Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers

Gastrointestinal neoplasms; Immunotherapy; Tumor biomarkersNeoplasias gastrointestinales; Inmunoterapia; Biomarcadores tumoralesNeoplàsies gastrointestinals; Immunoteràpia; Biomarcadors tumoralsBackground Despite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs. Methods We conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset. Results The mCRC cohort included 502 patients. After a median follow-up of 31.2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1.15, 95% CI 0.85 to 1.56 for progression-free survival (PFS); aHR 0.96, 95% CI 0.65 to 1.42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2.90, 95% CI 1.70 to 4.94; aHR 3.33, 95% CI 1.88 to 5.91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17.4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3.83, 95% CI 1.68 to 8.72; aHR 3.44, 95% CI 1.39 to 8.53, respectively), but not in patients with only peritoneal metastases (aHR 1.87, 95% CI 0.64 to 5.46; aHR 2.15, 95% CI 0.64 to 7.27) when compared with patients without peritoneal involvement. Conclusions Patients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastases and ascites should be considered as a peculiar subgroup with highly unfavorable outcomes to current ICI-based therapies. Novel strategies to target the immune-suppressive niche in malignant effusions should be investigated, as well as next-generation ICIs or intraperitoneal approaches

Epidemiological assessment of Respiratory Syncytial Virus infection in hospitalized infants, during the season 2005–2006 in Palermo, Italy

<p>Abstract</p> <p>Objectives</p> <p>Respiratory Syncytial Virus (RSV) is the leading cause of hospitalization for lower respiratory tract infections (LRTI) in young children worldwide.</p> <p>We evaluate the epidemiological and clinical patterns of RSV infection in infants hospitalized for LRTI in in Palermo, South Italy, Sicily.</p> <p>Methods</p> <p>We collected the demographic details of infants hospitalized to G. Di Cristina Children's Hospital in Palermo for LRTI between November 2005 and May 2006. We also included all cases occurred in newborns hospitalized in the Neonatal Intensive Care Unit (NICU) Of Palermo.</p> <p>Results</p> <p>During the studied period, 335/705 hospitalized infants for LRTI were enrolled in the study. The trend of hospitalization started in late winter and lasting until May 2006 with an epidemic peak in spring. 178/335 infants tested for viral infection showed RSV disease. Three cases occurred in preterm newborns hospitalized from birth in NICU. The likelihood to be RSV+, rather than RSV negative (RSV-) was higher for infants < 6 months and lower for infants with history of breast feeding (P < 0.05). RSV infection was associated with a higher likelihood to be admitted to intensive care unit and to a longer hospitalization and oxygen therapy.</p> <p>Conclusion</p> <p>The study shows that, in Sicily, RSV is an important cause of LRTI in infants. The seasonal distribution shows that both LRTI and RSV infections peak in late spring, in contrast to Northern Italy. Our data could help to define the regional appropriate start of prophylactic interventions.</p

Investigating the Concordance in molecular subtypes of primary colorectal tumors and their matched synchronous liver metastasis

To date, no systematic analyses are available assessing concordance of molecular classifications between primary tumors (PT) and matched liver metastases (LM) of metastatic colorectal cancer (mCRC). We investigated concordance between PT and LM for four clinically relevant CRC gene signatures. Twenty-seven fresh and 55 formalin-fixed paraffin-embedded pairs of PT and synchronous LM of untreated mCRC patients were retrospectively collected and classified according to the MSI-like, BRAF-like, TGFB activated-like and the Consensus Molecular Subtypes (CMS) classification. We investigated classification concordance between PT and LM and association of TGFBa-like and CMS classification with overall survival. Fifty-one successfully profiled matched pairs were used for analyses. PT and matched LM were highly concordant in terms of BRAF-like and MSI-like signatures, (90.2% and 98% concordance, respectively). In contrast, 40% to 70% of PT that were classified as mesenchymal-like, based on the CMS and the TGFBa-like signature, respectively, lost this phenotype in their matched LM (60.8% and 76.5% concordance, respectively). This molecular switch was independent of the microenvironment composition. In addition, the significant change in subtypes was observed also by using methods developed to detect cancer cell-intrinsic subtypes. More importantly, the molecular switch did not influence the survival. PT classified as mesenchymal had worse survival as compared to nonmesenchymal PT (CMS4 vs CMS2, hazard ratio [HR] = 5.2, 95% CI = 1.5-18.5, P = .0048; TGFBa-like vs TGFBi-like, HR = 2.5, 95% CI = 1.1-5.6, P = .028). The same was not true for LM. Our study highlights that the origin of the tissue may have major consequences for precision medicine in mCRC

Nanobiotechnology and Immunotherapy: Two Powerful and Cooperative Allies against Cancer

