Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials.

AIM: To conduct a meta-analysis of randomized clinical trials (RCTs) to investigate whether there is an association between glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and thyroid cancer. MATERIALS AND METHODS: In this meta-analysis of RCTs, we included studies comparing a GLP-1RA with any comparator, lasting at least 52 weeks, and reporting the incidence of adverse events independently of the principal endpoint and population. All cases of thyroid cancer were collected. RESULTS: We retrieved 64 trials, 26 of which reported at least one incident case of thyroid cancer. GLP-1RA treatment was associated with a significant increase in the risk of overall thyroid cancer (Mantel-Haenzel odds ratio [MH-OR] 1.52 [95% confidence interval {CI} 1.01, 2.29]; P = 0.04, I2 = 0%), with a fragility index of 1, and a 5-year number needed to harm of 1349. The association remained significant when including only trials lasting at least 104 weeks (MH-OR 1.76 [95% CI 1.00, 3.12]; P = 0.05). No significant association was found for papillary thyroid cancer (MH-OR 1.54 [95% CI 0.77, 3.06]; P = 0.22) or medullary thyroid cancer (MH-OR 1.44 [95% CI 0.23, 9.16]; P = 0.55). CONCLUSIONS: Our meta-analysis showed that GLP-1RA treatment could be associated with a moderate increase in relative risk for thyroid cancer in clinical trials, with a small increase in absolute risk. Studies of longer duration are required to assess the clinical implications of this finding.

Effects of glucose-lowering agents on cardiovascular and renal outcomes in subjects with type 2 diabetes: An updated meta-analysis of randomized controlled trials with external adjudication of events.

AIMS: To investigate the effects of glucose-lowering agents on all-cause mortality, and cardiovascular and renal outcomes in adults with type 2 diabetes. METHODS: A MEDLINE and EMBASE search was performed to identify randomized controlled trials, published up to 28 February 2022, with a follow-up ≥52 weeks, in which glucose-lowering drugs were compared with either placebo or active comparators. We included only trials reporting formal external adjudication of events. All-cause mortality, 3-point MACE (major cardiovascular events), and hospitalization for heart failure (HHF) were considered as principal outcomes. Doubling of serum creatinine, worsening albuminuria, and renal death were considered as secondary endpoints. RESULTS: We included randomized controlled trials performed on metformin (n = 17), pioglitazone (n = 20), alpha-glucosidase inhibitors (n = 9), insulin secretagogues (n = 42), dipeptidyl-peptidase-4 inhibitors (n = 67), glucagon-like peptide-1 receptor agonists (n = 45) or sodium-glucose co-transporter-2 inhibitors (SGLT-2i; n = 42) and insulin (n = 18). Glucagon-like peptide-1 receptor agonist and SGLT-2i were associated with a significant reduction in all-cause mortality [Mantel-Haenszel odds ratio (MH-OR), 95% confidence interval: 0.88 (0.83; 0.95) and 0.85 (0.79; 0.91), respectively] and MACE [MH-OR, 95% confidence interval: 0.89 (0.84; 0.94) and 0.90 (0.84; 0.96), respectively]. SGLT-2i was associated with a reduced risk of HHF [MH-OR 0.68 (0.62; 0.75)], worsening albuminuria [MH-OR 0.67 (0.55; 0.80)] and doubling of serum creatinine [MH-OR 0.58 (0.44; 0.79)]. Metformin and pioglitazone were associated with a significantly lower risk of MACE [MH-OR 0.60 (0.47; 0.80) and 0.85 (0.74; 0.97), respectively] and pioglitazone with a higher risk of HHF [MH-OR 1.30 (1.04; 1.62)]. Insulin secretagogues were associated with increased risk of all-cause mortality [MH-OR 1.12 (1.01; 1.24)] and MACE [MH-OR 1.19 (1.02; 1.39)]. CONCLUSIONS: The results of this updated meta-analysis need to be considered in the choice of drug treatment for type 2 diabetes mellitus, which cannot be merely based on the effect of glucose-lowering drugs on long-term glycaemic control.

Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy.

Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare 'outlier' clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy.

High-resolution structural genomics reveals new therapeutic vulnerabilities in glioblastoma.

We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating sub-5-kb resolution 3D genome maps by in situ Hi-C. Contact maps at sub-5-kb resolution allow identification of individual DNA loops, domain organization, and large-scale genome compartmentalization. We observed differences in looping architectures among GSCs from different patients, suggesting that 3D genome architecture is a further layer of inter-patient heterogeneity for glioblastoma. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including the convergence of multiple super enhancers to individual stemness genes within individual cells. We show that the number of loops contacting a gene correlates with elevated transcription. These results indicate that stemness genes are hubs of interaction between multiple regulatory regions, likely to ensure their sustained expression. Regions of open chromatin common among the GSCs tested were poised for expression of immune-related genes, including CD276 We demonstrate that this gene is co-expressed with stemness genes in GSCs and that CD276 can be targeted with an antibody-drug conjugate to eliminate self-renewing cells. Our results demonstrate that integrated structural genomics data sets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.

Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data.

BACKGROUND: Juvenile Pilocytic Astrocytomas (JPAs) are one of the most common pediatric brain tumors, and they are driven by aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway. RAF-fusions are the most common genetic alterations identified in JPAs, with the prototypical KIAA1549-BRAF fusion leading to loss of BRAF's auto-inhibitory domain and subsequent constitutive kinase activation. JPAs are highly vascular and show pervasive immune infiltration, which can lead to low tumor cell purity in clinical samples. This can result in gene fusions that are difficult to detect with conventional omics approaches including RNA-Seq. METHODS: To this effect, we applied RNA-Seq as well as linked-read whole-genome sequencing and in situ Hi-C as new approaches to detect and characterize low-frequency gene fusions at the genomic, transcriptomic and spatial level. RESULTS: Integration of these datasets allowed the identification and detailed characterization of two novel BRAF fusion partners, PTPRZ1 and TOP2B, in addition to the canonical fusion with partner KIAA1549. Additionally, our Hi-C datasets enabled investigations of 3D genome architecture in JPAs which showed a high level of correlation in 3D compartment annotations between JPAs compared to other pediatric tumors, and high similarity to normal adult astrocytes. We detected interactions between BRAF and its fusion partners exclusively in tumor samples containing BRAF fusions. CONCLUSIONS: We demonstrate the power of integrating multi-omic datasets to identify low frequency fusions and characterize the JPA genome at high resolution. We suggest that linked-reads and Hi-C could be used in clinic for the detection and characterization of JPAs.

Effects of insulin on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin with this respect. DATA SYNTHESIS: A MEDLINE database search was performed to identify all RCTs, up to June 1st, 2021, with duration≥52 weeks, in which insulin was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Six RCTs (enrolling 8091 patients and 10,139 in the insulin and control group, respectively) were included in the analysis for MACEs and HF, and 18 in that for all-cause mortality (9760 and 11,694 patients in the insulin and control group, respectively). Treatment with insulin neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 1.09, 95% CI 0.97-1.23; 0.99, 95% CI 0.91, 1.08; and 0.90, 95% CI 0.78, 1.04, respectively). CONCLUSIONS: This meta-analysis showed no significant effects of insulin on incident MACE, all-cause mortality, and HHF.

All-cause mortality and cardiovascular events in patients with type 2 diabetes treated with alpha-glucosidase inhibitors: A meta-analysis of randomized controlled trials.

AIM: Alpha-glucosidase inhibitors are approved drugs for treating type 2 diabetes (T2DM); however, their effects on mortality and cardiovascular safety are unclear. This meta-analysis was aimed at evaluating the effects of alpha-glucosidase inhibitors on all-cause mortality and major cardiovascular events (MACE). DATA SYNTHESIS: A Medline, Embase, Cochrane database searching for alpha-glucosidase inhibitors was performed up to July 1st, 2021. All randomized controlled trials (RCT) with a duration ≥52 weeks and comparing the effects of alpha-glucosidase inhibitors with placebo or active drugs were collected. Further inclusion criteria were: RCT reporting MACE within their primary outcome, or as pre-defined secondary outcome; and RCT enrolling at least 100 patients with T2DM. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence intervals were calculated for the aforementioned outcomes. A total of eight RCTs, enrolling 1124 and 908 patients on alpha-glucosidase inhibitors and comparators, respectively, were identified. No trials reported information on MACE. Treatment with alpha-glucosidase inhibitors was not associated with a significant increase of all-cause mortality compared with other therapies or no therapy/placebo (MH-OR 0.76 [0.28; 2.05]). CONCLUSIONS: The evidence of beneficial or detrimental effects of alpha-glucosidase inhibitors on all-cause mortality and cardiovascular events is not sufficient to draw any conclusions.

Effects of pioglitazone on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. After identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, the experts decided to perform a systematic review and meta-analysis on the effect of pioglitazone with this respect. DATA SYNTHESIS: A MEDLINE database search was performed to identify RCTs, up to June 1st, 2021, with duration≥52 weeks, in which pioglitazone was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Eight RCTs were included in the analysis for MACEs and HF (5048 and 5117 patients in the pioglitazone and control group, respectively), and 24 in that for all-cause mortality (10,682 and 9674 patients). Pioglitazone neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 0.90, 95% CI 0.78-1.03, 0.91, 95% CI 0.77, 1.09, and 1.16, 95% CI 0.73, 1.83, respectively). Pioglitazone was associated with a significant reduction of MACE in patients with prior cardiovascular events (MH-OR 0.84, 95% CI 0.72-0.99). CONCLUSIONS: This meta-analysis showed no significant effects of pioglitazone on incident MACE, all-cause mortality, and HHF.

Self-management in patients with type 2 diabetes: Group-based versus individual education. A systematic review with meta-analysis of randomized trails.

AIM: Patient education is an essential component of the treatment of type 2 diabetes mellitus (T2DM). The present meta-analysis was aimed at verifying the efficacy of group-based versus individual education for self-management in patients with T2DM. DATA SYNTHESIS: A Medline and Embase search up to January 1st, 2021, was performed, including Randomized Controlled Trials (RCT) with duration>6 months, enrolling patients with T2DM and comparing individual-based with group-based educational programs. The primary outcome was endpoint HbA1c; secondary endpoints were lipid profile, body weight, blood pressure, patients' adherence/knowledge, and quality of life. The weighed difference in means (WMD) and Mantel-Haenzel Odds Ratio (MH-OR), with 95% Confidence Interval (CI), were calculated. We retrieved 14 RCT. No significant between-group difference in HbA1c (WMD -0.39[-0.89; 0.09] mmol/mol, p = 0.11) was observed. At metaregression analyses, longer trial duration, higher baseline mean age and duration of diabetes, and lower baseline HbA1c were correlated with greater efficacy of group-based programs in reducing HbA1c. When analyzed separately, trials excluding insulin-treated patients showed a significant reduction of HbA1c in favor of group education. CONCLUSIONS: In patients with T2DM, group education has similar efficacy as individual education on glucose control. Group programs are associated with an improved quality of life and patients' knowledge. PROSPERO AND OSF REGISTRATION: ID243149.

Clinical profiles and quality of care of subjects with type 2 diabetes according to their cardiovascular risk: an observational, retrospective study.

BACKGROUND: The European Society of Cardiology (ESC) recently defined cardiovascular risk classes for subjects with diabetes. Aim of this study was to explore the distribution of subjects with type 2 diabetes (T2D) by cardiovascular risk groups according to the ESC classification and to describe the quality indicators of care, with particular regard to cardiovascular risk factors. METHODS: The study is based on data extracted from electronic medical records of patients treated at the 258 Italian diabetes centers participating in the AMD Annals initiative. Patients with T2D were stratified by cardiovascular risk. General descriptive indicators, measures of intermediate outcomes, intensity/appropriateness of pharmacological treatment for diabetes and cardiovascular risk factors, presence of other complications and overall quality of care were evaluated. RESULTS: Overall, 473,740 subjects with type 2 diabetes (78.5% at very high cardiovascular risk, 20.9% at high risk and 0.6% at moderate risk) were evaluated. Among people with T2D at very high risk: 26.4% had retinopathy, 39.5% had albuminuria, 18.7% had a previous major cardiovascular event, 39.0% had organ damage, 89.1% had three or more risk factors. The use of DPP4-i markedly increased as cardiovascular risk increased. The prescription of secretagogues also increased and that of GLP1-RAs tended to increase. The use of SGLT2-i was still limited, and only slightly higher in subjects with very high cardiovascular risk. The overall quality of care, as summarized by the Q score, tended to be lower as the level of cardiovascular risk increased. CONCLUSIONS: A large proportion of subjects with T2D is at high or very high risk. Glucose-lowering drug therapies seem not to be adequately used with respect to their potential advantages in terms of cardiovascular risk reduction. Several actions are necessary to improve the quality of care.

