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Funding Acknowledgements Type of funding sources: None. Introduction Competitive sports activity may increase the risk of life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in athletes with underlying cardiovascular diseases (CVD). Preparticipation screening (PPS) offers the potential to early identify CVD and reduce this risk, but the optimal age of sport PPS start is not known. Purpose The aim of this study is to assess the burden of sudden cardiac arrest (SCA) and the diagnostic yield of PPS for CVD at risk of SCA in two different age groups: 8-11 year-old and 12-15 year-old. Methods Data on the incidence and causes of SCA from 2011 to 2020 were retrieved from the sudden death registry of our region, hospital records and local press. During the same period, we assessed 25,251 young competitive athletes aged 8-15 years who underwent 58,185 annual PPS (mean 2.3/athlete) including history, physical examination, ECG and exercise testing. Further tests were required in case of abnormalities at first-line screening. Results Over 10 years, 21 sudden deaths and 5 resuscitated SCA occurred: 6 in athletes (incidence 0.7/100.000/year) versus 20 in non-athletes (0.7/100.000/year). 67% athletes versus 5% non-athletes who suffered SCA were successfully resuscitated (aborted sudden cardiac death=aSCD), (results according to the age-group in Figure 1). Idiopathic ventricular fibrillation was the most common diagnosis accounting for 14/26 (54%) cases. The incidence of SCA was 0.2/100.000/year in the age group 8-11 year-old versus 1.3/100.000/year in the age group 12-15 year-old. By PPS, 26 (0.1%) athletes received a diagnosis of at-risk CVD, significantly more often in children ≥12 year-old (0.06%/evaluation) than Conclusions The incidence of SCA was 6 times higher in the age group 12-15 years compared with the 8-11 years group. Similarly, the diagnostic yield of PPS for at-risk CVD was significantly higher after 12 years of age. This suggests that systematic PPS may not be justified before 12 year-old.

Fragment crystallizable (Fc) fusion is commonly used for extending the half-life of biotherapeutics such as cytokines. In this work, we studied the pharmacokinetics of Fc-fused interleukin-10 (IL-10) proteins that exhibited potent antitumor activity in mouse syngeneic tumor models. At pharmacologically active doses of ≥0.1 mg/kg, both mouse Fc-mouse IL-10 and human Fc-human IL-10, constructed as the C terminus of the Fc domain fused with IL-10 via a glycine-serine polypeptide linker, exhibited nonlinear pharmacokinetics after intravenous administration to mice at the doses of 0.05, 0.5, and 5 mg/kg. With a nominal dose ratio of 1:10:100; the ratio of the area under the curve for mouse Fc-mouse IL-10 and human Fc-human IL-10 was 1:181:1830 and 1:75:633, respectively. In contrast, recombinant mouse or human IL-10 proteins exhibited linear pharmacokinetics in mice. Compartmental analysis, using the Michaelis-Menten equation with the in vitro IL-10 receptor alpha binding affinity inputted as the K

Elotuzumab (Elo) is an IgG1 monoclonal antibody targeting SLAMF7 (CS1, CRACC, and CD319), which is highly expressed on multiple myeloma (MM) cells, natural killer (NK) cells, and subsets of other leukocytes. By engaging with FcγRIIIA (CD16), Elo promotes potent NK cell–mediated antibody-dependent cellular cytotoxicity (ADCC) and macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) toward SLAMF7+ MM tumor cells. Relapsed/refractory MM patients treated with the combination of Elo, lenalidomide, and dexamethasone have improved progression-free survival. We previously showed that Elo enhances NK cell activity via a costimulation mechanism, independent of CD16 binding. Here, we further studied the effect of Elo on cytotoxicity of CD16-negative NK-92 cells. Elo, but not other SLAMF7 antibodies, uniquely enhanced cytotoxicity mediated by CD16-negative NK-92 cells toward SLAMF7+ target cells. Furthermore, this CD16-independent enhancement of cytotoxicity required expression of SLAMF7 containing the full cytoplasmic domain in the NK cells, implicating costimulatory signaling. The CD16-independent costimulation by Elo was associated with increased expression of NKG2D, ICAM-1, and activated LFA-1 on NK cells, and enhanced cytotoxicity was partially reduced by NKG2D blocking antibodies. In addition, an Fc mutant form of Elo that cannot bind CD16 promoted cytotoxicity of SLAMF7+ target cells by NK cells from most healthy donors, especially if previously cultured in IL2. We conclude that in addition to promoting NK cell–mediated ADCC (CD16-dependent) responses, Elo promoted SLAMF7–SLAMF7 interactions in a CD16-independent manner to enhance NK cytotoxicity toward MM cells.

