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Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p

In this paper, we prove an extension of Hadamard's classical theorem for determining the radius of mmeromorphy of an analytic function in terms of its Taylor coefficients. Our extension is expressed in terms of Fourier coefficients with respect to an orthonormal polynomial system on the unit circle. Our main result confirms a conjecture posed in [Dolomit Res Notes Approx 17 (2024):12-21]. [ABSTRACT FROM AUTHOR]

Endometrial carcinoma (EC) has different molecular subtypes associated with varied prognosis. We sought to characterize the molecular features of ECs with POLE hotspot mutations and concurrent mismatch repair (MMR) deficiency/high microsatellite instability (MSI). We identified POLE- mutated (POLE mut), MMR-deficient (MMRd)/MSI-high (MSI-H), or combined POLE mut/MMRd ECs subjected to clinical tumor-normal panel sequencing between 2014 and 2023. Clonality of somatic mutations, MSI scoring, tumor mutational burden (TMB), proportion of somatic insertions and deletions (indels), and single base substitution (SBS) mutational signatures were extracted. We identified 41 ECs harboring POLE exonuclease domain hotspot mutations, 138 MMRd and/or MSI-H ECs, and 14 POLE mut/MMRd ECs. Among the 14 POLE mut/MMRd ECs, 11 (79 %) exhibited clonal POLE hotspot mutations; 4 (29 %) had a dominant POLE -related mutational signature, 4 (29 %) displayed dominant MMRd-related signatures, and 6 (43 %) had mixtures of POLE , aging/clock, MMRd, and POLE mut/MMRd-related SBS mutational signatures. The number of single nucleotide variants was higher in POLE mut/MMR-proficient (MMRp) and in POLE mut/MMRd ECs compared to POLE wild-type (wt)/MMRd EC (both p < 0.001). Small indels were enriched in POLE wt/MMRd ECs (p < 0.001). TMB was highest in POLE mut/MMRd EC compared to POLE mut/MMRp and POLE wt/MMRd ECs (both p < 0.001). Of 14 patients with POLE mut/MMRd EC, 21 % had a recurrence, versus 10 % of those with POLE mut/MMRp EC. Similar findings were noted in 3 POLE mut ECs in patients with Lynch syndrome; akin to somatic POLE mut ECs, these tumors had high TMB. POLE mut/MMRd ECs may be genetically distinct. Further studies are needed to assess the impact on outcomes and treatment response within this population. • