusions Early-stage CCOC is associated with a longer RFI, similar CSS and a shorter prCSS compared to HGSOC. No prognostic differences were observed between CC and HGE OC. The relapse risk was the lowest in IA/IB/IC1 CC compared to HGS, whereas CC displayed poor sensitivity to chemotherapy after relapse.

BACKGROUND:The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis.METHODS:In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138.FINDINGS:Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported.INTERPRETATION:This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival.FUNDING:Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

Oral squamous cell carcinoma is an extremely malignant tumour: in order to reduce mortality and morbidity, early diagnosis and treatment is the clinician's best weapon., Oral squamous cell carcinoma is an extremely malignant tumor: In order to reduce mortality and morbidity, early diagnosis and treatment is the clinician's best weapon.

Today, it is known that the prognosis of human neoplasms depends not only on the genetic characteristics of tumor cells, but also on the immunobiological response of patients. Moreover, despite its complexity, at present it is known that the antitumor immunity is generally suppressed by the macrophage system, and stimulated by T lymphocytes, with the only exception of regulatory T cells, which in contrast inhibit the anticancer immunity through the release of immunosuppressive cytokines, the most important of them is TGF-beta. Finally, it is known that lymphocytopenia may predict a negative prognosis in the advanced neoplasms, and a more negative significance is played by the occurrence of abnormally low values of lymphocyte-to-monocyte ratio (LMR), whose decline could depend on both lymphocyte decrease and monocyte increase. At present, the only cytokine able to enhance lymphocyte count still remains IL-2. Therefore, because of the negative prognostic significance of cancer-related lymphocytopenia, the use of IL-2 to correct cancer-related lymphocytopenia could constitute a new strategy in the immunotherapy of cancer. On these bases, a study was planned to evaluate the effects of a neuro-immunotherapeutic combination with SC very-low dose IL-2 in association with the antitumor immunostimulating pineal hormone melatonin (MLT) on lymphocyte count, and their persistence on time in a group of untreatable lymphocytopenic advanced cancer patients. The study included 14 lymphocytopenic cancer patients, who were eligible for the only palliative therapy. IL-2 was SC injected at 1.8 MIU/day for 5 days/week for 2 consecutive weeks, in association with MLT at 100 mg/day orally during the dark period of the day. A normalization of lymphocyte count was achieved in 9/14 (64%) patients within the two weeks of therapy. Both lymphocyte and LMR mean values significantly increased on therapy with respect to the pre-treatment values. On the other hand, monocyte mean values diminished on therapy, without, however, significant differences. The median duration of lymphocyte count normalization was 160 days (range 39-240 days). These preliminary results would suggest a new possible clinical use of IL-2 immunotherapy to counteract advanced cancer-related lymphocytopenia, because of its well documented negative effects on the survival, in an attempt to control tumor growth by activating the natural antitumor immunobiological response, which is fundamentally an IL-2-dependent phenomenon, and which is altered in the advanced human neoplasms. Keywords: Cancer immunotherapy, Interleukin-2, Lymphocytopenia, Immunosuppression, Melatonin, Pineal gland

Despite the well-known importance of lymphocytes in tumor cell destruction and the evidence that lymphocytopenia is associated with a poor prognosis and lower survival in almost all tumor histotypes, lymphocyte count is not generally taken into consideration by the oncologists and no specific protocol has been proposed to treat cancer-related lymphocytopenia because of its negative impact on the clinical course of the neoplastic disease. Obviously, the most effective agents to stimulate the proliferation of lymphocytes would have to be their major growth factor, consisting of IL-2, whose in vivo biological activity may be further amplified by an association with some neuro-immunomodulating agents, such as the pineal hormone melatonin (MLT). This study was performed to evaluate the effects of subcutaneous (SC) low-dose IL-2 plus high-dose MLT in a group of metastatic cancer patients with persistent lymphocytopenia, who failed to respond to the standard anticancer therapies. The study included 14 patients who received MLT orally at 100 mg/day in the evening every day without interruption plus IL-2 SC at 1.8 MIU/day for five days a week for two consecutive weeks, corresponding to one complete cycle. A second cycle was repeated after a rest period of two weeks. A normalization of lymphocyte count was achieved in 9/14 (64%) patients, 4 of them (29%) just after the first week of therapy. Because of the association between cancer-related lymphocytopenia and lower survival and the fundament role of lymphocyte in mediating cancer cell destruction, the correction of advanced cancer-related lymphocytopenia by a short-term SC low-dose IL-2 therapy could improve the clinical course of cancer patients, including those suitable for the only palliative treatment.

