Role of brain 2-[18F]fluoro-2-deoxy-D-glucose-positron-emission tomography as survival predictor in amyotrophic lateral sclerosis.

PURPOSE: The identification of prognostic tools in amyotrophic lateral sclerosis (ALS) would improve the design of clinical trials, the management of patients, and life planning. We aimed to evaluate the accuracy of brain 2-[18F]fluoro-2-deoxy-D-glucose-positron-emission tomography (2-[18F]FDG-PET) as an independent predictor of survival in ALS. METHODS: A prospective cohort study enrolled 418 ALS patients, who underwent brain 2-[18F]FDG-PET at diagnosis and whose survival time was available. We discretized the survival time in a finite number of classes in a data-driven fashion by employing a k-means-like strategy. We identified "hot brain regions" with maximal power in discriminating survival classes, by evaluating the Laplacian scores in a class-aware fashion. We retained the top-m features for each class to train the classification systems (i.e., a support vector machine, SVM), using 10% of the ALS cohort as test set. RESULTS: Data were discretized in three survival profiles: 0-2 years, 2-5 years, and > 5 years. SVM resulted in an error rate < 20% for two out of three classes separately. As for class one, the discriminant clusters included left caudate body and anterior cingulate cortex. The most discriminant regions were bilateral cerebellar pyramid in class two, and right cerebellar dentate nucleus, and left cerebellar nodule in class three. CONCLUSION: Brain 2-[18F]FDG-PET along with artificial intelligence was able to predict with high accuracy the survival time range in our ALS cohort. Healthcare professionals can benefit from this prognostic tool for planning patients' management and follow-up. 2-[18F]FDG-PET represents a promising biomarker for individual patients' stratification in clinical trials. The lack of a multicentre external validation of the model warrants further studies to evaluate its generalization capability.

Biliary Atresia in an Infant Presenting With Kabuki Syndrome: An Autopsy Report and Review of the Literature.

Biliary atresia (BA) is an inflammatory obliterative cholangiopathy which is very common during neonatal and infancy period. We present an autopsy report of a BA in an infant suffering from a genetic syndrome.

Placental diabesity: placental VEGF and CD31 expression according to pregestational BMI and gestational weight gain in women with gestational diabetes.

PURPOSE: The aim of this study is to investigate the placental expression of VEGF and CD31 in pregnancies complicated by gestational diabetes (GDM) and the influence of pregestational BMI and gestational weight gain (GWG) on this expression. METHODS: We prospectively enrolled pregnant women with diagnosis of GDM and healthy controls who delivered in our Center between December 2016 and May 2017. Patients were grouped according to the presence of GDM and we compared pregnancy characteristics, placental VEGF and CD31 expression between the cases and controls. Immunochemistry analysis was performed to assess biomarkers positivity. Positivity of biomarkers was assessed in a dichotomic fashion with positivity set at 5% for VEGF and 1% for CD31. RESULTS: 39 patients matched inclusion criteria, 29 (74.3%) women with GDM and 10 (25.7%) healthy controls. Immunochemistry analysis showed that VEGF was more expressed in placentas from women with GDM compared to controls (21/29, 72.4% vs 2/10, 20%; p = 0.007), and CD31 was more expressed in placentas from women with GDM compared to controls (6/29, 20.7% vs 0/10, 0%; risk difference 0.2). VEGF positivity was associated with the presence of GDM (aOR 22.02, 95% CI 1.13-428.08, p = 0.04), pregestational BMI (aOR 1.53, 1.00-2.34, p = 0.05) and GWG (aOR 1.47, 95% CI 1.03-2.11, p = 0.03). CD31 positivity was associated with the pregestational BMI (aOR 1.47, 95% CI 1.00-2.17, p = 0.05) and with the gestational weight gain (aOR 1.32, 95% CI 1.01-1.72, p = 0.04). CONCLUSION: Pregnancies complicated by GDM are characterized by increased placental expression of VEGF and CD31, and the expression of these markers is also independently associated to maternal increased pregestational BMI and GWG, defining the concept of "placental diabesity".

