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Angelica Petrillo,1 Giuseppe Tirino,1 Federica Zito Marino,2 Luca Pompella,1 Rosalaura Sabetta,2 Iacopo Panarese,2 Annalisa Pappalardo,1 Marianna Caterino,1 Anna Ventriglia,1 Maria Maddalena Laterza,1 Floriana Morgillo,1 Michele Orditura,1 Fortunato Ciardiello,1 Renato Franco,2 Ferdinando De Vita1 1Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Study of Campania “Luigi Vanvitelli”, Naples 80131, Italy; 2Pathology Unit, University of Study of Campania “Luigi Vanvitelli”, Naples 80138, ItalyCorrespondence: Angelica Petrillo Tel +39-0815666729Email angelic.petrillo@gmail.comFerdinando De Vita Tel +39-0815666713Email ferdinando.devita@unicampania.itPurpose: ATTRACTION-2 trial assessed the role of Nivolumab as a new standard treatment for Asian patients with pretreated metastatic gastric cancer (mGC). The aim of this analysis was to evaluate the safety and efficacy of Nivolumab in a real-life Western population, considering the lack of evidence to date.Patients and Methods: Patients progressed after ≥ 2 chemotherapy regimens and able to receive Nivolumab (3 mg/kg q14) were eligible for the analysis.Results: 16 patients received Nivolumab as third (81.3%) or fourth line (18.7%) from September 2017 to July 2019. The safety was in line with the literature and only one patient discontinued treatment due to persistent hematological toxicity. Overall response rate and disease control rate were 18.7% and 31.2%, respectively. Median duration of response was 5 months. With a median follow-up of 21 months, median OS was 6 months (7, 21 and 22 months in the responders) and median PFS 3 months. PD-L1 and microsatellite status were retrospectively collected in 12 patients. All the major responders were MSI, although no statistically significant difference in OS or PFS was observed according to molecular analysis.Conclusion: Nivolumab is feasible and effective in Western patients with mGC. Further investigation is urgently needed also in non-Asians.Keywords: immune-checkpoint inhibitors, nivolumab, immunotherapy, third line, PD-L1, MSI

Alessandra Fabi,1 Diana Giannarelli,2 Paola Malaguti,1 Gianluigi Ferretti,1 Sabrina Vari,1 Paola Papaldo,1 Cecilia Nisticò,1 Mauro Caterino,3 Roy De Vita,4 Marcella Mottolese,5 Laura Iacorossi,6 Francesco Cognetti1 1Department of Medical Oncology, 2Biostatistic Unit, 3Service of Radiology, 4Operative Unit of Plastic and Reconstructive Surgery, Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy; 5Department of Pathology, 6Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy Background: There is a deep need to improve the care of metastatic breast cancer (MBC) patients, since even today it remains an incurable disease. Taxanes are considered the most effective cytotoxic drugs for the treatment of MBC, both in monotherapy and in combined schedules, but the need for synthetic solvents contributes to the severe toxicities and may have a negative impact on the efficacy. Nanoparticle albumin-bound paclitaxel (Nab-paclitaxel) is a colloidal suspension of paclitaxel and human serum albumin initially developed to avoid the toxicities associated with conventional taxanes.Patients and methods: The aim of this prospective, single-center open-label, noncomparative study was to evaluate the efficacy and safety of nab-paclitaxel in MBC patients pretreated with taxanes. The patients were treated with nab-paclitaxel as a single agent, 260 mg/m2 on day 1 of each 3-week cycle or 125 mg/m2 weekly. The primary endpoint was the overall response rate (ORR). Secondary objectives were duration of response, clinical benefit rate, progression-free survival (PFS), overall survival, and safety.Results: A total of 42 patients (median age 48 years, median Eastern Cooperative Oncology Group performance status 0, triple-negative MBC 19%, all pretreated with a taxane-based therapy, mainly in advanced disease) were enrolled in the study. The ORR was 23.8%, including one complete response (2.4%) and nine partial responses (21.4%); the disease control rate was 50%. The median duration of response was 7.2 months. After a median follow-up of 9 months, the median PFS was 4.6 months. ORR and PFS were similar irrespective of the previous chemotherapy lines, metastatic sites, and biomolecular expression. Nab-paclitaxel was well tolerated, and the most frequent treatment-related toxicities were mild to moderate (grades 1–2).Conclusion: This real-life study shows that nab-paclitaxel has a significant antitumor activity and a manageable safety profile in patients pretreated with taxanes and experiencing a treatment failure after at least one line of chemotherapy. Keywords: nab-paclitaxel, metastatic breast cancer, anthracyclines

