AIM： To investigate if high-definition （HD） colonoscope with i-Scan gave a higher detection rate of mucosal le- sions vs standard white-light instruments. METHODS： Data were collected from the ...computer- ized database of the endoscopy unit of our tertiary referral center. We retrospectively analyzed 1101 con- secutive colonoscopies that were performed over 1 year with standard white-light （n = 849） or HD＋ with i-Scan （n = 252） instruments by four endoscopists, in an outpatient setting. Colonoscopy records included patients＇ main details and family history for colorectal cancer, indication for colonoscopy （screening, diagnos- tic or surveillance）, type of instrument used （standard white-light or HD＋ plus i-Scan）, name of endoscopist and bowel preparation. Records for each procedure included whether the cecum was reached or not and the reason for failure, complications during or imme- diately after the procedure, and number, size, location and characteristics of the lesions. Polyps or protruding lesions were defined as sessile or pedunculated, and nonprotruding lesions were defined according to Paris classification. For each lesion, histological diagnosis was recorded. RESULTS： Eight hundred and forty-nine colonosco- pies were carried with the standard white-light video colonoscope and 252 with the HD＋ plus i-Scan video colonoscope, The four endoscopists did 264, 300, 276 and 261 procedures, respectively; 21.6%, 24.0%, 21.7% and 24.1% of them with the HD＋ plus i-Scan technique. There were no significant differences be- tween the four endoscopists in either the number of procedures done or the proportions of each imaging technique used. Both techniques detected one or more mucosal lesions in 522/1101 procedures （47.4%）. The overall number of lesions recognized was 1266; 645 in the right colon and 621 in the left. A significantly higher number of colonoscopies recognized lesions in the HD＋ plus i-Scan mode （171/252 = 67.9%） than with the standard white-light technique （408/849 = 48.1%） （P 〈 0.0001）. HD＋ with i-Scan colonoscopies identified more lesions than standard white-light imag- ing （459/252 and 807/849, P 〈 0.0001）, in the right or left colon （mean ：1： SD, 1.62±1.36 vs 1.33±0.73, P 〈 0.003 and 1.55±0.98 vs 1.17±0.93, P = 0.033）, more lesions 〈 10 mm （P 〈 0.0001） or nonprotruding （P 〈 0.022）, and flat polyps （P = 0.04）. The cumulative mean number of lesions per procedure detected by the four endoscopists was significantly higher with HD＋ with i-Scan than with standard white-light imaging （1.82 ± 2.89 vs 0.95± 1.35, P 〈 0.0001）. CONCLUSION： HD imaging with i-Scan during the withdrawal phase of colonoscopy significantly increased the detection of colonic mucosal lesions, particularly small and nonprotruding polyps.
Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in approximately 5-7% of gastrointestinal stromal tumours (GIST). Over half of all PDGFRA mutations are represented by the ...substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V), recognized as D842V, conferring primary resistance to imatinib in vitro and in clinical observations due to the conformation of the kinase domain, which negatively affects imatinib binding. The lack of interaction between imatinib and the D842V PDGFRA mutated model has been established and widely confirmed in vivo. However, for the other PDGFRA mutations, the correlation between pre-clinical and clinical data is still unclear. An in silico evaluation of the p.His845_Asn848delinsPro mutation involving exon 18 of PDGFRA in a metastatic GIST patient responding to first-line imatinib has been provided. Docking analyses were performed, and the ligand-receptor interactions were evaluated with the jCE algorithm for structural alignment. The docking simulation and structural superimposition analysis show that PDGFRA p.His845_Asn848delinsPro stabilizes the imatinib binding site with the residues that are conserved in KIT. The in vivo evidence that PDGFRA p.His845_Asn848delinsPro is sensitive to imatinib was confirmed by the molecular modelling, which may represent a reliable tool for the prediction of clinical outcomes and treatment selection in GIST, especially for rare mutations.