Amyotrophic lateral sclerosis with SOD1 mutations shows distinct brain metabolic changes.

PURPOSE: Neuropathological data suggest that ALS with SOD1 mutations (SOD1-ALS) is a distinct form of ALS. We evaluated brain metabolic changes characterizing SOD1-ALS as compared to sporadic ALS (sALS), employing 18fluorodeoxyglucose-positron-emission tomography (18F-FDG-PET). METHODS: We included 18 SOD1-ALS patients, 40 healthy controls (HC), and 46 sALS patients without mutations in SOD1, TARDBP, FUS, and C9ORF72, randomly selected from 665 subjects who underwent brain 18F-FDG-PET at diagnosis between 2008 and 2019 at the ALS Centre of Turin. We excluded patients with frontotemporal dementia. We used the full factorial design in SPM12 to evaluate whether differences among groups exist overall. In case the hypothesis was confirmed, group comparisons were performed through the two-sample t-test model of SPM12. In all the analyses, the height threshold was P < 0.001 (P < 0.05 FWE-corrected at cluster level). RESULTS: The full factorial design resulted in a significant main effect of groups. We identified a relative hypometabolism in sALS patients compared to SOD1-ALS cases in the right precentral and medial frontal gyrus, right paracentral lobule, and bilateral postcentral gyrus. SOD1 patients showed a relative hypermetabolism as compared to HC in the right precentral gyrus and paracentral lobule. As compared to HC, sALS patients showed relative hypometabolism in frontal, temporal, and occipital cortices. CONCLUSION: SOD1-ALS was characterized by a relative hypermetabolism in the motor cortex as compared to sALS and HC. Since promising, targeted, therapeutic strategies are upcoming for SOD1-ALS, our data support the use of PET to study disease pathogenesis and to track its course in clinical trials, in both asymptomatic and symptomatic mutation carriers.

SARS-CoV-2 viral load and replication in postmortem examinations.

We examined 29 autopsy cases (investigated between October 2020 and February 2021) whose postmortem swabs tested positive for SARS-CoV-2. Twenty-two of 29 cases died while hospitalized (H), while the remaining 7 cases were not hospitalized (NH). Since we included only cases in which the time since death was known (excluding unwitnessed NH deaths), the interval between death and postmortem swab(s) was registered, with a mean NH value of 5.50 days and a mean H value of 3.98 days. The mean age of NH was 65 years, while H were older (mean age: 73 years). Twenty-eight nasopharyngeal and 27 lungs postmortem swabs were obtained and real-time reverse transcriptase‒polymerase chain reaction assay for total and replicative SARS-CoV-2 RNA and mRNA detection was performed. Although the mean death-postmortem swabs interval was higher in NH than in H, the mean viral load of NH was higher than that of H (2.53 × 1011 copies/mL vs 9.31 × 108 copies/mL). In 13/29 cases (6 NH and 7 H), indicators of active replication were found. The relationship between the presence of replicative mRNA and death without hospitalization and that between the minimum cycle threshold value of SARS-CoV-2 RNA and the cycle threshold value of replicative SARS-CoV-2 mRNA were found to be statistically significant (with respective P values of 0.013 and 0.000). Therefore, especially in NH, full compliance with guidelines on biological safety in the autopsy room is essential, and no autopsy can be performed on infected cases in a structure that does not meet the established safety criteria.

The role of retinal imaging in the management of abusive head trauma cases.