Solitary plasmacytoma (SP) is a rare malignant tumor of plasma cells with no systemic spread; however, when it disseminates and affects multiple skeletal sites, it is called multiple myeloma (MM). The etiology of solitary plasmacytoma is unknown, with two possible subtypes: solitary extramedullary plasmacytoma (EMP) and solitary bone plasmacytoma (SBP). We present a case of EMP arising as asymptomatic erythroplakia of the palate, which is rarely described in the literature. The definitive diagnosis was obtained with immunohistochemical studies, after which the lesion was subjected to excisional biopsy. At present, after two years of close follow-up, the patient has shown no signs of relapse or conversion to MM. The uniqueness of the case highlights the possibility of an atypical EMP lesion in the head and neck, thus posing a diagnostic and therapeutic challenge for physicians.

Background/Aim: The aim of the study was to assess the outcome of advanced ovarian cancer patients who i) underwent primary surgery followed by carboplatin/paclitaxel-based chemotherapy with or without bevacizumab, ii) were in complete response after chemotherapy, iii) and subsequently recurred. Patients and Methods: The hospital records of 138 complete responders after chemotherapy with (n=58) or without (n=80) bevacizumab were reviewed. Results: Both survival after recurrence and overall survival were related to age (=61 vs. >61 years, p=0.002 and p=0.0001), performance status (0 vs. =1, p=0.002 and p=0.001), histotype (serous vs. non serous, p=0.005 and p=0.01), time to recurrence (=12 vs.

BACKGROUND: Prone position (PP) improves acute respiratory distress syndrome (ARDS) survival by reducing the risk of ventilation-induced lung injury. However, inter-individual variability is a hallmark of ARDS and lung protection by PP might not be optimal in all patients. In the present study, we dynamically assessed physiologic effects of PP by electrical impedance tomography (EIT) and identified predictors of improved lung protection by PP in ARDS patients. METHODS: Prospective physiologic study on 16 intubated, sedated and paralyzed patients with ARDS undergoing PP as per clinical decision. EIT data were recorded during two consecutive steps: 1) baseline supine position before and after a recruitment maneuver (RM); 2) prone position before and after a RM. “Improved lung protection” by PP was defined in the presence of simultaneous improvement of ventilation homogeneity (Hom), alveolar overdistension and collapse (ODCL) and amount of recruitable lung volume by RM in comparison to supine. RESULTS: PP versus supine increased the tidal volume distending the dependent regions (Vtdep), resulting in improved Hom (1.1±0.9 vs. 1.7±0.9, P=0.021). PP also reduced ODCL (19±9% vs. 28±8%, P=0.005) and increased the recruitable lung volume (80 [71-157] vs. 59 [1-110] mL, P=0.025). “Improved lung protection” by PP was predicted by lower Vtdep, higher Vtndep and poorer Hom measured during baseline supine position (P