Supplementary Figures 1-9

Antibody blockade of programmed death-1 (PD-1) or its ligand, PD-L1, has led to unprecedented therapeutic responses in certain tumor-bearing individuals, but PD-L1 expression's prognostic value in stratifying cancer patients for such treatment remains unclear. Reports conflict on the significance of correlations between PD-L1 on tumor cells and positive clinical outcomes to PD-1/PD-L1 blockade. We investigated this issue using genomically related, clonal subsets from the same methylcholanthrene-induced sarcoma: a highly immunogenic subset that is spontaneously eliminated in vivo by adaptive immunity and a less immunogenic subset that forms tumors in immunocompetent mice, but is sensitive to PD-1/PD-L1 blockade therapy. Using CRISPR/Cas9-induced loss-of-function approaches and overexpression gain-of-function techniques, we confirmed that PD-L1 on tumor cells is key to promoting tumor escape. In addition, the capacity of PD-L1 to suppress antitumor responses was inversely proportional to tumor cell antigenicity. PD-L1 expression on host cells, particularly tumor-associated macrophages (TAM), was also important for tumor immune escape. We demonstrated that induction of PD-L1 on tumor cells was IFNγ-dependent and transient, but PD-L1 induction on TAMs was of greater magnitude, only partially IFNγ dependent, and was stable over time. Thus, PD-L1 expression on either tumor cells or host immune cells could lead to tumor escape from immune control, indicating that total PD-L1 expression in the immediate tumor microenvironment may represent a more accurate biomarker for predicting response to PD-1/PD-L1 blockade therapy, compared with monitoring PD-L1 expression on tumor cells alone. Cancer Immunol Res; 5(2); 106–17. ©2017 AACR.

Supplementary Figure S1. Genomic sequence of the PD-L1 locus and expression of immunogenic neoantigens in T3deltaPDL1 lines. Supplementary Figure S2. Expression of PD-L1 and neoantigens in the escape T3deltaPDL1 cells. Supplementary Figure S3. PD-L1 but not PD-L2 is upregulated on MCA sarcomas in vitro and in vivo following exposure to IFNgamma. Supplementary Figure S4. T9-PDL1 cells form progressively growing tumors in WT mice. Supplementary Figure S5. T9-PDL1ovr but not T9-PDL1phy cells inhibit antigen-specific T cell killing in vitro. Supplementary Figure S6. Extrinsic IFNgamma stimulation controls upregulation and maintenance of tumor PD-L1 expression. Supplementary Figure S7. Sixteen immune subsets in MCA sarcomas by flow cytometry. Supplementary Figure S8. Comprehensive analysis of cell types expressing PD-L1 in T3 tumors.

Supplementary Table S1. Staining panels for comprehensive analysis of cell types expressing PD-L1.

Figure Legends for Supplementary Data

Aortitis is an inflammatory process affecting the arterial wall. There are infectious and non–infectious forms. While the non–infectious forms can be linked to arteritis of the large vessels, the infectious forms are a rare but fearful complication of infective endocarditis. In this case the most affected pathogenic species are gram positive bacteria such as streptococci and enterococci. An 81–year–old patient, hypertensive, with permanent atrial fibrillation, subjected to previous aortic valve replacement (with Intuity 27 mm bioprosthesis for severe stenosis in 2016) and with previous pulmonary embolism in 2021, was admitted to emergency department for oliguria and worsening ankle swelling in December 2022. The haemodynamic parameters at the hospital admission were stable. A transthoracic echocardiography was performed, which highlighted a vegetation of about 2 cm on the aortic bioprosthesis with mild stenosis and negligible intraprosthesis regurgitation. A cerebral and thoraco–abdominal CT angiography showed multiple thromboembolic outcomes involving the splanchnic vessels, kidney and spleen. The patient was then subjected to transesophageal echocardiography which highlighted the presence of vegetation on the bioprosthesis with diameters of 12x12 mm; moreover, aneurysmal dilatation of the aortic root was found with the presence, both anteriorly and posteriorly of the wall, of a thickening of about 1 cm which extended up to the sino–tubular junction. The patient‘s hospitalization was also complicated by intestinal subocclusion without urgent surgical indications.The patient‘s case was discussed collectively and it was decided, in the light of the high risk of intestinal ischemia (linked to the thromboembolic occlusion of the splanchnic vessels) not to subject the patient to cardiac surgery. In a recent publication of a case report with literature review, 12 cases were reported, all treated surgically, of which 2 died. Our patient, unable to undergo surgical therapy, represents the first case treated with medical therapy alone. To date, the patient is still hospitalized, in stable haemodynamic conditions, with a unfavorable long–term prognosis.