BACKGROUND: As retinal hemorrhage (RH) is the most frequent and reliable finding of abusive head trauma (AHT), an ophthalmology consultation should be systematically required in suspected cases. Full retinal examination through pharmacologically dilated pupil can detect the type and pattern of RHs, helping to distinguish abusive from non-abusive head trauma. METHODS: We performed a retrospective analysis of a case series of 6 infants (aged 0.6-10 months) with AHT who were admitted to the Emergency Department of Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome with severe intracranial hemorrhages. Children underwent full multidisciplinary assessment including dilated fundus examination, optical coherence tomography (OCT) and digital wide-field fundus photography (DWFFP - in our case RetCam). In our paper we report the clinical presentation, the ocular findings and outcome at discharge. RESULTS: The mean age at the hospital admission was 6.28 months. In all infants, intracranial hemorrhages were found. Preretinal and intraretinal hemorrhages were detected, collecting good-quality retinal images. CONCLUSIONS: Imaging of retinal hemorrhages represents a fundamental moment of AHT diagnosis and documentation. Although RetCam is the gold standard for the acquisition of retinal images in suspected cases, OCT is extremely valuable in forensic evaluation since it can detect even small macular hemorrhages. Therefore, the combination of RetCam and OCT imaging can give relevant hints for the diagnosis of AHT, allowing to evaluate the extent, spread and morphology of RHs.

Postmortem CT pulmonary findings in SARS-CoV-2-positive cases: correlation with lung histopathological findings and autopsy results.

INTRODUCTION/PURPOSE: Postmortem computed tomography (PMCT) is a valuable tool for analyzing the death of patients with SARS-CoV-2 infection. The purpose of this study was to investigate the correlation between PMCT lung findings in autopsy cadavers positive for SARS-CoV-2 infection and the severity of COVID-19 lung disease by histopathological analysis. MATERIALS AND METHODS: We reviewed chest PMCT findings, paying particular attention to the lung parenchyma, in 8 autopsy cases positive for SARS-CoV-2. Correlations between chest PMCT and histopathological findings were assessed. Clinical conditions and comorbidities were also recorded and discussed. The primary cause of death was finally considered. RESULTS: In 6/8 cases, pulmonary PMCT findings were massive consolidation (4/8) and bilateral diffuse mixed densities with a crazy-paving pattern (2/8). These cases showed severe pulmonary signs of COVID-19 at histopathological analysis. In the remaining 2/8 cases, pulmonary PMCT findings were scant antideclive ground-glass opacities in prevalent gradient densities attributed to hypostasis. In 4/8 cases with massive consolidations, important comorbidities were noted. In 6/8 cases with severe pulmonary histopathological signs of lung COVID-19, autopsy found that the cause of death was cardiorespiratory failure. In the remaining 2/8 cases, histopathological analysis revealed lung alterations due to edema and some signs of SARS-CoV-2 infection; the cause of death was not attributed to SARS-CoV-2 infection (Table 1). DISCUSSION AND CONCLUSION: Chest PMCT findings correlate with the severity of COVID-19 lung disease at histopathology examination. According to our results, there may also be a relationship between cause of death and PMCT findings in COVID-19, which must be critically analyzed considering clinical antemortem data.

Eosinophilic Infiltration of the Sino-Atrial Node in Sudden Cardiac Death Caused by Long QT Syndrome.

Sudden death is defined as the unexpected death of a healthy person that occurs within the first hour of the onset of symptoms or within 24 h of the victim being last seen alive. In some of these cases, rare deleterious variants of genes associated with inherited cardiac disorders can provide a highly probable explanation for the fatal event. We report the case of a 21-year-old obese woman who lost consciousness suddenly in a public place and was pronounced dead after hospital admission. Clinical autopsy showed an inconclusive gross examination, while in the histopathological analysis an eosinophilic inflammatory focus and interstitial fibrosis in the sino-atrial node were found. Molecular autopsy revealed an intronic variant in the KCNQ1 gene (c.683 + 5G > A), classified as likely pathogenic for long QT syndrome according to the guidelines provided by the American College of Medical Genetics and Genomics. Therefore, there were many anomalies that could have played a role in the causation of the sudden death, such as the extreme obesity, the cardiac anomalies and the KNCQ1 variant. This case depicts the difficult interpretation of rare cardiac structural abnormalities in subjects carrying rare variants responsible for inherited arrhythmic disorders and the challenge for the forensic pathologist to make causal inferences in the determinism of the unexpected decease.