BACKGROUND: Angiosarcoma (AS) of the breast is very rare, accounting for 1% of all soft tissue breast tumors. AS may present as primary tumors of the breast or as secondary lesions usually associated with previous radiotherapy. Commonly, secondary AS affects older women (median age 67-71 years) with a clinical history of breast cancer. The preferred site of onset of RIAS is the edge of radiation fields, where radiation doses and tumor necrosis may be heterogeneous, resulting in a DNA damage and instability. Radical surgery is the treatment of choice, but no clear consensus exists on surgical management of breast AS. CASE REPORT: We describe an atypical case of relapsed RIAS after radical mastectomy, treated with new surgery and, considering the higher risk of recurrence, subsequent adjuvant chemotherapy with weekly paclitaxel. CONCLUSIONS: The frequency of radiation-induced angiosarcomas (RIAS) after breast-conserving surgery and radiotherapy has been increased to 0.14-0.5% among long survivors. Nevertheless, even if RIAS continues to be prognostically an extremely unfavorable cancer due to a high rate of recurrence, distant spread, and median overall survival (OS) of about 60 months, the benefits of loco-regional breast radiotherapy are clearly higher than the risk in developing angiosarcoma. [ABSTRACT FROM AUTHOR]

Among freshwater organisms, water flow is frequently considered to be one of the most important environmental variables affecting life-history traits such as dispersal abilities and therefore genetic structure. Recent studies have suggested that habitat type alone as defined by water flow is predictive of genetic population differentiation, while others have advocated against broad generalizations in favour of more conservative, species-specific conclusions. If aquatic habitat type is predictive of population differentiation, then one would expect sympatric taxa that occupy the same aquatic habitat to converge on a similar genetic structure. We tested this prediction by examining the haplotype diversity, phylogeographical concordance, population connectivity and population isolation of three lotic water beetle species in southern California: Anacaena signaticollis, Eubrianax edwardsii and Stictotarsus striatellus. In addition to coarse habitat and geography, we also controlled for the potentially confounding factors of range size, method of dispersal and clade independence. Together, the species spanned extremes of genetic and phylogeographical structure in all measures examined, suggesting that a coarse dichotomy of aquatic habitat type is not predictive of genetic structure. While there is little question that water flow plays a major role in shaping the life-history traits of freshwater organisms, it is perilous to confer predictive properties to an artificially simplistic dichotomy or use it as a surrogate for other unmeasured variables. [ABSTRACT FROM AUTHOR]

Abstract: UN1 is a membrane glycoprotein that is expressed in immature human thymocytes, a subpopulation of peripheral T lymphocytes, the HPB acute lymphoblastic leukemia (ALL) T-cell line and fetal thymus. We previously reported the isolation of a monoclonal antibody (UN1 mAb) recognizing the UN1 protein that was classified as “unclustered” at the 5th and 6th International Workshop and Conference on Human Leukocyte Differentiation Antigens. UN1 was highly expressed in breast cancer tissues and was undetected in non-proliferative lesions and in normal breast tissues, indicating a role for UN1 in the development of a tumorigenic phenotype of breast cancer cells. In this study, we report a partial purification of the UN1 protein from HPB-ALL T cells by anion-exchange chromatography followed by immunoprecipitation with the UN1 mAb and MALDI-TOF MS analysis. This analysis should assist in identifying the amino acid sequence of UN1. [Copyright &y& Elsevier]