Background Left ventricular (LV) fibrosis has a key role in arrhythmogenesis in mitral valve prolapse (MVP) patients. Cardiac magnetic resonance (CMR) demonstrated able to clearly identify LV fibrosis with the post-contrast late gadolinium enhancement (LGE) images. Despite the pivotal role of LV fibrosis in the arrhythmogenesis, a quantification and identification of reproducible method able to accurately measure LGE in arrhythmic MVP patients has not been recognized. Purpose We aimed to measure and compare different semi-quantitative methods for LGE quantification assessed by CMR, in order to identify the most reproducible one, in arrhythmic MVP patients. Methods 66 arrhythmic MVP patients with normal systolic function and without significant regurgitation were enrolled. Semi-automated gray-scale thresholding technique using full with at half maximum (FWHM) and 2, 3 and 5 standard deviation (SD) above the remote myocardium were used and compared with visual assessment (Fig. 1). Results LGE was identified in 41 arrhythmic MVP patients (62%) and quantified (Fig. 2). The mean quantity of LGE visually assessed was 2.40±1.07% or 1.40±0.82 g. With FWHM, LGE resulted 3.56±1.23% or 1.99±1.13 g. Using thresholding, the mean LGE quantity was 9.2±3.1% or 4.82±2.28 g for 2-SD, 5.72±1.75% or 3.06±1.47 g for 3-SD and 2.36±0.99% or 1.29±0.79 g for 5-SD. The 5-SD measurement in percentage demonstrated a good correlation with LGE quantification visually assessed (2.402±1.075 vs 2.363±0.9909, p: 0.543). Despite all semi-quantitative methods for LGE quantification demonstrated a good intra and inter-observer agreement, the 5-SD threshold quantification, both in percentage and in grams, revealed the less intra-observer (respectively, ICC: 0.976 and 0.966) and inter-observer variability (respectively ICC: 0.948 and 0.935) when compared with visual assessment. Conclusion This is the first study that quantified and compared different CMR semi-automated methods for LGE assessment in a population of arrhythmic MVP patients. The 5-SD gray-scale threshold technique in percentage revealed the best correlation with the visual assessment and an optimal reproducibility. Funding Acknowledgement Type of funding sources: None.

Background Non-ischemic left ventricular scar (NLVS) at cardiac magnetic resonance (CMR) is a common substrate of apparently idiopathic premature ventricular beats (PVBs) in athletes. PVBs morphology, complexity and exercise-behavior are known predictors of NLVS. It remains to be established whether reproducibility of PVBs at exercise testing correlates with CMR findings. Purpose We aimed to evaluate the possible role of PVBs reproducibility at repeated exercise testing in predicting the presence of an underlying NLVS in athletes who underwent CMR for apparently idiopathic ventricular arrhythmias. Methods We included all consecutive competitive athletes referred to our center for the evidence of PVBs during pre-participation screening, who underwent two maximal exercise testings within one month (the first at the time of pre-participation screening, the second at the time of outpatient evaluation at our sports cardiology clinic). Exclusion criteria were known heart disease, family history of cardiomyopathy or channelopathy, abnormal ECG and echocardiography. We also excluded athletes with “common/usually benign” PVBs (non-exercise-induced infundibular or fascicular PVBs) as well as those on ongoing antiarrhythmic therapy. Reproducibility was defined as the presence of PVBs with same morphology and exercise-behavior in two subsequent tests. LGE on CMR was quantified with 5-SD method, using a threshold of 5% to define the presence of pathological LVNS. Results A total of 64 apparently healthy competitive athletes (86% males, mean age of 33±14 years old) were included. On CMR, NLVS was identified in 26 (41%). PVBs reproducibility criteria was met in 32 athletes (50%). A statistically significant difference in PVBs reproducibility was found between patients with and without LVNS [26 (100%) versus 6 (16%), p Conclusion In apparently healthy athletes who underwent CMR for “uncommon” PVBs, the presence of underlying LVNS was predicted by ventricular arrhythmia reproducibility. Specifically, reproducibility of PVBs with RBBB/superior axis morphology was highly predictive of a positive CMR. This finding may be very relevant for appropriate prescription of CMR in athletes with apparently idiopathic ventricular arrhythmias. Funding Acknowledgement Type of funding sources: None.