Accuracy of 18F-FDG in Detecting Stage I Lung Adenocarcinomas According to IASLC/ATS/ERS Classification.

BACKGROUND: Only a small number of studies have explored the clinicopathological features of pulmonary adenocarcinoma (PA) associated with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) false-negative (FN) results. Herein, we investigated the FDG-PET diagnostic performance by stratifying PAs according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification. METHODS: From January 2002 to December 2016, all consecutive patients who underwent pulmonary resection for stage I PA at six thoracic surgery institutions were retrospectively reviewed. The diagnostic performance of FDG-PET was analysed according to IASLC/ATS/ERS classification and two validated subclassifications. Univariable and multivariable logistic analysis were used to identify predictors of FDG-PET FN results. RESULTS: Five hundred and fifty (550) patients with stage I PA were included in the analyses. Most of the patients were male (n=354 [64.4%]) and smokers (n=369 [67.1%]). Ninety-seven (n=97 [17.6%]) FN cases were observed at FDG-PET imaging. On multivariable analysis, a lepidic pattern was found to be independently associated with FDG-PET FN results (odds ratio [OR], 3.20; p<0.001), while a solid pattern more commonly presented with a positive finding (OR, 0.40; p=0.066). According to Nakamura's classification, we observed an independent association between lepidic pattern and FDG-PET FN results (OR, 3.17; p<0.001), while solid/micropapillary patterns were independently related with increased FDG uptake (OR, 0.35; p=0.021). According to Yoshizawa's classification, Intermediate-grade tumours were independently correlated with FN FDG-PET results (OR, 2.78; p=0.005). CONCLUSIONS: In our cohort, histopathological features were significantly associated with FDG uptake. In particular, some adenocarcinoma subtypes (mostly Lepidic pattern) have a tendency towards FN FDG-PET findings. The correlation between computed tomography findings, clinical characteristics, and FDG uptake is mandatory, in order to tailor the precise diagnostic and therapeutic pathway for each patient.

Association between carotid plaque vulnerability and high mobility group box-1 serum levels in a diabetic population.

BACKGROUND: Carotid atherosclerosis represents one of the complications of diabetes mellitus. In particular, plaque instability contributes to disease progression and stroke incidence. High mobility group box-1 (HMGB1) is a nuclear protein involved in promotion and progression of atherosclerosis and cardiovascular diseases. The aim of this study was to analyze the relationship between HMGB1 serum levels, main inflammatory cytokines, the presence of internal carotid stenosis and unstable plaque in a diabetic population. RESEARCH DESIGN AND METHODS: We studied 873 diabetic patients, including 347 patients with internal carotid artery stenosis (ICAS) who underwent carotid endarterectomy and 526 diabetic patients without internal carotid artery stenosis (WICAS). At baseline, HMGB1 and the main inflammatory cytokines serum levels were evaluated. For ICAS patients, the histological features of carotid plaque were also collected to differentiate them in patients with stable or unstable atherosclerotic lesions. RESULTS: We found that HMGB1 serum levels, osteoprotegerin, high-sensitivity C-reactive protein, tumor necrosis factor-alpha and interleukin-6, were significantly higher in diabetic ICAS patients compared to diabetic WICAS patients. Among ICAS patients, individuals with unstable plaque had higher levels of these cytokines, compared to patients with stable plaque. A multivariable stepwise logistic regression analysis showed that HMGB1 and osteoprotegerin remained independently associated with unstable plaque in ICAS patients. CONCLUSIONS: The present study demonstrated that HMGB1 is an independent risk factor for carotid plaque vulnerability in an Italian population with diabetes mellitus, representing a promising biomarker of carotid plaque instability and a possible molecular target to treat unstable carotid plaques and to prevent stroke.