To verify whether or not ciliary motility can be reliably assessed by light microscopy alone, we examined the nasal brushings of 53 patients with suspected ciliary dyskinesia and 10 healthy controls. The results of light microscopy were compared with cilia ultrastructure assessed with electron microscopy. Ciliary motility was significantly related with cilia ultrastructure. However, eight cases of lung disease due to bronchiectasis of unknown origin had immotile cilia on light microscopy, but normal ciliary ultrastructure on electron microscopy. Instances of normal and abnormal ultrastructure were detected in one case with motile cilia. There was an 83% agreement between electron microscopy and light microscopy. Sensitivity and specificity of light microscopy were 92% and 80%, respectively. In conclusion, light microscopy evaluation of ciliary motility does not appear to be a reliable screening test for ciliary dyskinesia because it does not quantify ciliary beat activity, which is a criterion for deranged ciliary motion. A complete evaluation of ciliary ultrastructure together with in vivo, if applicable, or in vitro function test (namely, the analysis of ciliary beat frequencies and/or waveform) is required for a definite diagnosis of ciliary dyskinesia. [ABSTRACT FROM AUTHOR]

Sixty patients with anterior mediastinal neoplasms undergoing computed tomography before surgical exploration were entered in a prospective study to assess the value of computed tomography in the preoperative staging of anterior mediastinal tumours. Correct prediction of location, size, and tissue density was obtained in all 60 cases. Correct identification of the nature of the tumours was achieved by computed tomography in 37 of the 54 previously undiagnosed cases. Particular attention was given to the evaluation of the relation of the tumour to adjacent mediastinal structures, to predict the feasibility of radical surgical procedures. Overall sensitivity, specificity, and accuracy in identifying resectability were 46%, 85%, and 64%, with positive and negative predictive indices of 78% and 58%. Capsulated or highly invasive lesions were clearly distinguished, and the presence or absence of infiltration of mediastinal vessels, pericardium, and chest wall was correctly recognised in most cases. It is suggested that the evaluation of anterior mediastinal neoplasms should include computed tomography because of its accuracy in predicting size, location, and tissue density of the neoplasm. Computed tomography may suggest, often with good reliability, the histological type of the tumour and its relation to contiguous mediastinal structures, thus contributing to the choice of the appropriate surgical approach or route for biopsy. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Clinical analysis of patients of cirrhosis complicated with adrenal insufficiency" published in a 2016 issue of the periodical is presented.

White matter hyperintensities (WMH) are considered magnetic brain imaging (MRI) biomarkers of cerebral small vessel disease but their clinical role in neurodegenerative-related disorders is poorly understood. This study describes the distribution of WMH on brain MRI in Progressive Supranuclear Palsy (PSP) in comparison with Parkinson's disease (PD) and explores their possible impact on disease's features. Sixty PSP and 33 PD patients were included. Motor symptoms, cardiovascular risk factors and the age-related white matter changes (ARWMC) score was computed to rate WMH for both groups. Pearson's correlation and linear or logistic regression analysis were used to check for relationships between ARWMC and PSP clinical scores. The mean (standard deviation) ARWMC total score in the PSP cohort was 4.66 (3.25). Any degree of WMH was present in 68% of PSP (ARWMC +). Compared to ARWMC-, ARWMC + did not have greater disease severity or more cardiovascular risk factors. WMH were frequently localized in fronto-parietal lobes and were mild in severity. Linear regression analysis showed that ARWMC total score was related to the PSP-rating scale, irrespective of age, disease duration and the Charlson modified comorbidity index. Logistic regression analysis confirmed that ARWMC total score was related to the use of wheelchair, irrespective of above-mentioned covariates. Vascular risk factors as well as severity and distribution of WMH did not have an impact on the PSP phenotype. No differences were found with PD patients. Our results suggest that WMH in PSP might be markers of neurodegenerative-related pathology rather than being simple expression of atherosclerotic cerebrovascular changes., (© 2024. The Author(s).)