This paper focuses on the authigenic mineralization processes acting on “Tufo Rosso a Scorie Nere” (TRS), i.e. one of the main pyroclastic units of the Vico stratovolcano (Latium, Italy). The pyroclastic deposits appear in general massive and made of “black vitreous vesiculated juvenile scoriae”, immersed in an ashy matrix lithified after zeolitization processes. The main minerals are chabazite and phillipsite, and the zeolitic content is locally variable, reaching 68 % wt. Zeolites grow replacing both amorphous fraction and pre-existing phases, occurring inside both matrix and scoriae. Concerning scoriae, zeolitization moves from the rim to the core of the scoriaceous fragment as a function of (a) temperature of the fluids and (b) permeability (primary or secondary). Composition of parental fresh glass and that of zeolitized rocks is compatible with trachyte chemistry, lightly undersaturated in SiO2, and the alteration processes modified the parental rock chemical features. Zeolites genesis is ascribed to a “geoautoclave-like system”, and zeolites display a Si/Al ratio similar to that of the parental glasses. TRS presents promising mineralogical characteristics as supplementary cementitious material in the production of mixed cements.

Background. Alzheimer’s cognitive-behavioral syndrome is the result of impaired connectivity between nerve cells, due to misfolded proteins, which accumulate and disrupt specific brain networks. Electroencephalography, because of its excellent temporal resolution, is an optimal approach for assessing the communication between functionally related brain regions. O bjective. To detect and compare EEG resting-state networks (RSNs) in patients with amnesic mild cognitive impairment (aMCI), and healthy elderly (HE). Methods. We recruited 125 aMCI patients and 70 healthy elderly subjects. One hundred and twenty seconds of artifact-free EEG data were selected and compared between patients with aMCI and HE. We applied standard low-resolution brain electromagnetic tomography (sLORETA)-independent component analysis (ICA) to assess resting-state networks. Each network consisted of a set of images, one for each frequency (delta, theta, alpha1/2, beta1/2). Results. The functional ICA analysis revealed 17 networks common to groups. The statistical procedure demonstrated that aMCI used some networks differently than HE. The most relevant findings were as follows. Amnesic-MCI had: i) increased delta/beta activity in the superior frontal gyrus and decreased alpha1 activity in the paracentral lobule (ie, default mode network); ii) greater delta/theta/alpha/beta in the superior frontal gyrus (i.e, attention network); iii) lower alpha in the left superior parietal lobe, as well as a lower delta/theta and beta, respectively in post-central, and in superior frontal gyrus(ie, attention network). Conclusions. Our study confirms sLORETA-ICA method is effective in detecting functional resting-state networks, as well as between-groups connectivity differences. The findings provide support to the Alzheimer’s network disconnection hypothesis.

Funding Acknowledgements Type of funding sources: None. Introduction In Italy, preparticipation screening of competitive athletes is mandatory. The age at which pre-participation screening (PPS) should start is established by each sport federation and it is sometimes under 10 years old. The aim of this study is to detect both PPS efficacy and cost in paediatric age and to define the cut-off age from which it is more cost-effective. Methods We retrospectively enrolled 25251 athletes aged ≤15 to evaluate the prevalence of cardiovascular (CV) diseases and cost-effectiveness ratio who underwent PPS from 2011 to 2020. In addition, we retrospectively studied a subgroup of 1307 competitive athletes aged 7-15 who underwent PPS from January 2019 to February 2020 for an in-depth analysed regarding costs. Cardiovascular preparticipation screening included first-line investigations (history, physical examination, resting ECG and exercise testing) and further examinations in case of abnormalities at first-line tests. Results In the period 2010-2020, 66 athletes were permanently disqualified for a CV disease (0,11%), 26 for a CV disease at risk of sudden cardiac death (0.05%), with a prevalence of 0.15% over 12 years old versus 0.01% under 12 (p Conclusion The cost-effectiveness of PPS before competitive sports in the pediatric age is lower than reported for older athletes in previously published studies. According to our data, starting PPS before 12 years of age does not appear to be justified.