From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell?

Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host's metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host's immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.

Expected and paradoxical effects of obesity on cancer treatment response.

Obesity, whose prevalence is pandemic and continuing to increase, is a major preventable and modifiable risk factor for diabetes and cardiovascular diseases, as well as for cancer. Furthermore, epidemiological studies have shown that obesity is a negative independent prognostic factor for several oncological outcomes, including overall and cancer-specific survival, for several site-specific cancers as well as for all cancers combined. Yet, a recently growing body of evidence suggests that sometimes overweight and obesity may associate with better outcomes, and that immunotherapy may show improved response among obese patients compared with patients with a normal weight. The so-called 'obesity paradox' has been reported in several advanced cancer as well as in other diseases, albeit the mechanisms behind this unexpected relationship are still not clear. Aim of this review is to explore the expected as well as the paradoxical relationship between obesity and cancer prognosis, with a particular emphasis on the effects of cancer therapies in obese people.

Nutritional status and follicular-derived thyroid cancer: An update.

The incidence of differentiated thyroid cancer has been increasing in the last decades all over the world. Such a steady growth cannot be entirely attributable to more intensive thyroid nodule screening and more sensitive diagnostic procedures. Several environmental factors have changed with sufficient rapidity in the same time frame and may represent credible candidates for this increase. They include modified iodine intake, lifestyle-associated risk factors, exposure to various toxic compounds, pollutants and xenobiotics, nutritional deficiencies, eating habits and comorbidities. Foremost, nutritional patterns have gained high interest as possible promoters and modifiable risk factors for thyroid cancer in recent years. The aim of this narrative review is to focus on the relationship between thyroid cancer and nutritional factors, dietary habits and obesity. Low iodine intake has been associated to increased risk of thyroid cancer, favoring the development of more aggressive histotypes. Moreover, correction of iodine deficiency can shift thyroid cancer subtypes toward less aggressive forms, without affecting the overall risk for cancer. Actually, evidence regarding the association between selenium and vitamin D deficiency and thyroid cancer is very limited, despite their well-known anti-cancer potentials, and the clinical usefulness of their supplementation is still uncertain in this setting. Albeit the relationship between single foods and thyroid cancer is difficult to examine, fish and iodine-rich foods, vegetables, and fruits might exert protective effects on thyroid cancer risk. Conversely, no clear association has been found for other foods to date. Lastly, a clear association between obesity and the risk of thyroid cancer, with more aggressive behavior, seems to emerge from most studies, likely involving variations in thyroid function and chronic inflammation mediated by cytokines, insulin, leptin and adiponectins. Although no definite association between dietary factors and thyroid cancer has been firmly established so far, some nutritional patterns, together with excessive weight, seem to play a relevant role in thyroid cancer carcinogenesis as well as in its severity and aggressiveness. These effects may play an additive role to the well-established one exerted by environmental carcinogens, such as pollutants and radiation exposure.

Dysregulation of chromatin organization in pediatric and adult brain tumors: oncoepigenomic contributions to tumorigenesis and cancer stem cell properties.

The three-dimensional (3D) organization of the genome is a crucial enabler of cell fate, identity, and function. In this review, we will focus on the emerging role of altered 3D genome organization in the etiology of disease, with a special emphasis on brain cancers. We discuss how different genetic alterations can converge to disrupt the epigenome in childhood and adult brain tumors, by causing aberrant DNA methylation and by affecting the amounts and genomic distribution of histone post-translational modifications. We also highlight examples that illustrate how epigenomic alterations have the potential to affect 3D genome architecture in brain tumors. Finally, we will propose the concept of "epigenomic erosion" to explain the transition from stem-like cells to differentiated cells in hierarchically organized brain cancers.