Background: Postoperative delirium (POD) following surgery is a prevalent and distressing condition associated with adverse patient outcomes and an increased healthcare burden., Objectives: To assess the effectiveness of the Safe Brain Initiative care bundle (SBI-CB) in reducing POD in the postanesthesia care unit (PACU)., Design: A multicenter, quality-improvement initiative with retrospective analysis of collected data., Setting: The study was conducted in the operating rooms and postanesthesia care units (PACUs) of four hospitals across Denmark and Turkey., Patients: The convenience sample of patients were aged ≥18 years, scheduled for surgery, and could communicate verbally. Age, sex, preoperative delirium, and the American Society for Anesthesiology physical status classification were used in statistical methods to control for potential confounding influences., Intervention: The SBI-CB, 18 delirium-reducing recommendations aligned with international guidelines. The intervention included patient education, staff training, coordination meetings across centers, and a dashboard for the monitoring of outcomes in the PACU., Main Outcome Measures: The primary outcome was the POD trend in the PACU during implementation months, assessed through Nu-DESC screening at up to three time points in the PACU. We also examined the length of hospital stay., Results: Data were collected from 18,697 adult patients across four hospitals. Initial POD incidence in the PACU after the first three months was 16.36% across all sites (n = 1021). POD in the PACU was observed across all age groups, with peak incidence in younger (18-35 years) and older (>75 years) patients. General anesthesia and longer surgical duration (>1 h) were identified as significant risk factors for POD in the PACU. Matched patients who experienced POD in the PACU had longer stays in hospital, with a mean increase from 35 to 69 h (p < 0.001). Implementation of the SBI-CB was associated with a decreased risk of POD in the PACU for each month of SBI-CB implementation (adjusted odds ratio 0.96, 95% confidence interval: [0.94, 0.97], p < 0.001)., Conclusions: The presented pragmatic implementation of a multidisciplinary care bundle, encompassing pre-, intra-, and postoperative measures alongside outcome monitoring, has the potential to significantly reduce the incidence of POD in the PACU. Improved patient outcomes may be achieved for general surgical departments with patient cohorts not typically considered at risk for developing POD., Trial Registration: Clinicaltrials.gov, identifier NCT05765162., Competing Interests: Declaration of competing interest SS, MC, and FP are employed at Coreva Scientific GmbH & Co. KG that received compensation for their work. JBE is a member of the ESAIC eLearning and Examinations Committee. She also has received support for travel expenses from Medtronic. WB is the President Elect of the European Society of Anaesthesiology and Intensive Care Medicine (ESAIC) and received fees for a lecture from BD Diagnostics. WB is also the coordinating investigator of the PHOENICS/THEHYS study Fresenius Kabi and ESAIC. EDR received honoraria from Baxter, Fresenius Kabi, MSD, Fisher & Paykel, Drager, and GE health. FMR received unrestricted research and educational grants from Medtronic and is active on the advisory board of GE health. DHP, BCM, FB, KJ, LAE, PRK, NA, and SK claim no competing interests. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Finn M Radtke reports financial support was provided by Medtronic Inc. Finn M Radtke reports a relationship with Coreva Scientific GmbH und Co KG that includes: non-financial support. SS, MC, and FP are Coreva Scientific GmbH & Co. KG employees that received consultancy fees for performing, analyzing, and communicating the work from the Hospital of Nykøbing Falster. FMR received an unrestricted research grant from Medtronic Inc. Medtronic had no scientific input, and no benefits to their products are presented in this work. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Glycogen storage disease type Ia (GSDIa) is a rare, inherited glucose-6-phosphatase-α (G6Pase-α) deficiency-induced carbohydrate metabolism disorder. Although hyperlipidaemia is a hallmark of GSDI, the extent of lipid metabolism disruption remains incompletely understood. Lipidomic analysis was performed to characterise the serum lipidome in patients with GSDIa, by including age- and sex-matched healthy controls and age-matched hypercholesterolemic controls. Metabolic control and dietary information biochemical markers were obtained from patients with GSDIa. Patients with GSDIa showed higher total serum lysophosphatidylcholine (Fold Change, FC 2.2, p < 0.0001), acyl-acyl-phosphatidylcholine (FC 2.1, p < 0.0001), and ceramide (FC 2.4, p < 0.0001) levels and bile acid (FC 0.7, p < 0.001), acylcarnitines (FC 0.7, p < 0.001), and cholesterol esters (FC 1.0, p < 0.001) than those of healthy controls, and higher di- (FC 1.1, p < 0.0001; FC 0.9, p < 0.01) and triacylglycerol (FC 6.3, p < 0.0001; FC 3.9, p < 0.01) levels than those of healthy controls and hypercholesterolemic subjects. Both total cholesterol (TC) and TG values correlated with Cer(d16:1/22:0), Cer(d18:1/20:0), Cer(d18:1/20:0(OH)), Cer(d18:1/22:0), Cer(d18:1/23:0), Cer(d18:1/24:1), Cer(d18:2/22:0), Cer(d18:2/24:1). TC also correlated with Cer(d18:1/24:0), Cer(d18:2/20:0), HexCer(d16:1/22:0), HexCer(d18:1/18:0), and Hex2Cer(d18:1/20:0). TGlevels correlated with Cer(d18:0/24:1). Alanine transaminase values correlated with Cer(d18:0/22:0), insulin with Cer(d18:1/22:1) and Cer(d18:1/24:1), and HDL with hexosylceramide (HexCer)(d18:2/23:0). These results expand on the currently known involvement of lipid metabolism in GSDIa. Circulating Cer may allow for refined dietary assessment compared with traditional biomarkers. Because specific lipid species are relatively easy to assess, they represent potential novel biomarkers of GSDIa., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Alterations in metabolic status, body composition, and food intake are present in all neurodegenerative diseases. Aim of this study was to detect the progression of these changes in Progressive Supranuclear Palsy (PSP)., Methods: We conducted a longitudinal study of 15 patients with PSP. The assessments were performed at baseline (T0) and after 7(IQR = 5) months of follow-up (T1). We collected anthropometric measures including body weight, height, body mass index and waist circumference, metabolic parameters through indirect calorimeters, body composition using bioimpedance analysis, and dietary habits with a validated questionnaire. PSP-rating scale (PSP-rs) was used to evaluate disease severity and dysphagia., Results: The majority of patients (66.66%) presented PSP-Richardson Syndrome and 33.33% the other variant syndromes of the disease. At T1 there was a decrease in intake of total daily calories (p < 0.001), proteins (p < 0.001), fibers (p = 0.001), calcium (p = 0.008), iron (p < 0.001), zinc (0.034), vitamin E (p = 0.006) and folates (p = 0.038) compared to T0. No other changes were found. As for T1 data, no significant differences were shown according to disease phenotypes or the presence of clinically significant dysphagia for solids., Conclusions: Within a mid-term follow up, PSP patients presented reduced caloric and proteins intake regardless the presence of dysphagia. The PSP-rs is likely not adequate to assess dysphagia, which should be investigated by specific clinical scales or instrumental examinations. With the goal of maintaining adequate nutritional status, the administration of protein and vitamin supplements should be considered even in the absence of dysphagia evidenced by the rating scales., (© 2024. The Author(s).)

