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Background and purpose: The aim of the study was to evaluate the metabolic correlates of Apolipoprotein E (APOE) genotype in amyotrophic lateral sclerosis (ALS) and to investigate the role of ε2 as a risk factor for cognitive impairment. Methods: A total of 159 ALS cases underwent APOE and ALS‐related genes analysis, neuropsychological assessment and cerebral 18F‐2‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography. The APOE genotype was regressed against whole brain metabolism as assessed by 18F‐2‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography, with age, sex, education, type of onset and C9orf72 status as covariates. Results: Brain metabolism was significantly positively correlated with APOE genotype from ε2/ε2 to ε3/ε4 in the left prefrontal [Brodmann area (BA) 10], orbitofrontal (BAs 11, 45, 47) and anterior cingulate (BA 32) cortices. There was a tendency to a relative hypometabolism going towards the ε2/ε2 extreme. Conclusions: We found a highly significant, relatively lower metabolism in association with the ε2 allele in extra‐motor areas typically affected in frontotemporal dementia (left prefrontal, orbitofrontal and anterior cingulate cortices), strengthening the finding of a role of ε2 as a risk factor for cognitive impairment in ALS. Our data suggested a link between cholesterol homeostasis and neurodegeneration. [ABSTRACT FROM AUTHOR]

We classify the 6-dimensional Lie algebras that can be endowed with an abelian complex structure and parametrize, on each of these algebras, the space of such structures up to holomorphic isomorphism. [ABSTRACT FROM AUTHOR]

Aims: In patients of Black African ethnicity, breast cancer is reportedly characterized by aggressive, poorly differentiated phenotype(s). To highlight possible differences between breast cancer in indigenous sub-Saharan African and European patients, two breast cancer case series, from Central Sudan (Khartoum) and Northern Italy (Milan), were compared for clinicopathological characteristics, expression of oestrogen receptor (ER), progesterone receptor (PR), Her-2/neu, basal cytokeratin (CK) 5/6 and CK17, and breast cancer subtypes. Methods and results: After careful antigen retrieval, 114 and 138 consecutive formalin-fixed paraffin-embedded (FFPE) breast cancer cases from the Radiation and Isotope Centre (Khartoum) and from MultiMedica (Milan), respectively, were screened by immunohistochemistry for ER, PR, Her-2/neu, CK5/6 and CK17. Compared with the Italian patients, the Sudanese patients were younger ( P < 0.0001) and their tumours were larger ( P < 0.0001), more advanced in stage ( P < 0.00001), higher grade ( P < 0.00001) and more frequently positive for nodal metastases ( P < 0.00001). ER expression varied between the two series ( P < 0.0008), but no significant differences were found for PR ( P < 0.32), combined hormone receptors ( P < 0.12), Her-2/neu ( P < 0.09), CK5/6 ( P < 0.1), CK17 ( P = 0.4), combined basal CK status ( P = 1) or breast cancer subtypes ( P = 0.12). Conclusion: The differences between the Sudanese and Italian breast cancer series reflect stage at diagnosis rather than intrinsic biological characteristics. This may have relevant implications for breast cancer prevention and treatment in Africa. [ABSTRACT FROM AUTHOR]

Background: Whole gene duplication of the lamin B1 gene ( LMNB1), encoding for a protein of the nuclear lamina, causes an adult-onset autosomal dominant leukodystrophy (ADLD). Clinical features of ADLD (onset in adult life, dysautonomic symptoms, followed by pyramidal and cerebellar dysfunctions) partially resemble those of multiple sclerosis (MS), particularly the primary-progressive form. Our aim was to test whether LMNB1 gene mutations were present amongst patients with a diagnosis of MS. Methods: One hundred eighty-two MS patients were screened for copy number variations of the LMNB1 gene using a qPCR assay. Point mutations in the LMNB1 gene were searched by denaturing high-performance liquid chromatography and direct sequencing in a subgroup of 16 patients with familial MS. Results: No duplication/deletion of the lamin B1 gene was found amongst MS patients, and no point mutation was identified in the familial cases. Conclusion: Our work indicates that lamin B1 defects are probably not responsible for signs and symptoms resembling multiple sclerosis. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article about the immunohistochemical study of prostatic intraepithelial neoplasia and adenocarcinoma.

Background: Programmed death-ligand 1 (PD-L1) expression with combined positive score (CPS) ≥1 is required for administration of checkpoint inhibitor therapy in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). The 22C3 pharmDx Dako immunohistochemical assay is the one approved as companion diagnostic for pembrolizumab, but many laboratories work on other platforms and/or with other clones, and studies exploring the potential interchangeability of assays have appeared., Evidence From the Literature: After review of the literature, it emerges that the concordance among assays ranges from fair to moderate, with a tendence of assay SP263 to yield a higher quota of positivity and of assay SP142 to stain better immune cells. Moreover, pathologists achieve very good concordance in assessing PD-L1 CPS, particularly with SP263., Conclusions: Differences in terms of platforms, procedures, and study design still preclude a quantitative synthesis of evidence and clearly further work is needed to draw stronger conclusions on the interchangeability of PD-L1 assays in HNSCC., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Artificial genomic reference standards in a cytocentrifuge/cytospin format with well-annotated genomic data are useful for validating next-generation sequencing (NGS) on routine cytopreparations. Here, reference standards were optimized to be stained by different laboratories before DNA extraction and to contain a lower number of cells (2 × 10 5 ). This was done to better reflect the clinical challenge of working with insufficient cytological material., Methods: A total of 17 worldwide laboratories analyzed customized reference standard slides (slides A-D). Each laboratory applied its standard workflow. The sample slides were engineered to harbor epidermal growth factor receptor (EGFR) c.2235&#95;2249del15 p.E746&#95;A750delELREA, EGFR c.2369C>T p.T790M, Kirsten rat sarcoma viral oncogene homolog (KRAS) c.38G>A p.G13D, and B-Raf proto-oncogene, serine/threonine kinase (BRAF) c.1798&#95;1799GT>AA p.V600K mutations at various allele frequencies (AFs)., Results: EGFR and KRAS mutation detection showed excellent interlaboratory reproducibility, especially on slides A and B (10% and 5% AFs). On slide C (1% AF), either the EGFR mutation or the KRAS mutation was undetected by 10 of the 17 laboratories (58.82%). A reassessment of the raw data in a second-look analysis highlighted the mutations (n = 10) that had been missed in the first-look analysis. BRAF c.1798&#95;1799GT>AA p.V600K showed a lower concordance rate for mutation detection and AF quantification., Conclusions: The data show that the detection of low-abundance mutations is still clinically challenging and may require a visual inspection of sequencing reads to detect. Genomic reference standards in a cytocentrifuge/cytospin format are a valid tool for regular quality assessment of laboratories performing molecular studies on cytology with low-AF mutations., (© 2019 American Cancer Society.)

Background: Molecular testing of cytological lung cancer specimens includes, beyond epidermal growth factor receptor (EGFR), emerging predictive/prognostic genomic biomarkers such as Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral [v-ras] oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA). Next-generation sequencing (NGS) and other multigene mutational assays are suitable for cytological specimens, including smears. However, the current literature reflects single-institution studies rather than multicenter experiences., Methods: Quantitative cytological molecular reference slides were produced with cell lines designed to harbor concurrent mutations in the EGFR, KRAS, NRAS, BRAF, and PIK3CA genes at various allelic ratios, including low allele frequencies (AFs; 1%). This interlaboratory ring trial study included 14 institutions across the world that performed multigene mutational assays, from tissue extraction to data analysis, on these reference slides, with each laboratory using its own mutation analysis platform and methodology., Results: All laboratories using NGS (n = 11) successfully detected the study's set of mutations with minimal variations in the means and standard errors of variant fractions at dilution points of 10% (P = .171) and 5% (P = .063) despite the use of different sequencing platforms (Illumina, Ion Torrent/Proton, and Roche). However, when mutations at a low AF of 1% were analyzed, the concordance of the NGS results was low, and this reflected the use of different thresholds for variant calling among the institutions. In contrast, laboratories using matrix-assisted laser desorption/ionization-time of flight (n = 2) showed lower concordance in terms of mutation detection and mutant AF quantification., Conclusions: Quantitative molecular reference slides are a useful tool for monitoring the performance of different multigene mutational assays, and this could lead to better standardization of molecular cytopathology procedures. Cancer Cytopathol 2017;125:615-26. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background & Aims: Sorafenib is the standard of care in advanced hepatocellular carcinoma (HCC), however no criteria have been established to select patients likely to benefit from this therapy. In this study, we evaluated the predictive role of microRNAs (miRNAs) in this setting of patients., Methods: We profiled 522 miRNA in a series of 26 HCC patients treated with sorafenib (training set) and validated the results in an independent series of 58 patients (validation set). Formalin-fixed paraffin-embedded tumour and cirrhotic liver biopsies were used for RNA extraction and miRNAs profiling with TaqMan Arrays technology. Statistical analyses were used to correlate miRNA levels with clinical outcome, including time to progression (TTP), progression free (PFS), and overall survival. Cell viability and cell motility of HuH-7 or HepG2 HCC cells were tested in vitro after transfection with specific miRNA precursor, inhibitor or controls and sorafenib treatment., Results: Six miRNAs were significantly associated with clinical variables in the training set and only miR-425-3p could be further validated. Higher levels of miR-425-3p were associated with longer TTP and PFS (P = 0.0008; HR = 0.4; 95% CI = 0.2-0.7 and P = 0.007; HR = 0.5; 95% CI = 0.3-0.9 respectively). Multivariate analysis confirmed the predictive significance of miR-425-3p. Furthermore, an association between increased miR-425-3p, cell death and reduced cell motility was defined in vitro in HCC cell lines treated with sorafenib., Conclusions: Assessment of miR-425-3p levels in liver biopsies could help in stratifying patients with advanced HCC for sorafenib treatment. These promising results need to be confirmed in a large prospective study., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)