Cardiovascular events and all-cause mortality in patients with type 2 diabetes treated with dipeptidyl peptidase-4 inhibitors: An extensive meta-analysis of randomized controlled trials.

AIMS: Meta-analyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on major cardiovascular events (MACE), mortality, and heart failure. Aim of this meta-analysis of randomized trials is the assessment of the cardiovascular safety of DPP4i. DATA SYNTHESIS: A Medline, Embase, Cochrane database search for sitagliptin, vildagliptin, omarigliptin, saxagliptin, alogliptin, trelagliptin, anagliptin, linagliptin, gemigliptin, evogliptin, and teneligliptin was performed up to up January 1st, 2020. All trials with a duration ≥24 weeks and comparing the effects of DPP4i with placebo or active drugs were collected. Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. A total of 182 eligible trials were identified. DPP-4i were not associated with an increased risk of MACE (MH-OR 0.99 [0.93, 1.04]), all-cause mortality (MH-OR 0.99 [0.93, 1.06]), and heart failure (MH-OR 1.05 [0.96, 1.15]) with no significant differences across individual molecules, except for saxagliptin, which was associated with an increased risk of heart failure. CONCLUSIONS: As a class, DPP4i are not associated with any increase or reduction of MACE, all-cause mortality, and heart failure. Saxagliptin seems to be associated with an increased risk of hospitalization for heart failure.

Pituitary metastases from neuroendocrine neoplasms: case report and narrative review.

PURPOSE: Pituitary metastases (PM) are uncommon findings and are mainly derived from breast and lung cancers. No extensive review of PM from neuroendocrine neoplasms (NENs) is on record. Here we describe a clinical case of PM from pancreatic NEN and review the clinical features of PM from NENs reported in the literature. METHODS: A case of PM from a pancreatic NEN followed at our institution is described. We also reviewed the 43 cases of PM from NENs reported in the literature. RESULTS: A 59-year old female patient, previously submitted to duodeno-cephalo-pancreasectomy for a well-differentiated pancreatic NEN, with known hepatic metastases, underwent a 68 Ga-DOTATOC PET/CT that revealed an uptake in the pituitary gland. A subsequent MRI displayed a pituitary lesion, with suprasellar extension. After a hormonal and genetic diagnostic workup that excluded the diagnosis of MEN 1, the worsening of headache and visual impairment and the growth of the lesion lead to its surgical removal. A pituitary localization of the pancreatic NEN was identified. Regarding the published cases of PM from NENs, the most common tumour type was small cell lung cancer (SCLC), accounting for nearly half of the cases, followed by bronchial and pancreatic well differentiated NENs. The most frequent symptom was a variable degree of visual impairment, while headache was reported in half of the cases. Partial or total anterior hypopituitarism was present in approximately three quarters of the cases, while diabetes insipidus was less common. The most frequent treatment for PM was surgical resection, followed by radiotherapy and chemotherapy. The clinical outcome was in line with previous reports of PM from solid tumours, with a median survival of 14 months. Surgery of PM was associated with prolonged survival. CONCLUSIONS: PM from NENs have clinical features similar to metastases derived from other solid tumours, albeit the involvement of the anterior pituitary seems more frequent; a thorough pituitary hormonal evaluation is mandatory, after focused radiological studies, particularly if a surgical approach is considered. The optimal management of PM remains disputed and seems mainly driven by the aggressiveness of the primary tumour and the presence of symptoms. In well-differentiated NENs, particularly in the case of symptomatic PM, surgical removal may be a reasonable approach.

Analytical evaluation of direct bicarbonate measurement with the new gem premier chemstat in hemodialysis patients.