Brain metabolic changes across King's stages in amyotrophic lateral sclerosis: a 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography study.

PURPOSE: To assess the brain metabolic correlates of the different regional extent of ALS, evaluated with the King's staging system, using brain 18F-2-fluoro-2-deoxy-D-glucose-PET (18F-FDG-PET). METHODS: Three hundred ninety ALS cases with King's stages 1, 2, and 3 (n = 390), i.e., involvement of 1, 2, and 3 body regions respectively, underwent brain 18F-FDG-PET at diagnosis. King's stage at PET was derived from ALSFRS-R and was regressed out against whole-brain metabolism in the whole sample. The full factorial design confirmed the hypothesis that differences among groups (King's 1, King's 2, King's 3, and 40 healthy controls (HC)) existed overall. Comparisons among stages and between each group and HC were performed. We included age at PET and sex as covariates. RESULTS: Brain metabolism was inversely correlated with stage in medial frontal gyrus bilaterally, and right precentral and postcentral gyri. The full factorial design resulted in a significant main effect of groups. There was no significant difference between stages 1 and 2. Comparing stage 3 to stage 1+2, a significant relative hypometabolism was highlighted in the former in the left precentral and medial frontal gyri, and in the right medial frontal, postcentral, precentral, and middle frontal gyri. The comparisons between each group and HC showed the extension of frontal metabolic changes from stage 1 to stage 3, with the larger metabolic gap between stages 2 and 3. CONCLUSIONS: Our findings support the hypothesis that in ALS, the propagation of neurodegeneration follows a corticofugal, regional ordered pattern, extending from the motor cortex to posterior and anterior regions.

Brain metabolic correlates of apathy in amyotrophic lateral sclerosis: An 18F-FDG-positron emission tomography stud.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate brain metabolic correlates of apathy in amyotrophic lateral sclerosis (ALS). METHODS: A total of 165 ALS patients underwent 18 F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18 F-FDG-PET) and Frontal Systems Behaviour Scale (FrSBe) evaluation. FrSBe provides "before" and "after" apathy subscores, referring to premorbid and morbid conditions. "After" apathy subscore and "before-after" gap, i.e. the difference between "before" and "after" subscores, were regressed against whole-brain metabolism. Among patients with a pathological "after" apathy subscore (i.e., ≥65), we compared patients with "before" apathy subscores ≥65 and <65, and patients with "before-after" gaps of <22 and ≥22. RESULTS: In the whole sample, the "after" apathy subscore negatively correlated with metabolism in the dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), ventrolateral prefrontal cortex (VLPFC), premotor cortex (PMC) and anterior cingulate cortex (ACC), and insula bilaterally. A positive correlation was found in the cerebellum and pons. The "before-after" gap negatively correlated with metabolism in bilateral DLPFC, DMPFC and PMC, and left VLPFC and ACC, and positively correlated with cerebellar and pontine clusters. Among patients with an "after" apathy subscore ≥65, we found no difference between those with "before" apathy subscores ≥65 and <65. Patients with a "before-after" gap ≥22, compared to patients with a gap <22, showed relative hypometabolism in bilateral DLPFC and DMPFC, and left ACC and PMC, and relative cerebellar and pontine hypermetabolism. CONCLUSION: No studies on brain 18 F-2-fluoro-2-deoxy-D-glucose positron emission tomography correlates of apathy have been performed in ALS. We found that FrSBe "after" apathy subscore correlated with metabolic changes in brain regions known as neuroanatomical correlates of apathy. Furthermore, our findings support the relevance of the gap between premorbid and morbid conditions to detect behavioural changes due to the neurodegenerative process underlying ALS.

A case of fatal embolization during laser lithotripsy.