BACKGROUND: Switching patients affected by early severe ARDS and undergoing extracorporeal membrane oxygenation (ECMO) from controlled ventilation to spontaneous breathing can be either beneficial or harmful, depending on how effectively the breathing pattern is controlled with ECMO. Identifying the factors associated with ineffective control of spontaneous breathing with ECMO may advance our pathophysiologic understanding of this syndrome. METHODS: We conducted a prospective study in subjects with severe ARDS who were on ECMO support ≤ 7 d. Subjects were switched to minimal sedation and pressure-support ventilation while extracorporeal CO2 removal was increased to approximate the subject’s total CO2 production ( V ˙ C O 2 ). We calculated the rapid shallow breathing index (RSBI) as breathing frequency divided by tidal volume. We explored the correlation between certain characteristics recorded during pretest controlled ventilation and the development of apnea (ie, expiratory pause lasting > 10 s; n= 3), normal breathing pattern (ie, apnea to RSBI ≤ 105 breaths/min/L; n= 6), and rapid shallow breathing (RSBI > 105 breaths/min/L; n= 6) that occurred during the test study. RESULTS: The ratio of extracorporeal CO2 removal to the subjects’ V ˙ C O 2 was >90% in all 15 subjects, and arterial blood gases remained within normal ranges. Baseline pretest Sequential Organ Failure Assessment score, total V ˙ C O 2 and ventilatory ratio increased steadily, whereas P aO 2 / F IO 2 was higher in subjects with apnea compared to intermediate RSBI ≤105 breaths/min/L and elevated RSBI >105 breaths/min/L. In subjects with rapid shallow breathing, baseline lung weight measured with quantitative computed tomography scored higher, as well. CONCLUSIONS: In early severe ARDS, the factors associated with rapid shallow breathing despite maximum extracorporeal CO2 extraction include less efficient CO2 and O2 exchange by the natural lung, higher severity of organ failure, and greater magnitude of lung edema.

Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.

Background Parameters measured during implantable cardioverter defibrillator (ICD) implant also depend on bioelectrical properties of the myocardium. We aimed to explore their potential association with clinical outcomes in patients with single/dual‐chamber ICD and cardiac resynchronization therapy defibrillator (CRT‐D). Methods In the framework of the Home Monitoring Expert Alliance, baseline electrical parameters for all implanted leads were compared by the occurrence of all‐cause mortality, adjudicated ventricular arrhythmia (VA), and atrial high‐rate episode lasting ≥24 hours (24 h AHRE). Results In a cohort of 2976 patients (58.1% ICD) with a median follow‐up of 25 months, event rates were 3.1/100 patient‐years for all‐cause mortality, 18.1/100 patient‐years for VA, and 9.3/100 patient‐years for 24 h AHRE. At univariate analysis, baseline shock impedance was consistently lower in groups with events than without, with a 40 Ω cutoff that better identified high‐risk patients. However, at multivariable analysis, the adjusted‐hazard ratios (HRs) lost statistical significance for any endpoint. Baseline atrial sensing amplitude during sinus rhythm was lower in patients with 24 h AHRE than in those without (2.45 [IQR: 1.65‐3.85] vs 3.51 [IQR: 2.37‐4.67] mV, P 1.5 mV vs those with values ≤1.5 mV was 0.52 (95% CI: 0.33‐0.83), P = .006. Conclusions Although lower baseline shock impedance was observed in patients with events, the association lost statistical significance at multivariable analysis. Conversely, low sinus rhythm atrial sensing (≤1.5 mV) measured with standard transvenous leads could identify subjects at high risk of atrial arrhythmia., Some of the electrical parameters routinely measured at ICD/CRT‐D implant differed according to long‐term clinical outcome. Shock impedance values were lower in patients who experienced death and both atrial and ventricular arrhythmias during follow‐up. Subjects with atrial signal amplitude below 1.5 mV showed a significant higher risk of atrial arrhythmias as compared to those with >1.5 mV, potentially revealing the presence of a more impaired atrial tissue.

Mucosal melanomas of the head and neck region are uncommon pathologies that can affect the oral cavity, and are characterized by a high rate of mortality. Considering the lack of knowledge regarding risk and prognostic factors, current best clinical practice is represented by a large surgical excision with disease-free margins, eventually associated with a reconstructive flap. Indeed, given the frequent necessity of postoperative radiotherapy and fast healing process, a reconstruction of the surgical gap is advisable. Even if several flaps have been most commonly used, the submental island flap represents a valid alternative thanks to local advantages and similar oncologic outcomes compared to free flaps.