Background: Progressive supranuclear palsy (PSP) is a rare 4R-tauopathy. Transcranial direct current stimulation (tDCS) may improve specific symptoms., Objectives: This randomized, double-blinded, sham-controlled trial aimed at verifying the short-, mid-, and long-term effect of multiple sessions of anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) cortex in PSP., Methods: Twenty-five patients were randomly assigned to active or sham stimulation (2 mA for 20 minute) for 5 days/week for 2 weeks. Participants underwent assessments at baseline, after the 2-week stimulation protocol, then after 45 days and 3 months from baseline. Primary outcomes were verbal and semantic fluency. The efficacy was verified with analysis of covariance., Results: We failed to detect a significant effect of active stimulation on primary outcomes. Stimulation was associated to worsening of specific behavioral complaints., Conclusions: A 2-week protocol of anodal left DLPFC tDCS is not effective in PSP. Specific challenges in running symptomatic clinical trials with classic design are highlighted. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

Introduction: Lymphopenia is a known side effect of dimethyl fumarate (DMF), a disease-modifying therapy (DMT) for patients with multiple sclerosis (pwMS). A body mass index ≥ 30 kg/m 2 has been identified as a protective factor; however, no data are available on lymphopenia in pwMS undergoing to weight loss due to bariatric surgery., Methods: We described two pwMS with history of bariatric surgery who started DMF as DMT., Results: The two pwMS experienced persistent lymphopenia during DMF-treatment, which was resolved after its discontinuation., Conclusions: Several mechanisms might modify DMF pharmacokinetic profiles after bariatric surgery and its bioavailability. Absolute lymphocyte count should be monitored in pwMS treated with DMF and history of bariatric surgery and weight loss., (© 2023. Fondazione Società Italiana di Neurologia.)

Background: Methylmalonic acidemia (MMA) is a rare inborn error of propionate metabolism caused by deficiency of the mitochondrial methylmalonyl-CoA mutase (MUT) enzyme. As matter of fact, MMA patients manifest impairment of the primary metabolic network with profound damages that involve several cell components, many of which have not been discovered yet. We employed cellular models and patients-derived fibroblasts to refine and uncover new pathologic mechanisms connected with MUT deficiency through the combination of multi-proteomics and bioinformatics approaches., Results: Our data show that MUT deficiency is connected with profound proteome dysregulations, revealing molecular actors involved in lysosome and autophagy functioning. To elucidate the effects of defective MUT on lysosomal and autophagy regulation, we analyzed the morphology and functionality of MMA-lysosomes that showed deep alterations, thus corroborating omics data. Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells. These results indicate a strict connection between MUT deficiency and lysosomal-autophagy dysfunction, providing promising therapeutic perspectives for MMA., Conclusions: Defective homeostatic mechanisms in the regulation of autophagy and lysosome functions have been demonstrated in MUT-deficient cells. Our data prove that MMA triggers such dysfunctions impacting on autophagosome-lysosome fusion and lysosomal activity., (© 2024. The Author(s).)

This systematic review aims to evaluate the role of ultrasound (US) radiomics in assessing lymphadenopathy in patients with cancer and the ability of radiomics to predict metastatic lymph node involvement. A systematic literature search was performed in the PubMed (MEDLINE), Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE (Ovid) databases up to June 13, 2023. 42 articles were included in which the lymph node mass was assessed with a US exam, and the analysis was performed using radiomics methods. From the survey of the selected articles, experimental evidence suggests that radiomics features extracted from US images can be a useful tool for predicting and characterizing lymphadenopathy in patients with breast, head and neck, and cervical cancer. This noninvasive and effective method allows the extraction of important information beyond mere morphological characteristics, extracting features that may be related to lymph node involvement. Future studies are needed to investigate the role of US-radiomics in other types of cancers, such as melanoma., Competing Interests: The authors declare that Dr. Cantisani is a member of the Editorial Board of the journal., (Thieme. All rights reserved.)

Mucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and lysosomal defects in MPS I, IIIA and IIIB patient fibroblasts. We investigated PI3K/Akt pathway, which is of crucial importance for neuronal function and survival, and demonstrate that PI3K inhibition abolishes NK1 therapeutic effects. We identified that autophagy inhibition, by Beclin1 silencing, reduces MPS IIIB phenotype and that NK1 downregulates autophagic-lysosome (ALP) gene expression, suggesting a possible contribution of autophagosome biogenesis in MPS. Indeed, metabolomic analyses revealed defects of mitochondrial activity accompanied by anaerobic metabolism and inhibition of AMP-activated protein kinase (AMPK), which acts on metabolism and autophagy, rescues lysosomal defects. These results provide insights into the molecular mechanisms of MPS IIIB physiopathology, supporting the development of new promising approaches based on autophagy inhibition and metabolic rewiring to correct lysosomal pathology in MPSs., Competing Interests: Luigi Michele Pavone has licensed compositions comprising hepatocyte growth factor or variants thereof for use in the treatment of mucopolysaccharidoses (granted Italian patent MI2014A001454)., (© 2024 The Author(s).)