A number of novel cancer therapies have recently emerged that have rapidly moved from the bench to the clinic. Onco-immunotherapies, such as immune checkpoint blockade inhibitors and adoptive cell therapies, have revolutionized the field, since they provide a way to induce strong anti-tumor immune responses, which are able to fight cancer effectively. However, despite showing great efficacy in hematological and some solid tumors, unresponsiveness, development of therapy resistance and the development of serious adverse effects, limit their capacity to impact the vast majority of tumors. Nanoparticle-based delivery systems are versatile vehicles for a wide variety of molecular cargoes and provide an innovative strategy to improve conventional onco-immunotherapies. They can be finely tuned to release their contents in the tumor microenvironment, or to deliver combinations of adjuvants and antigens in the case of nanovaccines. In this review, we summarize the recent advancements in the field of nanobiotechnology, to remodel the tumor microenvironment and to enhance immunotherapies

Psychiatric Comorbidities in Children and Adolescents with High-Functioning Autism Spectrum Disorder: A Study on Prevalence, Distribution and Clinical Features in an Italian Sample

This study investigated the prevalence and distribution of psychiatric comorbidities in a group of 472 children and adolescents with ASD aged 3–18 years. We examined differences in age, sex, IQ, adaptive skills, and ASD symptom severity by comparing participants with ASD (ASD group) with participants with ASD and a psychiatric disorder (ASD/PSY group). Overall, 32.2% of participants had a comorbid psychiatric condition. Attention deficit/hyperactivity disorder (ADHD) was the most frequent diagnosis among preschoolers (20.4%); among school-age children, ADHD and anxiety/obsessive-compulsive disorders were the most frequent conditions (21% and 10.6%, respectively); finally, adolescents exhibit higher prevalence of anxiety/obsessive-compulsive disorders (21.8%). The ASD/PSY group showed a higher percentage of males, they were older and showed lower adaptive skills than the group with ASD; moreover, their mothers exhibited higher stress levels than mothers of participants in the ASD group. The comparison between age groups in participants within ASD/PSY group revealed that preschoolers had lower IQ than school-age children and adolescents, and worse adaptive skills, more repetitive behaviors, and restricted interests than adolescents. This study highlights the importance of an accurate diagnosis of psychiatric comorbidities in children and adolescents with ASD, also considering individual and family impairment

Event-Based Prospective Memory Deficit in Children with ADHD: Underlying Cognitive Factors and Association with Symptoms

Event-based prospective memory (PM) was investigated in children with Attention deficit/hyperactivity disorder (ADHD), using a novel experimental procedure to evaluate the role of working memory (WM) load, attentional focus, and reward sensitivity. The study included 24 children with ADHD and 23 typically-developing controls. The experimental paradigm comprised one baseline condition (BC), only including an ongoing task, and four PM conditions, varying for targets: 1 Target (1T), 4 Targets (4T), Unfocal (UN), and Reward (RE). Children with ADHD were slower than controls on all PM tasks and less accurate on both ongoing and PM tasks on the 4T and UN conditions. Within the ADHD group, the accuracy in the RE condition did not differ from BC. A significant relationship between ADHD-related symptoms and reduced accuracy/higher speed in PM conditions (PM and ongoing trials), but not in BC, was detected. Our data provide insight on the adverse role of WM load and attentional focus and the positive influence of reward in the PM performance of children with ADHD. Moreover, the relation between PM and ADHD symptoms paves the road for PM as a promising neuropsychological marker for ADHD diagnosis and intervention

Morcellation worsens survival outcomes in patients with undiagnosed uterine leiomyosarcomas: A retrospective MITO group study

Objective To investigate the impact of morcellation on survival outcomes of patients affected by undiagnosed uterine sarcoma. Methods This is a retrospective study performed in 8 referral centers of MITO group. Data of women undergoing morcellation for apparent benign uterine myomas who were ultimately diagnosed with stage I uterine sarcoma on final pathology were compared with data of women who did not undergo morcellation. Uterine sarcoma included: leiomyosarcomas (LMS), smooth muscle tumors of uncertain malignant potential (STUMP), low-grade endometrial stromal sarcomas (LG-ESS) and undifferentiated uterine sarcomas (UUS). Two-year survival outcomes were evaluated using Kaplan-Meir and Cox models. Results Overall 125 patients were identified: 31(24.8%), 21(16.8%) and 73(58.4%) patients had power morcellation during laparoscopy, non power morcellation during open surgery and non morcellation during open procedures, respectively. Considering patients affected by LMS, morcellation did not correlated with disease-free survival. However, patients undergoing either morcellation or power morcellation experienced a 3-fold increase risk of death in comparison to patients who had not morcellation (p&nbsp;=&nbsp;0.02). A trend towards an increase of recurrence was observed for patients undergoing morcellation for STUMP (HR 7.7, p&nbsp;=&nbsp;0.09); while no differences in survival outcomes were observed for patients with LG-ESS and UUS. Conclusions Our data suggest that morcellation increase the risk of death in patients affected by undiagnosed LMS. Further prospective studies are warranted in order to assess the risk to benefit ratio of power morcellator utilization in patients with apparent benign uterine myomas