PURPOSE: To report in literature the first case of fatal multi-organ embolization of ureteral stones fragments during laser lithotripsy. CASE PRESENTATION: A tetraplegic 43-year-old woman was admitted to the hospital to undergo laser lithotripsy because of bilateral ureteral stones and right ureteral infected stent. During the removal of the right ureteral stent, the patient developed a sudden severe bradycardia followed by a reduction in the arterial oxygen saturation. In spite of a rapid and intensive medical intervention, the clinical picture did not improve; the woman was therefore transferred to the nearest Emergency Room where she was rescued but a cardiocirculatory arrest occurred. A claim of alleged medical malpractice was brought against the urologists. A complete autopsy was performed 8 days after death. AUTOPSY FINDINGS: The diagnosis was determined by the microscopic findings: they have unequivocally shown a massive embolization of calculus fragments in the lungs and in the heart. In the light of all these findings, the cause of death was attributable to a disseminated intravascular coagulation due to this unforeseeable embolization of calcified amorphous material. CONCLUSION: Embolization of calculus fragments represents an important challenge because it is extremely unpredictable. Indeed, a prompt diagnosis of non-thrombotic pulmonary embolism, during the urologic procedure, is extremely difficult because the condition presents with no specific clinical signs: this life-threatening pathology is often underestimated. For this reason, the autopsy and the subsequent histopathological examination are indispensable in order to prove lethal embolization: microscopic findings play a key role in the final diagnosis of death.

Feasibility and safety of a new endoscopic synthetic sealant nebulizing device over gastric endoscopic submucosal dissections.

BACKGROUND: Endoscopic Submucosal Dissection (ESD) is the treatment of choice of superficial neoplastic gastrointestinal lesions. Delayed bleedings and perforations are still current clinical concerns. Glubran 2 is a synthetic cyanoacrylate-derived glue nowadays already widely used as an effective tissue adhesive. ENDONEB is a novel device thought for enabling the sealant nebulization over a specific targeted surface during laparotomy, laparoscopy, and thoracotomy. The aim of this single-center preclinical animal trial is to evaluate the feasibility and safety of the same nebulization technique during ESD in the perspective that further clinical studies would demonstrate the efficacy of Glubran 2 in preventing post-ESD adverse events. METHODS: Four live Landrace pigs were enrolled. Two approximately 30-mm-wide gastric ESDs were performed in each pig (experimental ESD and control ESD). About 0.5 mL of Glubran 2 was nebulized on the experimental ESDs. Subjective perception of the feasibility of the Glubran 2 nebulization was reported. Pigs were clinically monitored at follow-up and upper GI endoscopy was performed at 24 and 48 hours, when animals were euthanized to perform a macroscopic and histological analysis of the specimens. RESULTS: No peri-procedural adverse events were reported. Glubran 2 nebulization over experimental ESDs showed to be technically easy and time-effective. Clinical and endoscopic animal monitoring was negative at follow-up. At 24 hours, the Glubran 2 film was clearly visible on the eschar of the ESDs and signs of initial hydrolysis were discernable at 48 hours. No signs of peritoneal reaction were observed at the macroscopic examination. Equal transmural inflammation was described at the histological examination of both types of ESDs. CONCLUSIONS: Safety and feasibility profiles of Glubran 2 nebulizing ENDONEB device over ESD surfaces were excellent. Further evidences and human trials are needed to investigate its effectiveness in ESDs' eschars sealing and, thus, in delayed micro-perforations and bleedings prevention and treatment.

Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies.