Abstract BACKGROUND The high risk medulloblastoma remains a leading cause of cancer-related death in children. METHODS A total of 18 patients have been enrolled from February 2018 to May 2022.The ...median age was 7,5 years (range; 12 males and 6 female). The protocol predicted the first phase of induction with 4 cycles of chemotherapy. After induction patients with favorable histology without evidence of disease were enrolled to proton therapy (with concomitant vinorelbine biweekly). The maintenance phase with Lomustine repeated every 9 weeks and vinorelbine every 3 weeks for overall 12-18 months (PR). Conversely LC/A MB, were subjected to consolidation phase with high dose of chemotherapy with tiothepa followed by autologous HSC transplant and successive maintenance phase of 6 months. RESULTS At October 2023, the median follow up was 24 months. After the induction phase 14 patients showed CR, 2 PR, 1PD, 1SD. At subsequent re-evaluations two with PR, showed disease control, one CR and the other SD and the patient with PD showed CR. Patient with SD showed an unchanged state of the disease. During the reporting period two patient died for progression of the underlying disease. At 24 months from the start of treatment the PFS was 75,4 % (95% CI: 34.1% - 87.6%) and at 15 months the OS was 86,1% (95% CI: 68.1% - 99.2%). The principal expected side effects of chemotherapy were hematology toxicity and 58% rate of GH deficiency. Among the unexpected side effect was CMV retinopathy with complete blindness and leukoencephalopathy after high dose of thiotepa and proton irradiation. We reported only one case of ototoxicity. CONCLUSIONS The use of proton therapy combined with intensive chemotherapy and myeloablative chemotherapy only in selected cases and always before irradiation has proven feasible and effective in the treatment of high-risk patients medulloblastomas and other embryonic tumors.
About 20-40% of gastrointestinal stromal tumors (GISTs) lacking KIT/PDGFRA mutations show defects in succinate dehydrogenase (SDH) complex. This study uncovers the gene expression profile (GEP) of ...SDH-deficient GIST in order to identify new signaling pathways or molecular events actionable for a tailored therapy.
We analyzed 36 GIST tumor samples, either from formalin-fixed, paraffin-embedded by microarray or from fresh frozen tissue by RNA-seq, retrospectively collected among KIT-mutant and SDH-deficient GISTs. Pathway analysis was performed to highlight enriched and depleted transcriptional signatures. Tumor microenvironment and immune profile were also evaluated.
SDH-deficient GISTs showed a distinct GEP with respect to KIT-mutant GISTs. In particular, SDH-deficient GISTs were characterized by an increased expression of neural markers and by the activation of fibroblast growth factor receptor signaling and several biological pathways related to invasion and tumor progression. Among them, hypoxia and epithelial-to-mesenchymal transition emerged as features shared with SDH-deficient pheochromocytoma/paraganglioma. In addition, the study of immune landscape revealed the depletion of tumor microenvironment and inflammation gene signatures.
This study provides an update of GEP in SDH-deficient GISTs, highlighting differences and similarities compared to KIT-mutant GISTs and to other neoplasm carrying the SDH loss of function. Our findings add a piece of knowledge in SDH-deficient GISTs, shedding light on their putative histology and on the dysregulated biological processes as targets of new therapeutic strategies.
Background: Previous studies suggest that different metabotropic glutamate (mGlu) receptor subtypes are potential drug targets for treating absence epilepsy. However, no information is available on ...mGlu3 receptors. Objective: To examine whether (i) changes of mGlu3 receptor expression/signaling are found in the somatosensory cortex and thalamus of WAG/Rij rats developing spontaneous absence seizures; (ii) selective activation of mGlu3 receptors with LY2794193 affects the number and duration of spikewave discharges (SWDs) in WAG/Rij rats; and (iii) a genetic variant of GRM3 (encoding the mGlu3 receptor) is associated with absence epilepsy. Methods: Animals: immunoblot analysis of mGlu3 receptors, GAT-1, GLAST, and GLT-1; realtime PCR analysis of mGlu3 mRNA levels; assessment of mGlu3 receptor signaling; EEG analysis of SWDs; assessment of depressive-like behavior. Humans: search for GRM3 and GRM5 missense variants in 196 patients with absence epilepsy or other Idiopathic Generalized Epilepsy (IGE)/ Genetic Generalized Epilepsy (GGE) and 125,748 controls. Results: mGlu3 protein levels and mGlu3-mediated inhibition of cAMP formation were reduced in the thalamus and somatosensory cortex of pre-symptomatic (25-27 days old) and symptomatic (6-7 months old) WAG/Rij rats compared to age-matched controls. Treatment with LY2794193 (1 or 10 mg/kg, i.p.) reduced absence seizures and depressive-like behavior in WAG/Rij rats. LY2794193 also enhanced GAT1, GLAST, and GLT-1 protein levels in the thalamus and somatosensory cortex. GRM3 and GRM5 gene variants did not differ between epileptic patients and controls. Conclusion: We suggest that mGlu3 receptors modulate the activity of the cortico-thalamo-cortical circuit underlying SWDs and that selective mGlu3 receptor agonists are promising candidate drugs for absence epilepsy treatment.