Extracorporeal membrane oxygenation (ECMO) bridge to lung transplantation (LuTX) exposes the patients to a high risk of perioperative bleeding secondary to systemic anticoagulation and coagulation factors deficiency. With this case series, we propose innovative "no-heparin" management of ECMO-bridge support during LuTX, based upon 1) control heparin resistance with antithrombin III in the preoperative period; 2) relying upon a fully functional, brand new heparinized ECMO circuit; 3) completely avoiding perioperative heparin; 4) hampering fibrinolysis with tranexamic acid; and 5) limiting venoarterial (VA) ECMO escalation, and the following need for full anticoagulation. Following the application of this new approach, we carried out three challenging clinical cases of bilateral ECMO-bridged LuTX effectively, with limited intraoperative blood requirement and no major postoperative bleeding or thromboembolic events. Of note, two of them had an extremely high risk for hemorrhage due to complete right lung anatomic derangement in case number 2 and surgical adhesion following first LuTX in case number 3, while for the case number 1, no blood products were administered during surgery. Despite the limited patient population, such an approach relies on a strong rationale and may be beneficial for managing ECMO bridging to LuTX. Prospective studies are necessary to confirm the validity of our strategy.

Fil: Lissoni, Paolo. Instituto de Medicina Biológica; Italia Fil: Messina, Giusy. Instituto de Medicina Biológica; Italia Fil: Boniardi, Barbara. Instituto de Medicina Biológica; Italia Fil: Monzon, Alejandra. Instituto de Medicina Biológica; Italia Fil: Di Fede, Giuseppe. Instituto de Medicina Biológica; Italia Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Colciago, Massimo. Instituto Nacional de Descanso y Atención al Adulto Mayor; Italia Fil: Rovelli, Franco. Instituto de Medicina Biológica; Italia Fil: Simoes-e-Silva, Ana Cristina. Universidad Federal de Minas Gerais. Facultad de Medicina. Laboratorio Interdisciplinar de Investigación Médica,; Brasil Fil: Marroccoli, Savino. Fundación Interbion; Suiza Fil: Pierpaoli, Walter. Fundación Interbion; Suiza Abstract: The recent advances in the immunobiological knowledges have shown that the immune system is not involved in the only defence against infections and tumours, but also in the regulation of cardiovascular, endocrine, and nervous functions. Moreover, the activity of the immune system mainly depends on the cytokine network. However, most cytokines play an inflammatory action, with a consequent unbalance between inflammatory and anti-inflammatory responses. Then, the prevalent inflammatory action of cytokines is counterbalanced by an anti-inflammatory neuroendocrine central system, mainly mediated by the pineal gland, cannabinoid system, and ACE2-angiotensin 1-7 (Ang 1-7). In fact, the pineal hormone melatonin (MLT), the cannabinoid agents, and Ang 1-7, produced by the enzymatic activity of ACE2 on angiotensin II (Ang II), have appeared to exert an anti-inflammatory activity due to the inhibition of the secretion of several inflammatory cytokines. Moreover, their anti-inflammatory activity is constantly associated with an antitumoral action, by constituting a fundamental anti-inflammatory anticancer functional system. One of the main connections between cytokine network and neuroendocrine system would be IL-17, which has appeared to inhibit Ang 1-7 secretion and to stimulate that of Ang II, and whose secretion may be inhibited by MLT, cannabinoids and Ang 1-7 itself. Most human systemic inflammatory diseases have appeared to present an endogenous Ang 1-7 deficiency. In addition, aging itself is characterized by a progressive decline in the secretion of both pineal hormone MLT and Ang 1-7. Therefore, because of their anti-inflammatory anticancer activity, the progressive decline in MLT and Ang1-7 production may explain age-related increase in the incidence of tumours and other systemic pathologies. Moreover, Ang 1-7 deficiency has been shown to be associated with a concomitant enhanced production of Ang II, which exerts hypertensive, inflammatory, protumoral, pro-thrombotic and profibrotic effects, being responsible for several biological damages. Then, a substitutive treatment with MLT and Ang 1-7 might opposite age-related human diseases and counteract aging itself. Both MLT and Ang 1-7 have appeared to exert anti-aging antioxidant anti-inflammatory effects. However, the anti-aging biological properties of Ang 1-7 would be superior to those of MLT itself, since MLT may only slow down aging mechanisms, while Ang 1-7 could also regenerate the human body by reversing the atherosclerotic and fibrotic processes, which are responsible for the progressive organ failure.

