Specifications and validation of the ACMG/AMP criteria for clinical interpretation of sequence variants in collagen genes associated with joint hypermobility.

Deleterious variants in collagen genes are the most common cause of hereditary connective tissue disorders (HCTD). Adaptations of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria are still lacking. A multidisciplinary team was set up for developing specifications of the ACMG/AMP criteria for COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL11A1, COL11A2 and COL12A1, associated with various forms of HCTD featuring joint hypermobility, which is becoming one of the most common reasons of referral for molecular testing in this field. Such specifications were validated against 209 variants, and resulted effective for classifying as pathogenic and likely pathogenic null alleles without downgrading of the PVS1 level of strength and recurrent Glycine substitutions. Adaptations of selected criteria reduced uncertainties on private Glycine substitutions, intronic variants predicted to affect the splicing, and null alleles with a downgraded PVS1 level of strength. Segregation and multigene panel sequencing data mitigated uncertainties on non-Glycine substitutions by the attribution of one or more benignity criteria. These specifications may improve the clinical utility of molecular testing in HCTD by reducing the number of variants with neutral/conflicting interpretations. Close interactions between laboratory and clinicians are crucial to estimate the a priori utility of molecular test and to improve medical reports.

Immune-checkpoint inhibitors in pituitary malignancies.

To date, there are no standardized systemic treatment options for patients with metastatic pituitary carcinoma progressed to chemo and radiation therapy. Immune-checkpoint inhibitors (ICIs) have been successfully assessed in other solid malignancies and could be a concrete hope for these patients. We performed a critical review of the literature aimed to evaluate studies assessing ICIs in pituitary malignancies. We also conducted research about published translational data assessing immune-contexture in these malignancies. Some preliminary reports reported a successful administration of pembrolizumab or the combination between nivolumab and ipilimumab in patients with metastatic ACTH-secreting pituitary carcinomas. Translational data suggest that adenomas secreting growth hormone and ACTH have a suppressed immune-microenvironment, which could be more likely to benefit from ICIs. Immune-checkpoint inhibitors can be an effective treatment in patients with pituitary carcinoma and maybe also recurrent adenoma. Tumors secreting growth hormone and ACTH are more likely to benefit from ICIs due to a different immune-microenvironment.

Clinical heterogeneity of Kabuki syndrome in a cohort of Italian patients and review of the literature.

Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10-26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG's abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient.Conclusions: These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known • Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability • Immune dysfunction is a common finding but autoimmune diseases are rarely seen • Neurological features are common What is New • Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus) • Higher prevalence of autoimmune disorders than previously reported • Particular neurological features are present in this cohort (EEG and MRI brain abnormalities).

Quality of life assessment in renal cell carcinoma Phase II and III clinical trials published between 2010 and 2020: a systematic review.

Aims: Quality of life (QoL) assessment is frequently not included among the end points of clinical trials (CTs) on renal cell carcinoma. Herein we aimed to describe the assessment and reporting of QoL in Phase II and Phase III CTs published between 2010 and 2020. Methods: A total of 25 CTs were included; 76% of trials included were conducted in metastatic renal cell carcinoma patients, while 20% of studies evaluated adjuvant systemic treatments. Results: In 13/25 publications, QoL was not listed among the end points, with secondary publications dedicated to QoL present in a minority of cases. Conclusions: QoL was not included among the end points of a large percentage of CTs. Implementing the inclusion of QoL represents an urgent need.

Lay abstract Recent years have seen growing attention toward quality of life (QoL) in medical oncology clinical trials and statistical measurement of this aspect of cancer treatment. Nonetheless, although most clinicians and researchers agree that QoL should represent a fundamental component of clinical trials, the inclusion of QoL results is still inadequate, and our systematic review confirms that implementing the inclusion of QoL remains an urgent need.

Italian adolescents' understandings of globalization.

INTRODUCTION: Having a clear understanding of the concept of globalization can be particularly relevant for adolescents to comprehend how the world functions and to reflect on the way their personal and professional identity and career future might be affected by globalization. Thus, this mixed design study aimed at examining Northeastern Italian adolescents' thinking about globalization and at exploring the potential role of education (the type of school) in conceptualizing globalization. METHODS: A total of 163 Italian adolescents (42.3% boys and 57.5% girls) aged 16-19 years, attending a scientific lyceum or a commercial, technological, or professional high school participated in the study. Participants were invited to explain the concept of globalization. Their answers were analyzed using a thematic analysis procedure. RESULTS: & Conclusions:. The analyses revealed adolescents' limited and inaccurate understandings of globalization, with almost exclusive emphasis on the positive aspects of globalization, and without a critical understanding of its consequences. Moreover, no differences related to their educational experience (the type of school they attended) or socio-economic status emerged when reporting their understanding of globalization. The results suggested the relevance of a training process for the promotion of critical thinking, especially in the field of career guidance.

Third- and later-line treatment in advanced or metastatic gastric cancer: a systematic review and meta-analysis.

Aim: We performed a systematic review and meta-analysis to investigate the efficacy and safety of third-line (TLT) and salvage treatment (ST) in advanced or metastatic gastric cancer. Materials & methods: Eligible studies included randomized clinical trials assessing TLT and ST versus placebo or best supportive care. Outcomes of interest included: overall survival, objective response rate and disease control rate in TLT; progression-free survival in ST; grade 3-4 adverse events in ST. Results: The use of TLT and ST was superior to placebo or best supportive care in terms of prolonging overall survival and progression-free survival. Hematological toxicities were more frequent in ST. Conclusion: TLT and ST are considerable and tolerable treatment options for patients with advanced or metastatic gastric cancer. Given the substantial heterogeneities affecting the efficacy analyses, these results have to be interpreted cautiously.

Prognostic impact of tumour burden in stage IV neuroendocrine neoplasia: A comparison between pancreatic and gastrointestinal localizations.

BACKGROUND: Although prognosis of NENs is affected by several features including tumour burden, the specific role of this factor in pancreatic NENs (PanNENs) and gastrointestinal NENs (GI NENs) is not well established. AIM: To compare the prognostic role of tumour burden in PanNENs and GI NENs. PATIENTS AND METHODS: This study was a retrospective analysis of stage IV PanNENs and GI NENs. Tumours were classified based on liver tumour volume (<25% or >25%). Overall survival as assessed by Kaplan-Meier curves, and Cox proportional hazards method was used to perform risk factor analysis. RESULTS: The analysis included 300 patients, including 166 panNENs (55.3%) and 134 GI NENs (44.7%). A total of 158 patients (52.7%) had G2 tumours, 107 had G1 tumours (35.7%), and 35 had G3 tumours (11.6%). Tumour liver involvement >25% was observed in 187 patients (62.3%): 106 PanNENs (56.7%), and 81 GI NENs (43.3%) (p = 0.551). Bone metastases were present in 45 patients (15%): 22 PanNENs (13.2%) and 23 GI NENs (17.1%) (p = 0.416). Characteristics of the PanNENs, including: grading (G2 vs G1, HR = 3.7; G3 vs G1, HR = 16.40), liver involvement > 25% (HR = 3.09), and bone metastases (HR = 2.27) were independent predictors for poor survival, whereas the only significant risk factor in GI NENs was grading (G2 vs G1, HR = 4.36; G3 vs G1, HR = 8.60). CONCLUSIONS: PanNENs and GI NENs have different risk profiles. Liver tumour volume and the presence of bone metastases significantly affect survival in patients with PanNENs but has no impact on the clinical outcomes of GI NENs.

Therapeutic options in lung neuroendocrine tumors: between established concepts and new hopes.