OBJECTIVES
The purpose of this study was to evaluate two different techniques of stent placement in bifurcation lesions.
BACKGROUND
Although stent placement with dedicated techniques has been ...suggested to be a useful therapeutic modality for bifurcation lesions, limited information is available if stent placement on the side branch and on the parent branch provides any advantage over a simpler strategy of stenting the parent vessel and balloon angioplasty of the side branch.
METHODS
Between March 1993 and April 1999, we treated a total of 92 patients with bifurcation lesions with two strategies: stenting both vessels (group B, n = 53) or stenting the parent vessel and balloon angioplasty of the side branch (group P, n = 39). Paired angiograms were analyzed by quantitative angiography, and clinical follow-up was obtained.
RESULTS
Stent placement on both branches resulted in a lower residual stenosis (7.4 ± 10.9% vs. 23.4% ± 18.7%, p < 0.001) in the side branch. Acute procedural success was similar in the two groups (group B: 87% vs. Group P: 92%). In-hospital major adverse cardiac events (MACE) occurred only in group B (13% vs. 0%, p < 0.05). At the six-month follow-up, the angiographic restenosis rate (group B: 62% vs. Group P: 48%) and the target lesion revascularization rate (38% vs. 36%, respectively) were similar in the two groups. There was no difference in the incidence of six-month total MACE (51% vs. 38%).
CONCLUSIONS
For the treatment of true bifurcation lesions, a complex strategy of stenting both vessels provided no advantage in terms of procedural success and late outcome versus a simpler strategy of stenting only the parent vessel.
Previous studies suggest that different metabotropic glutamate (mGlu) receptor subtypes are potential drug targets for treating absence epilepsy. However, no information is available on mGlu3 ...receptors.
To examine whether (i) changes of mGlu3 receptor expression/signaling are found in the somatosensory cortex and thalamus of WAG/Rij rats developing spontaneous absence seizures; (ii) selective activation of mGlu3 receptors with LY2794193 affects the number and duration of spikewave discharges (SWDs) in WAG/Rij rats; and (iii) a genetic variant of GRM3 (encoding the mGlu3 receptor) is associated with absence epilepsy.
Animals: immunoblot analysis of mGlu3 receptors, GAT-1, GLAST, and GLT-1; realtime PCR analysis of mGlu3 mRNA levels; assessment of mGlu3 receptor signaling; EEG analysis of SWDs; assessment of depressive-like behavior. Humans: search for GRM3 and GRM5 missense variants in 196 patients with absence epilepsy or other Idiopathic Generalized Epilepsy (IGE)/ Genetic Generalized Epilepsy (GGE) and 125,748 controls.
mGlu3 protein levels and mGlu3-mediated inhibition of cAMP formation were reduced in the thalamus and somatosensory cortex of pre-symptomatic (25-27 days old) and symptomatic (6-7 months old) WAG/Rij rats compared to age-matched controls. Treatment with LY2794193 (1 or 10 mg/kg, i.p.) reduced absence seizures and depressive-like behavior in WAG/Rij rats. LY2794193 also enhanced GAT1, GLAST, and GLT-1 protein levels in the thalamus and somatosensory cortex. GRM3 and GRM5 gene variants did not differ between epileptic patients and controls.
We suggest that mGlu3 receptors modulate the activity of the cortico-thalamo-cortical circuit underlying SWDs and that selective mGlu3 receptor agonists are promising candidate drugs for absence epilepsy treatment.
Results from a collaborative exercise with proficiency testing conducted by 20 Italian laboratories on the 15 loci included in the Identifiler
® kit were analyzed by allele sharing methods and by ...standard population genetics tests. The validated database, including about 1500 subjects, was merged with that of a previous exercise conducted on nine loci, and the resulting allele frequencies, subdivided by Italian region, were published on-line.
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