The XGIS (X and Gamma Imaging Spectrometer) is one of the three instruments onboard the THESEUS mission (ESA M5, currently in Phase-A). Thanks to its wide field of view and good imaging capabilities, it will efficiently detect and localize gamma-ray bursts and other transients in the 2-150 keV sky, and also provide spectroscopy up to 10 MeV. Its current design has been optimized by means of scientific simulations based on a Monte Carlo model of the instrument coupled to a state-of-the-art description of the populations of long and short GRBs extending to high redshifts. We describe the optimization process that led to the current design of the XGIS, based on two identical units with partially overlapping fields of view, and discuss the expected performance of the instrument., Comment: Proceedings of the SPIE 2020, paper 11444-276

Introduction About one third of vulvar carcinoma is diagnosed at an advanced stage and is either surgically unresectable or require pelvic exenteration. Neoadjuvant chemotherapy (NACT) has been introduced to reduce surgical invasivity. In this case series we describe our experience with NACT from January 2000 to December 2018. Methods This retrospective study analyzes 15 patients affected by locally advanced vulvar carcinoma (FIGO II-IVB) treated with NACT for large tumors (T2-T3) involving the anal sphincter or the urethra. The chemotherapy regimen mainly used a combination of Cisplatin Taxol and Ifosfamide. Clinical data were obtained by reviewing medical, radiological and pathological records. Results 14 patients completed all the expected cycles of NACT and only 3 presented G3-G4 toxicity. Locally, the treatment resulted in 3 complete responses (20%), 7 partial responses (46.6%), 3 stable diseases (20%) and 2 progressions of disease (13,3%) (Table 1). Excluding the latter, all patients underwent surgery. Among the 9 with urethra involvement before NACT, 2 required a partial urethral amputation, and out of 7 patients with anus involvement 2 required surgery on the digestive tract. Surgical margins were negative in all cases. Of the 13 patients who underwent surgery, 3 had persistent disease and 3 relapsed. The overall median survival was 55 months, with some long survivor patients (figure 1). Conclusion NACT followed by surgery for the treatment of locally advanced vulvar carcinoma is feasible, well tolerated and allows surgical modulation.

Over the past 20 years, European universities have increased their propensity to retain title of their faculty's inventions, but evidence on the value of such patents is at best mixed. Based on a longitudinal sample of Italian academic patents (patents over faculty's inventions), assigned either to universities or firms, we find that the lower value of university-owned patents, versus firm-owned ones, is owing to lower Technological Importance of the inventions and less effective Exploitation of the related patents. Lack of experience in managing patented inventions explains our results for Technological Importance, but not for Exploitation. Both are unrelated to the presence of a technology transfer office. Our study suggests caution in pushing universities to expand their patent portfolios and in using university-owned patents as indicators of technology-transfer activities.

Metastatic cancer and autoimmune diseases are commonly considered to be the expression and the consequence of two opposite...

It is known that lung injury due to COVID-19 responsible for the respiratory distress would mainly depend on host inflammatory response, depending on the excessive production of inflammatory cytokines, such as IL-6, and TNF-alpha, rather than direct virus-induced tissue damage, as well as for other forms of respiratory distress. Moreover, it is known that the inflammatory cytokines may induce profound changes in the behavior of the hematic cells, namely neutrophils, monocytes, and lymphocytes, with a following enhanced tissue infiltration by their inflammatory cells. According to the data available up to now, IL-6 and TNF-alpha would be the main cytokines involved in determining COVID-19-induced lung injury, as well as in other coronavirus infections, and most in general in all conditions of respiratory distress. Since it is known that the functionlessness of the whole immune system is namely depending on the interactions between lymphocyte and macrophage system, a preliminary study was planned to analyze the lymphocyte-to-monocyte ratio (LMR) in COVID-19 infective disease. The study included 17 consecutive patients, who underwent ventilator therapy for COVID-19-induced respiratory distress, and 100 healthy subjects, as a control group. Lymphocytopenia and monocytosis occurred in 14/17 (82%) and in 8/17(47%), respectively. Then, abnormally low values of LMR was found in 12/17 (71%) patients, and LMR men values observed in patients were significantly lower than in control (P