Typical (TC) and atypical (AC) carcinoids are low-grade neuroendocrine tumors (NETs) of the lung and, are neglected diseases in respect of both high-grade NETs of the lung (i.e. small-cell lung cancer and large-cell neuroendocrine carcinoma) and gastroenteropancreatic (GEP)-NETs. AC and TC account for 2 and 0.2% of all thoracic malignancies, respectively, and have a 12.9% chance of metastatic spread at diagnosis, reaching up to 20% during disease history. There are very few trials specifically designed for lung NETs, and therapeutic options are mainly derived by studies carried out in patients with GEP-NETs. We report a case of a patient affected by AC progressed to available standard treatments who received off-label treatment with sunitinib, a well-known multitarget tyrosine-kinase inhibitor with marked antiangiogenic activity, used routinely for the treatment of GEP-NETs. During treatment, the patient required the administration of an alternative schedule to improve tolerability, with benefit, and achieved a partial response according to the RECIST criteria, which is unusual in NETs. We critically reviewed available data supporting the use of somatostatin analogs, chemotherapy, and target therapies (everolimus and sunitinib) in advanced lung NETs. In the review, ongoing trials in lung NETs and future developments in this research field are also discussed.

The Role of mTOR in Neuroendocrine Tumors: Future Cornerstone of a Winning Strategy?

The mechanistic target of rapamycin (mTOR) is part of the phosphoinositide-3-kinase (PI3K)/protein kinase B (AkT)/mTOR pathway and owes its name to the inhibitory effect of rapamycin. The mTOR has a central converging role for many cell functions, serving as a sensor for extracellular signals from energy status and nutrients availability, growth factors, oxygen and stress. Thus, it also modulates switch to anabolic processes (protein and lipid synthesis) and autophagy, in order to regulate cell growth and proliferation. Given its functions in the cell, its deregulation is implicated in many human diseases, including cancer. Its predominant role in tumorigenesis and progression of neuroendocrine tumors (NETs), in particular, has been demonstrated in preclinical studies and late clinical trials. mTOR inhibition by everolimus is an established therapeutic target in NETs, but there are no identified predictive or prognostic factors. This review is focused on the role of mTOR and everolimus in NETs, from preclinical studies to major clinical trials, and future perspectives involving mTOR in the treatment of NETs.

Development and validation of an instrument to assess future orientation and resilience in adolescence.

The study is aimed at providing the development and initial validation of the Design My Future (DMF), which may be administered in career counseling and research activities to assess adolescents' future orientation and resilience. Two studies with two independent samples of Italian adolescents were conducted to examine psychometric requisites of DMF. Specifically, in the first study, after developing items and examined the content validity, the factorial structure, reliability and discriminant validity of the DMF were tested. In the second study, the measurement invariance across gender, conducing a sequence of nested CFA models, was evaluated. Results showed good psychometric support for the instrument with Italian adolescents.

Comprehensive Molecular Analysis of Disease-Related Genes as First-Tier Test for Early Diagnosis, Classification, and Management of Patients Affected by Nonsyndromic Ichthyosis.

Inherited ichthyoses are a group of clinically and genetically heterogeneous rare disorders of skin keratinization with overlapping phenotypes. The clinical picture and family history are crucial to formulating the diagnostic hypothesis, but only the identification of the genetic defect allows the correct classification. In the attempt to molecularly classify 17 unrelated Italian patients referred with congenital nonsyndromic ichthyosis, we performed massively parallel sequencing of over 50 ichthyosis-related genes. Genetic data of 300 Italian unaffected subjects were also analyzed to evaluate frequencies of putative disease-causing alleles in our population. For all patients, we identified the molecular cause of the disease. Eight patients were affected by autosomal recessive congenital ichthyosis associated with ALOX12B, NIPAL4, and TGM1 mutations. Three patients had biallelic loss-of-function variants in FLG, whereas 6/11 males were affected by X-linked ichthyosis. Among the 24 different disease-causing alleles we identified, 8 carried novel variants, including a synonymous TGM1 variant that resulted in a splicing defect. Moreover, we generated a priority list of the ichthyosis-related genes that showed a significant number of rare and novel variants in our population. In conclusion, our comprehensive molecular analysis resulted in an effective first-tier test for the early classification of ichthyosis patients. It also expands the genetic, mutational, and phenotypic spectra of inherited ichthyosis and provides new insight into the current understanding of etiologies and epidemiology of this group of rare disorders.