GEM Premier ChemSTAT is a whole-blood analyzer designed for providing a rapid basic metabolic panel, inclusive of creatinine and blood urea nitrogen, with the unique characteristic of providing measured bicarbonate (HCO3-) levels. The aim of this work was to evaluate the clinical performance of HCO3- assessment with this analyser in a real-life hemodialysis setting. Imprecision was calculated at different HCO3- levels, along with assay comparison with Gem Premier 4000 analysers. GEM Premier ChemSTAT displayed an imprecision and a bias (in comparison to GEM Premier 4000) for HCO3- of 0.4% and 37.3% at 20.8 mmol/L, 1.2% and 25.6% at 16.4 mmol/L, and 2.1% and 11.6% at 11.5 mmol/L, respectively, using three levels of HCO3- quality control sample ChemSTAT System Evaluator. At direct comparison with the GEM Premier 4000 in the hemodialysis setting, Bland-Altman analysis of HCO3- levels evidenced a bias (µ) of -4.9 (95% CI, -5.2 to -4.7) mmol/L. Such difference was attenuated by recalculating the GEM ChemSTAT expected HCO3- values from pH and pCO2 using the Henderson Hasselbach equation, µ=-0.07 (95%CI, -0.19 to 0.05) mmol/L (p = .24). In conclusion, our results show a remarkable difference between the HCO3- values reported by GEM ChemSTAT or GEM 4000. New reference values for GEM ChemSTAT HCO3- shall hence be defined according to our findings. We suggest that further investigation and a re-evaluation of the reference range should be made before extending the clinical use of this device.

Ancestry and frequency of genetic variants in the general population are confounders in the characterization of germline variants linked to cancer.

BACKGROUND: Pediatric high-grade gliomas (pHGGs) are incurable malignant brain cancers. Clear somatic genetic drivers are difficult to identify in the majority of cases. We hypothesized that this may be due to the existence of germline variants that influence tumor etiology and/or progression and are filtered out using traditional pipelines for somatic mutation calling. METHODS: In this study, we analyzed whole-genome sequencing (WGS) datasets of matched germlines and tumor tissues to identify recurrent germline variants in pHGG patients. RESULTS: We identified two structural variants that were highly recurrent in a discovery cohort of 8 pHGG patients. One was a ~ 40 kb deletion immediately upstream of the NEGR1 locus and predicted to remove the promoter region of this gene. This copy number variant (CNV) was present in all patients in our discovery cohort (n = 8) and in 86.3% of patients in our validation cohort (n = 73 cases). We also identified a second recurrent deletion 55.7 kb in size affecting the BTNL3 and BTNL8 loci. This BTNL3-8 deletion was observed in 62.5% patients in our discovery cohort, and in 17.8% of the patients in the validation cohort. Our single-cell RNA sequencing (scRNA-seq) data showed that both deletions result in disruption of transcription of the affected genes. However, analysis of genomic information from multiple non-cancer cohorts showed that both the NEGR1 promoter deletion and the BTNL3-8 deletion were CNVs occurring at high frequencies in the general population. Intriguingly, the upstream NEGR1 CNV deletion was homozygous in ~ 40% of individuals in the non-cancer population. This finding was immediately relevant because the affected genes have important physiological functions, and our analyses showed that NEGR1 expression levels have prognostic value for pHGG patient survival. We also found that these deletions occurred at different frequencies among different ethnic groups. CONCLUSIONS: Our study highlights the need to integrate cancer genomic analyses and genomic data from large control populations. Failure to do so may lead to spurious association of genes with cancer etiology. Importantly, our results showcase the need for careful evaluation of differences in the frequency of genetic variants among different ethnic groups.

The management of neuroendocrine tumours: A nutritional viewpoint.

Nutritional status in patients with neuroendocrine tumours (NETs), especially of gastroenteropancreatic origin, can be deeply affected by excessive production of gastrointestinal hormones, peptides, and amines, which can lead to malabsorption, diarrhoea, steatorrhea, and altered gastrointestinal motility. Besides, the surgical and/or medical management of NETs can lead to alteration of gastrointestinal secretory, motor, and absorptive functions, with both dietary and nutritional consequences. Indeed, disease-related malnutrition is a frequently encountered yet both underrecognized and understudied clinical phenomenon in patients with NETs, with substantial prognostic and socioeconomic consequences. Most of these conditions can be alleviated by a tailored nutritional approach, also with the aim of improving the efficacy of cancer treatments. In this setting, skilled nutritionists can play a fundamental role in the multidisciplinary health care team in NETs management and their presence should be recommended. The aim of this review is to provide dietary advices for each specific condition in patients with NETs, underlining the importance of a nutritional approach to treat malnutrition in this setting. Further, we will provide preliminary evidence coming from our data on the assessment of nutritional status in a single cohort of patients with NETs.