Inherited cardiomyopathies are frequent causes of sudden cardiac death (SCD), especially in young patients. Despite at the autopsy they usually have distinctive microscopic and/or macroscopic diagnostic features, their phenotypes may be mild or ambiguous, possibly leading to misdiagnoses or missed diagnoses. In this review, the main differential diagnoses of hypertrophic cardiomyopathy (e.g., athlete's heart, idiopathic left ventricular hypertrophy), arrhythmogenic cardiomyopathy (e.g., adipositas cordis, myocarditis) and dilated cardiomyopathy (e.g., acquired forms of dilated cardiomyopathy, left ventricular noncompaction) are discussed. Moreover, the diagnostic issues in SCD victims affected by phenotype-negative hypertrophic cardiomyopathy and the relationship between myocardial bridging and hypertrophic cardiomyopathy are analyzed. Finally, the applications/limits of virtopsy and post-mortem genetic testing in this field are discussed, with particular attention to the issues related to the assessment of the significance of the genetic variants.

TNF-Stimulated Gene-6 Is a Key Regulator in Switching Stemness and Biological Properties of Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) are well established to have promising therapeutic properties. TNF-stimulated gene-6 (TSG-6), a potent tissue-protective and anti-inflammatory factor, has been demonstrated to be responsible for a significant part of the tissue-protecting properties mediated by MSCs. Nevertheless, current knowledge about the biological function of TSG-6 in MSCs is limited. Here, we demonstrated that TSG-6 is a crucial factor that influences many functional properties of MSCs. The transcriptomic sequencing analysis of wild-type (WT) and TSG-6-/- -MSCs shows that the loss of TSG-6 expression leads to the perturbation of several transcription factors, cytokines, and other key biological pathways. TSG-6-/- -MSCs appeared morphologically different with dissimilar cytoskeleton organization, significantly reduced size of extracellular vesicles, decreased cell proliferative rate, and loss of differentiation abilities compared with the WT cells. These cellular effects may be due to TSG-6-mediated changes in the extracellular matrix (ECM) environment. The supplementation of ECM with exogenous TSG-6, in fact, rescued cell proliferation and changes in morphology. Importantly, TSG-6-deficient MSCs displayed an increased capacity to release interleukin-6 conferring pro-inflammatory and pro-tumorigenic properties to the MSCs. Overall, our data provide strong evidence that TSG-6 is crucial for the maintenance of stemness and other biological properties of murine MSCs.

Metabolic brain changes across different levels of cognitive impairment in ALS: a 18F-FDG-PET study.

OBJECTIVE: To identify the metabolic changes related to the various levels of cognitive deficits in amyotrophic lateral sclerosis (ALS) using 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) imaging. METHODS: 274 ALS patients underwent neuropsychological assessment and brain 18F-FDG-PET at diagnosis. According to the criteria published in 2017, cognitive status was classified as ALS with normal cognition (ALS-Cn, n=132), ALS with behavioural impairment (ALS-Bi, n=66), ALS with cognitive impairment (ALS-Ci, n=30), ALS with cognitive and behavioural impairment (ALS-Cbi, n=26), ALS with frontotemporal dementia (ALS-FTD, n=20). We compared each group displaying some degree of cognitive and/or behavioural impairment to ALS-Cn patients, including age at PET, sex and ALS Functional Rating Scale-Revised as covariates. RESULTS: We identified frontal lobe relative hypometabolism in cognitively impaired patients that resulted more extensive and significant across the continuum from ALS-Ci, through ALS-Cbi, to ALS-FTD. ALS-FTD patients also showed cerebellar relative hypermetabolism. ALS-Bi patients did not show any difference compared with ALS-Cn. CONCLUSIONS: These data support the concept that patients with cognitive impairment have a more widespread neurodegenerative process compared with patients with a pure motor disease: the more severe the cognitive impairment, the more diffuse the metabolic changes. Otherwise, metabolic changes related to pure behavioural impairment need further characterisation.

Pulmonary nodular lymphoid hyperplasia in pediatric patients with Hodgkin lymphoma.