Background: Over the Covid-19 pandemic, the compelling need of containing the virus spread while providing diseased people with adequate assistance has inevitably reflected on treatment priorities, which have been sometimes radically revised according to the intrinsic nature of the institution considered and its role and action within the pandemic context. We report on the experience matured at the Regina Elena National Cancer Institute concerning the effects of the restriction measures adopted during the pandemic on the outcomes of surgical site infections (SSIs) in breast cancer patients (BC-pts) undergoing non-deferrable breast cancer surgery. Methods: Within the frame of an observational study, we compared evidence from two cohorts, namely, the lockdown cohort (LDC) and non-lockdown cohort (NLDC). Patients from the LDC underwent breast cancer surgery between the 15th March 2020 and the 4th May 2020. Breast surgery was performed by the same team and postsurgical controls were performed regularly for a minimum of 12-months. SSIs were defined according to the criteria established by the Center for Disease Control and Prevention. Results: The LDC originally included 79 breast cancer patients, of whom 62 provided data to the final analysis. In the LDC, initially 64 breast cancer patients, only 52 were finally considered. No relevant differences emerged between LDC and NLDC by general characteristics. We observed significant evidence of lower SSIs in the subgroups of patients having undergone skin reducing mastectomy compared with the remaining subgroups (p=0.003). The overall number of surgical site infections was 10 (8.7%), and the median time to their occurrence17.1 days (7- 42). In the NLDC, 7 (13.5) SSIs were identified, with a median time to occurrence of 18.2 days (7-42). In the LDC, 3 (4.8%) SSIs occurred, with a median time to occurrence of 14.3 days (7 to 21). None of these patients was in need of re-hospitalization and there were no delays in adjuvant treatment starting. Conclusions: The restrictive measures issued during the lockdown period seemed to lower the SSI rates in breast cancer patients undergoing non-deferrable breast surgery, although, caution is needed due to the limited sample size.

Background Ulcerative proctitis (UP), defined as a colonic location limited to the rectum, is a poorly investigated condition in children, usually considered as a minor form of Ulcerative Colitis (UC). The aim of the present study was to compare the disease course of paediatric patients affected by UP at diagnosis with the other UC locations. Methods This multicentre retrospective observational study has been carried out starting from the data prospectively registered in the IBD Registry of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP). Seventeen IBD referral centres adhering to the registry were included in the study. Patients age 0 to 18 years, who were diagnosed with UC according to the Porto criteria starting from January 1, 2009, to May 1st, 2021 were identified. Only children with a minimum follow-up of 12 months were included in the study. Once enrolled, children were subsequently divided in two groups based on Paris classification: group 1 (E1) and group 2 (E2, E3 and E4). Results Eight-hundred-eighty-five children were finally included in the study (median age at diagnosis: 11.2 years, range: 0–18 years; M/F: 434/451), of whom 176 (19.8%) belonging to group 1 and 709 (80.1%) to group 2. The median age at diagnosis was significantly higher in group 1 when compared to group 2 [11.9 (0–18) versus 11 (0–18) years, respectively; (p Conclusion UP is a frequent location of paediatric onset UC and the risk of endoscopic extension of proctitis is similar to the more extensive forms. A considerable number of patients with UP required immunosuppressive or biologic therapy during the follow-up and no significant difference was observed in terms of surgery. Overall, UP cannot be considered as a minor form of UC.

Background: The association between inflammatory bowel disease (IBD) and immune thrombocytopenia (ITP) is still uncertain. In this multicenter retrospective study, the coexistence of both diseases was investigated in children diagnosed from 1 January 2000 to 31 December 2019. Methods: Clinical characteristics of both IBD and ITP, onset of disorders, and patient’s response to treatment were collected through a structured form sent to 55 Italian pediatric referring centers for hematological disorders. Result: Centers responded to the survey and reported the coexistence of IBD and ITP in 14 children. The first diagnosis was ITP in 57.1% and IBD in 35.7% of patients: it was simultaneous in 7.1%. IBD was classified as ulcerative colitis (57.1%), Crohn disease (35.7%), and unclassified (7.1%). No therapy for IBD other than steroids had any effect on ITP course. Colectomy resulted in recovery from ITP in 1 of the 2 patients surgically treated. ITP was always mild but turned to be chronic in half of patients. Conclusions: In all patients, ITP was mild without any evident impact on IBD severity, but the incidence of chronic ITP seems to be higher than what is usually observed in the pediatric age group. Colectomy had unpredictable effects on ITP.