In a world defined by rapid change, the search for solutions to societal challenges has become more complex calling for new paradigms of innovation focused on collaborations with the community and users. Co-creation approaches in the design and production of a service or product can bring low-cost innovation and unique and personalized customer experiences leading to user acceptance of a product or service. Under a co-creation perspective, the participatory approach developed in the MINDInclusion project aims to improve the inclusion of people with intellectual disabilities into public places and society by using a co-created online tool based on people with disabilities’ personal experiences. Paying special attention to the Design thinking method, the main goal of this experience was to co-create cognitive accessible design tools that guide the collection of users and other stakeholders experiences in the process of defining problems and solutions. To this end, 14 researchers and educators worked defining together a set of guiding exercises and design thinking methods for the 4 co-design cycles. To add an interactive and playful approach two tools were created to gather information to recreate as a final output “personas scenarios”, an “empathy map” and expected “use scenarios” that will guide the development of the web-tool based on user-centred specifications. The results have shown two tools. The former was an adapted game board about public places based on the traditional monopoly game and the latter a diary with a set of activities that will facilitate the collection of contextual information. Previous experiences have shown that co-design process can promote greater social cohesion, acceptance and empowerment. However, working with people with intellectual disability presents several challenges since the co-creation process needs to be cognitive accessible. This experience resulted in the creation of two cognitive accessible tools that can be extrapolated to other contexts.

Background Trabectedin, in addition to its antiproliferative effect, can modify the tumour microenvironment and this could be synergistic with bevacizumab. The efficacy and safety of trabectedin and bevacizumab ± carboplatin have never been investigated. Methods In this phase 2 study, women progressing between 6 and 12 months since their last platinum-based therapy were randomised to Arm BT: bevacizumab, trabectedin every 21 days, or Arm BT+C: bevacizumab, trabectedin and carboplatin every 28 days, from cycles 1 to 6, then trabectedin and bevacizumab as in Arm BT. Primary endpoints were progression-free survival rate (PFS-6) and severe toxicity rate (ST-6) at 6 months, assuming a PFS-6 ≤35% for BT and ≤40% for BT+C as not of therapeutic interest and, for both arms, a ST-6 ≥ 30% as unacceptable. Results BT+C (21 patients) did not meet the safety criteria for the second stage (ST-6 45%; 95%CI: 23%–69%) but PFS-6 was 85% (95%CI: 62%–97%). BT (50 patients) had 75% PFS-6 (95%CI: 60%–87%) and 16% ST-6 (95%CI 7%–30%). Conclusions BT compared favourably with other platinum- and non-platinum-based regimens. The combination with carboplatin needs to be assessed further in a re-modulated safer schedule to confirm its apparent strong activity. Clinical Trial Registration NCT01735071 (Clinicaltrials.gov).