Pulmonary lymphoid lesions span from benign to other forms of malignant diseases. Among these pulmonary lymphoid lesions, Nodular Lymphoid Hyperplasia (NLH) has an excellent prognosis. The surgical excision of NLH seems to be the only treatment, even if in some cases a spontaneous regression has been reported. Interestingly, these lesions may have similar clinical and radiographic presentations, making a histopathological examination vital for their differentiation. In this report we describe four cases of pediatric patients with a previous history of classical Hodgkin Lymphoma (HL) with documented or suspected NLH.

Platelet-Specific Deletion of Cyclooxygenase-1 Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice.

Inflammatory bowel disease (IBD) is associated with an increased risk for thromboembolism, platelet activation, and abnormalities in platelet number and size. In colitis, platelets can extravasate into the colonic interstitium. We generated a mouse with a specific deletion of cyclooxygenase (COX)-1 in megakaryocytes/platelets [(COX-1 conditional knockout (cKO)] to clarify the role of platelet activation in the development of inflammation and fibrosis in dextran sodium sulfate (DSS)-induced colitis. The disease activity index was assessed, and colonic specimens were evaluated for histologic features of epithelial barrier damage, inflammation, and fibrosis. Cocultures of platelets and myofibroblasts were performed. We found that the specific deletion of COX-1 in platelets, which recapitulated the human pharmacodynamics of low-dose aspirin, that is, suppression of platelet thromboxane (TX)A2 production associated with substantial sparing of the systemic production of prostacyclin, resulted in milder symptoms of colitis, in the acute phase, and almost complete recovery from the disease after DSS withdrawal. Reduced colonic accumulation of macrophages and myofibroblasts and collagen deposition was found. Platelet-derived TXA2 enhanced the ability of myofibroblasts to proliferate and migrate in vitro, and these effects were prevented by platelet COX-1 inhibition or antagonism of the TXA2 receptor. Our findings allow a significant advance in the knowledge of the role of platelet-derived TXA2 in the development of colitis and fibrosis in response to intestinal damage and provide the rationale to investigate the potential efficacy of the antiplatelet agent low-dose aspirin in limiting the inflammatory response and fibrosis associated with IBD. SIGNIFICANCE STATEMENT: Inflammatory bowel disease (IBD) is characterized by the development of a chronic inflammatory response, which can lead to intestinal fibrosis for which currently there is no medical treatment. Through the generation of a mouse with specific deletion of cyclooxygenase-1 in megakaryocytes/platelets, which recapitulates the human pharmacodynamics of low-dose aspirin, we demonstrate the important role of platelet-derived thromboxane A2 in the development of experimental colitis and fibrosis, thus providing the rationale to investigate the potential efficacy of low-dose aspirin in limiting the inflammation and tissue damage associated with IBD.

ER-/PR+/HER2- breast cancer type shows the highest proliferative activity among all other combined phenotypes and is more common in young patients: Experience with 6643 breast cancer cases.

The characterization of breast cancer according to its proliferative activity and the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2 is a laboratory routine that has been adopted worldwide for prognostic and therapeutic purposes. By combining data on the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2, it is possible to obtain 8 tumor patterns categorized as triple-negative, nonluminal (i.e. positive for human epidermal growth factor receptor-2 with four subtypes) and luminal (negative for human epidermal growth factor receptor-2 and positive for estrogen receptor and/or progesterone receptor with three subtypes) tumors. In general, luminal tumors are associated with a higher degree of tumor differentiation and have more favorable clinical outcomes. One of the subtypes of luminal tumors has an ER-/PR+ profile. This is a rather rare tumor subtype that behaves aggressively. The aim of this work was to analyse the proliferative activity of the eight tumor subgroups to verify if the ER-/PR+ type has a higher proliferative activity than the other subtypes, which might be correlated with its more aggressive behavior. To accomplish this, we examined estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 and Ki67 data from 6643 cases of breast cancer. We found that the tumor type that was positive for only the progesterone receptor and negative for both the estrogen receptor and human epidermal growth factor receptor-2 (1.3% of all cases) had a proliferative activity that was consistently much higher than those of the other luminal subtypes.