No real-life study on the comparative effectiveness of Vedolizumab (VDZ), Adalimumab (ADA), and Golimumab (GOL) in ulcerative colitis (UC) is currently available.To compare the effectiveness of the three biologics in consecutive patients with UC.A three-arms propensity score-adjusted analysis was performed using the Inverse Probability of Treatment Weighting method.463 treatments (VDZ: n = 187; ADA: n = 168; GOL: n = 108) were included (median follow-up: 47.6 weeks). At 12 weeks (n = 463), a steroid-free remission was reported in 24.1% patients in the VDZ group, in 33.3% patients in the ADA group, and in 30.6% patients in the GOL group (p = n.s. for all comparisons). At 52 weeks (n = 377), a steroid-free remission was reported in 51.5% patients in the VDZ group, in 31.2% patients in the ADA group, and in 29.4% patients in the GOL group (p = 0.002 for VDZ vs. ADA, p = 0.001 for VDZ vs. GOL, p = n.s. for ADA vs. GOL). Cox survival analysis demonstrated that patients treated with VDZ had reduced probability of treatment discontinuation compared to those treated with ADA (HR: 0.42, 95% CI 0.28-0.64, p 0.001) and GOL (HR: 0.30, 95% CI 0.19-0.46, p 0.001), while patients treated with ADA had reduced risk of treatment discontinuation compared to those treated with GOL (HR: 0.71, 95% CI 0.50-1.00, p = 0.048).VDZ was superior to ADA and GOL at 52 weeks and as treatment persistence, while ADA showed a superior treatment persistence compared to GOL.

Background Clinical data on the use of Adalimumab (ADA) biosimilar ABP 501 in inflammatory bowel disease (IBD) are lacking. Methods SPOSAB ABP 501 is a multicenter, observational, prospective study performed among the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD). All consecutive patients with Crohn’s Disease (CD) or Ulcerative Colitis (UC) treated with ABP 501 from the introduction of the drug in Sicily (February 2019) to February 2020 (12 months) were enrolled. Patients were divided into 3 groups (group A: naive to ADA and naive to anti-TNFs; group B: naive to ADA and previously exposed to anti-TNFs; group C: switch from ADA originator to ABP 501). The primary end-point was the assessment of safety, in terms of rate of serious adverse events (SAEs). Secondary end-point was the evaluation of effectiveness, in terms of clinical response and steroid-free clinical remission at 12 weeks for group A and B, and as treatment persistency for all 3 groups. Results 559 patients (median age 39 years; CD 88.0%, UC 12.0%) were included [group A: 189 (33.8%); group B: 30 (5.4%); group C: 340 (60.8]. Overall, the mean follow-up was 8.7 months (median 10.0 months, interquartile range: 6.0–12.0 months), and the total follow-up time was 403.4 patient-years. 36 SAEs occurred in 36 patients (6.4%), with an incidence rate of 8.9 per 100 person-years (PY), and 22 of them caused the withdrawal of the drug (incidence rate: 5.5 per 100 PY). The incidence rate of SAEs was higher among patients in group A compared with group C (17.4 vs. 4.8 per 100 PY; incidence rate ratio=3.61; p Conclusion This is the first prospective study on the use of ADA biosimilar ABP 501 in IBD. Safety and effectiveness of ABP 501 seem to be overall similar to those reported for ADA originator. Switching from originator to ABP 501 was safe and effective.