Dealing with COVID-19 stressful events, stress and anxiety: the mediating role of emotion regulation strategies in Italian women.

BACKGROUND: This study aims to better understand the causal relationship between COVID-19 stressful events, perceived stress, emotion regulation strategies and anxiety symptoms in Italian women. Specifically, we assumed that: (i) different COVID-19 stressful events can directly or indirectly influence the manifestation of anxiety symptoms; (ii) perceived stress and emotion regulation strategies can mediate the relationship between COVID-19 stressful events and anxiety symptoms. PARTICIPANTS AND PROCEDURE: An online survey was distributed during the Italian mandatory lockdown - between 18th and 28th April 2020 - across the national territory. The final sample was composed of 1132 women living in different Italian regions (North 63.30%, Centre 14.20%, South 18.50%, Islands 4.00%) with a mean age of 40.19 years, ranging from 19 to 83 years (SD = 12.87). Participants filled out the Perceived Stress Scale (PSS-10), Spielberger State-Trait Anxiety Inventory (STAI) X1/R, Emotion Regulation Questionnaire (ERQ-10), five dichotomous questions assessing the COVID-19 stressful events and a demographic form. Pearson correlation analyses were performed to examine whether associations between factors conformed to the prerequisites for path analysis. Path analysis was conducted to test the model. RESULTS: "Having contracted the flu during the COVID-19 pandemic" and "having a family member infected by COVID-19" have a direct effect on the level of perceived stress and an indirect effect on the manifestation of anxiety symptoms. Finally, we found that emotion regulation strategies mediate the relationship between perceived stress and state anxiety symptoms. CONCLUSIONS: Our results allow one to select the stressful events to which, in the pandemic era, it is necessary to pay particular attention in a clinical setting and suggest the implementation of psychological interventions that make emotion regulation an essential direct target of treatment in chronic stress-related pathology such as anxiety disorders.

The Potential Role of Adjuvant Chemoradiotherapy in Patients with Microscopically Positive (R1) Surgical Margins after Resection of Cholangiocarcinoma.

(1) Background: Biliary tract cancers (BTCs) are a heterogeneous group of neoplasms with dismal prognosis and the role of adjuvant chemoradiotherapy in high-risk resected patients is unclear. (2) Methods: We retrospectively analyzed the outcomes of BTC patients who received curative intent surgery with microscopically positive resection margins (R1) and adjuvant chemoradioradiotherapy (CCRT) or chemotherapy (CHT) from January 2001 to December 201. (3) Results: Out of 65 patients who underwent R1 resection, 26 received adjuvant CHT and 39 adjuvant CCRT. The median recurrence-free survival (RFS) in the CHT and CHRT groups was 13.2 and 26.8 months, respectively (p = 0.41). Median overall survival (OS) was higher in the CHRT group (41.9 months) as compared to the CHT group (32.2 months), but the difference was not statistically significant (HR 0.88; p = 0.7). A promising trend in favor of CHRT was observed in N0 patients. Finally, no statistically significant differences were observed between patients undergoing adjuvant CHRT after R1 resection and patients treated with chemotherapy alone after R0 surgery. (4) Conclusions: Our study did not show a significant survival benefit with adjuvant CHRT over CHT alone in BTC patients with positive resection margins, while a promising trend was observed.

Adverse Conditions, Psychological Aspects, and Teachers' Tendency Toward Sustainability and a Less Conservative Future.