BACKGROUND Orthodontic therapy is used to solve numerous oral problems, but the use of fixed oral devices can also impact negatively the oral cavity, if the treatment is not steadily under control. The aim of this study is to evaluate tooth, bone and soft tissues lesions due to the presence of fixed orthodontic appliances. METHODS One hundred patients with fixed orthodontic appliances were included in the study. In particular, 20 patients with rapid palatal expander (RPE), 20 patients with Forsus appliance, 20 patients with a fixed multibracket appliance treatment, 20 patients with just the lower vestibular multibracket treatment and 20 patients with both upper and lower vestibular multibracket treatment. An accurate oral examination of the oral cavity, comprehending teeth, bone and soft tissues, was carried out thoroughly, in order to find possible lesions caused by the fixed orthodontic treatment. RESULTS Concerning RPE, 35% patients had reversible palatal lesions, while 45% patients had the impression of the appliance on the tongue. Periodontal damages were observed in 5% of the patients, as well as tooth lesions (i.e. dental caries). 20% of the patients with Forsus appliance experienced the lesion on the cheek mucosa, while 10% individuals reported periodontal problems, and 15% of the subject suffered for WSL (white spot lesion) and dental caries. Upper vestibular multibracket appliance caused superior labial lesions (15%), cheek mucosal lesions (20%), gingivitis (55%), white spot lesions (WSL) of superior teeth (15%), while dental recessions and periodontitis due to the appliance were rarely observed (5%). Lower vestibular multibracket appliance was frequently the cause of inferior labial lesions (15%), cheek mucosal lesions (15%), gingivitis (50%), WSL of inferior teeth (20%) and also in lower arch dental recessions and periodontitis due to the appliance were rarely observed (5%). Patients with both superior and inferior multibracket appliance experienced upper and/or lower lip lesions (25%), lesions of cheek mucosa (25%), gingivitis (65%) and WSL (30%), and just in few cases periodontitis (10%). Data shows a more critical oral situation in patients with both superior and inferior appliances than people with one-arch therapy. CONCLUSIONS Orthodontic therapy offers a considerable number of advantages, but it is important to underline what may be the adverse consequences also. This allows the orthodontist to inform the patient of all the possible effects of their therapeutic choice. In most cases, RPE can cause an impression of the device on the tongue and reversible lesions of the palate. On the other hand, the orthodontic fixed therapy can cause gingivitis, followed by mucosal lesions, labial lesions and WSL. For these reasons, an accurate assessment of the patients before the application of fixed orthodontic treatment is necessary. Oral hygiene instructions and motivation are very important, as well as periodic controls of the fixed oral device.

In today’s multicultural world, digital tools may become a powerful means to building a culture of dialogue that supports ‘culturally responsive’ teaching within imaginative multicultural learning environments. Students can develop global competencies, learning more about others’ and their own culture as part of their personal development. Our paper presents the experience of Rete Dialogues, a network of Italian state schools that have created a professional learning community and enacted the international project Generation Global. Through technologies such as videoconferences and online communities, students, supported by their teachers, can meet peers from various cultures. After referencing the development of the notion of multiculturalism, we interpret our experience through the lenses of Banks’ five dimensions. We then focus on a ‘teamblogging’ initiative that involved 2000 students and over 200 teachers, discussing examples from students’ digital dialogues and brainstorming next steps in th...

In this case-report we describe an experience where alternative places – rather than the classroom – are exploited to implement learning processes. We maintain that this experience is a good example of materiality because it focuses on a project where students had the opportunity to re-design a public space. To this aim, various objects and tools are used to support discussions and exchanges with new stakeholders. Our theoretical vision combines Piaget’s and Vygotsky’s tradition with an innovative framework called the Trialogical Learning Approach (TLA). From such theoretical background an idea of materiality emerges, that refers to material in combination with the social relationships developed around the material. Our case-report concerns a participatory project run by Rete Dialogues, a national school network focusing on global citizenship education. Our research question is: how can this project highlight the connection between the TLA and socio-materiality? Since 2017, around 200 students (age 7–16) and 20 teachers from different schools have been engaged in tackling the degradation of an important square in Rome. The project – “Dialogues in the Square” (DiS) was developed with several stakeholders that contributed to the understanding of critical issues influencing the maintenance of the square, in the perspective of planning, and possibly implementing improvements proposed by students. Crucial is the cooperation with two important urban art projects: (i) the pilot-project MACRO-ASILO, run by the MACRO museum in Rome and aimed at connecting the world of art with the city life; (ii) the “building sites” of the Rome Rebirth Forum, inspired by the world-known artist Michelangelo Pistoletto’s “third paradise” methodology, that encourages responsibility and action taking on sustainability through art. Drawing on data collected through direct observations and video recordings, we aim to show and make sense of the connection between the TLA and socio-materiality, highlighting three key elements: the flexible use of mediation tools, the overcoming of the dichotomy between individual and collective learning through reflection, and the re-shaping of social practices.