Background Multiple clinical studies in children with Crohn’s disease (CD) have demonstrated the high efficacy of nutritional therapy with exclusive enteral nutrition (EEN) to induce remission and even to promote mucosal healing. However, EEN as inductive treatment may be not tolerated or inefficient and we are well aware of the paramount importance of a well conducted induction treatment for paediatric CD with the goal of an individualized induction treatment to improve the prognosis and the quality of life of inflammatory bowel disease (IBD) children. Methods A retrospective multicentre study including newly diagnosed children with CD treated with EEN as induction therapy was designed. The primary aim of the study was to study predictive factors of non- adherence to treatment. The secondary endpoint were predictive factors of clinical non-remission at the end of induction treatment. Those data together were analysed with the ultimate goal of trying to define an individualized induction treatment for children with CD. Results 376 CD children from, 14 IBD paediatric referral centres were enrolled in the study. The rate of EEN adherence was, 89 %. Colonic involvement and FC >, 600 μg/g at diagnosis were found associated with a reduced EEN adherence in univariate and multivariate analysis. The remission rate of those who completed induction treatment was, 67%. A multivariate analysis showed that factor determining lower remission rate were age >, 15 years and PCDAI >, 50. With those results we were able to create a decisional algorithm which is provided in figure 1. Conclusion EEN administered for, 8 weeks is effective for inducing clinical remission. The rate of adherence is high but there is a group of patients (colonic involvement + hight FC) which are at risk of non-adherence and thus may be candidate for alternative dietary induction regimens. Moreover, older patients with moderate to severe active disease (PCDAI>40), are at higher risk of failing clinical remission achievement after EEN and may benefit from an early anti-TNF alpha treatment. Personalized treatment strategies should be proposed weighing the benefits and risks based on each patient’s disease location, phenotype and disease activity with the overall aim of obtaining rapid control of inflammation to reduce long-term bowel damage.

TL1A, a tumor necrosis factor-like cytokine, is a ligand for the death domain receptor DR3. TL1A, upon binding to DR3, can stimulate lymphocytes and trigger secretion of proinflammatory cytokines. Therefore, blockade of TL1A/DR3 interaction may be a potential therapeutic strategy for autoimmune and inflammatory diseases. Recently, the anti-TL1A monoclonal antibody 1 (mAb1) with a strong potency in blocking the TL1A/DR3 interaction was identified. Here, we report on the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) to obtain molecular-level details of mAb1's binding epitope on TL1A. HDX coupled with electron-transfer dissociation MS provided residue-level epitope information. The HDX dataset, in combination with solvent accessible surface area (SASA) analysis and computational modeling, revealed a discontinuous epitope within the predicted interaction interface of TL1A and DR3. The epitope regions span a distance within the approximate size of the variable domains of mAb1's heavy and light chains, indicating it uses a unique mechanism of action to block the TL1A/DR3 interaction.

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Monoclonal antibodies can mediate antitumor activity by multiple mechanisms. They can bind directly to tumor receptors resulting in tumor cell death, or can bind to soluble growth factors, angiogenic factors, or their cognate receptors blocking signals required for tumor cell growth or survival. Monoclonal antibodies, upon binding to tumor cell, can also engage the host's immune system to mediate immune-mediated destruction of the tumor. The Fc portion of the antibody is essential in engaging the host immune system by fixing complement resulting in complement-mediated cytotoxicity (CDC) of the tumor, or by engaging Fc receptors for IgG (FcγR) expressed by leukocytes leading to antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) of tumor cells. Antibodies whose Fc portion preferentially engage activating FcγRs have shown greater inhibition of tumor growth and metastasis. Monoclonal antibodies can also stimulate the immune system by binding to targets expressed on immune cells. These antibodies may stimulate antitumor immunity by antagonizing a negative regulatory signal, agonizing a costimulatory signal, or depleting immune cells that are inhibitory. The importance of Fc:FcγR interactions in antitumor therapy for each of these mechanisms have been demonstrated in both mouse models and clinical trials and will be the focus of this chapter.

In vivo–based functional genomic screen identifies DDR2 as an important determinant of efficacy of anti–PD-1 immunotherapy., While a fraction of cancer patients treated with anti–PD-1 show durable therapeutic responses, most remain unresponsive, highlighting the need to better understand and improve these therapies. Using an in vivo screening approach with a customized shRNA pooled library, we identified DDR2 as a leading target for the enhancement of response to anti–PD-1 immunotherapy. Using isogenic in vivo murine models across five different tumor histologies—bladder, breast, colon, sarcoma, and melanoma—we show that DDR2 depletion increases sensitivity to anti–PD-1 treatment compared to monotherapy. Combination treatment of tumor-bearing mice with anti–PD-1 and dasatinib, a tyrosine kinase inhibitor of DDR2, led to tumor load reduction. RNA-seq and CyTOF analysis revealed higher CD8+ T cell populations in tumors with DDR2 depletion and those treated with dasatinib when either was combined with anti–PD-1 treatment. Our work provides strong scientific rationale for targeting DDR2 in combination with PD-1 inhibitors.