This study aimed to examine the effect of cognitive priming linked to the COVID-19 pandemic, through state anxiety and personal need for structure, on teachers' tendency toward sustainability and teachers' tendency toward a conservative socio-economic vision. We involved a sample of 984 Italian teachers, and by manipulating the saliency of the COVID-19 pandemic, we found that the saliency of the COVID-19 pandemic positively impacted state anxiety and that state anxiety impacted teachers' tendency toward sustainability both directly and indirectly through the mediational role of the personal need for structure. Finally, we found that state anxiety only indirectly through the personal need for structure impacted teachers' tendency toward a conservative socio-economic vision.

De Novo Mutation in KMT2C Manifesting as Kleefstra Syndrome 2: Case Report and Literature Review.

Diagnosis of pediatric intellectual disability (ID) can be difficult because it is due to a vast number of established and novel causes. Here, we described a full-term female infant affected by Kleefstra syndrome-2 presenting with neurodevelopmental disorder, a history of hypotonia and minor face anomalies. A systematic literature review was also performed. The patient was a 6-year-old Caucasian female. In the family history there was no intellectual disability or genetic conditions. Auxological parameters at birth were adequate for gestational age. Clinical evaluation at 6 months revealed hypotonia and, successively, delay in the acquisition of the stages of psychomotor development. Auditory, visual, somatosensory, and motor-evoked potentials were normal. A brain MRI, performed at 9 months, showed minimal gliotic changes in bilateral occipital periventricular white matter. Neuropsychiatric control, performed at 5 years, established a definitive diagnosis of childhood autism and developmental delay. Molecular analysis of the exome revealed a novel KMT2C missense variant: c.9244C > T (p.Pro3082Ser) at a heterozygous state, giving her a diagnosis of Kleefstra syndrome 2. Parents did not show the variant. Literature review (four retrieved eligible studies, 10 patients) showed that all individuals had mild, moderate, or severe ID; language and motor delay; and autism. Short stature, microcephaly, childhood hypotonia and plagiocephaly were also present. Conclusion. Kleefstra syndrome 2 is a difficult diagnosis of a rare condition with a high clinical phenotypic heterogeneity. This study suggests that it must be taken in account in the work-up of an orphan diagnosis of intellectual disability and/or autism spectrum disorder.

Clinical and Molecular Features of Patients with Gliomas Harboring IDH1 Non-canonical Mutations: A Systematic Review and Meta-Analysis.

INTRODUCTION: The canonical isocitrate dehydrogenase 1 R132 mutation (IDH1 R132) is the most frequent mutation among IDH-mutated gliomas. Non-canonical IDH1 mutations or IDH2 mutations are unusual and their clinical and biological role is still unclear. METHODS: We performed a systematic review and meta-analysis to assess the clinical role of IDH non-canonical mutations. RESULTS: Overall, we selected 13 of 3513 studies reporting data of 4007 patients with a diagnosis of grade 2 and grade 3 glioma including 3091 patients with a molecularly proven IDH1 or IDH2 mutation. Patients with non-canonical IDH1 mutations were younger and presented a higher DNA methylation level as compared to those with canonical IDH1 R132H alteration. The overall incidence of non-canonical IDH1 mutations was 7.9% (95% CI 5.4-10.7%) in patients with IDH-mutated gliomas. There was no statistical difference in terms of incidence between patients with grade 2 or grade 3 glioma. Patients with non-canonical IDH mutations had a lower rate of 1p19q codeletion (risk difference 31%, 95% CI 23-38%) and presented a significantly prolonged survival (pooled HR 0.47, 95% CI 0.28-0.81) as compared to those with IDH1 R132H mutation. CONCLUSION: Non-canonical IDH1 mutations occur in 7.9% of IDH-mutated gliomas and identify a specific subgroup of patients with an improved survival despite a lower rate of 1p19q codeletion. Data about the type of IDH mutation should be collected in clinical practice and within interventional trials as this could be a critical variable for improved stratification and selection of patients.

Two founder mutations in the SEC23B gene account for the relatively high frequency of CDA II in the Italian population.

Congenital Dyserythropoietic Anemia type II is an autosomal recessive disorder characterized by unique abnormalities in the differentiation of cells of the erythroid lineage. The vast majority of CDA II cases result from mutations in the SEC23B gene. To date, 53 different causative mutations have been reported in 86 unrelated cases (from the CDA II European Registry), 47 of them Italian. We have now identified SEC23B mutations in 23 additional patients, 17 Italians and 6 non-Italian Europeans. The relative allelic frequency of the mutations was then reassessed in a total of 64 Italian and 45 non-Italian unrelated patients. Two mutations, E109K and R14W, account for over one-half of the cases of CDA II in Italy. Whereas the relative frequency of E109K is similar in Italy and in the rest of Europe (and is also prevalent in Moroccan Jews), the relative frequency of R14W is significantly higher in Italy (26.3% vs. 10.7%). By haplotype analysis we demonstrated that both are founder mutations in the Italian population. By using the DMLE+ program our estimate for the age of the E109K mutation in Italian population is ≈2,200 years; whereas for the R14W mutation it is ≈3,000 years. We hypothesize that E109K may have originated in the Middle East and may have spread in the heyday of the Roman Empire. Instead, R14W may have originated in Southern Italy. The relatively high frequency of the R14W mutation may account for the known increased prevalence of CDA II in Italy.

The Role of Psychological Capital in Human Service Professionals' Work Experiences.

The study was set up as a first exploration of the predictive role of human service professionals' (i.e., teachers and healthcare professionals) psychological capital (PC) in their perception of work experiences and some core aspects of their own work, such as their efficacy to instill positive resources in their clients, the positive representation of their work and of the results that they can obtain, and positive beliefs about their career growth. Three hundred and eight Northern Italian human service professionals were involved, of which 163 were elementary school teachers of inclusive classrooms and 145 were healthcare professionals in day and residential centers. The regression analyses which were carried out-controlling for age, gender, years of work experience and the typology of the human service jobs-confirmed the predictive role of PC in the efficacy to instill positive resources in one's clients, the positive representation of the work and of the results that can be obtained, and positive beliefs about career growth. These results have important implications for practice, and they emphasize that specific interventions aimed at promoting human service professionals' PC may positively impact the effectiveness of their actions for the adaptation and psychosocial development of their clients.

Engineered CAR-T and novel CAR-based therapies to fight the immune evasion of glioblastoma: gutta cavat lapidem.

INTRODUCTION: The field of cancer immunotherapy has achieved great advancements through the application of genetically engineered T cells with chimeric antigen receptors (CAR), that have shown exciting success in eradicating hematologic malignancies and have proved to be safe with promising early signs of antitumoral activity in the treatment of glioblastoma (GBM). AREAS COVERED: We discuss the use of CAR T cells in GBM, focusing on limitations and obstacles to advancement, mostly related to toxicities, hostile tumor microenvironment, limited CAR T cells infiltration and persistence, target antigen loss/heterogeneity and inadequate trafficking. Furthermore, we introduce the refined strategies aimed at strengthening CAR T activity and offer insights in to novel immunotherapeutic approaches, such as the potential use of CAR NK or CAR M to optimize anti-tumor effects for GBM management. EXPERT OPINION: With the progressive wide use of CAR T cell therapy, significant challenges in treating solid tumors, including central nervous system (CNS) tumors, are emerging, highlighting early disease relapse and cancer cell resistance issues, owing to hostile immunosuppressive microenvironment and tumor antigen heterogeneity. In addition to CAR T cells, there is great interest in utilizing other types of CAR-based therapies, such as CAR natural killer (CAR NK) or CAR macrophages (CAR M) cells for CNS tumors.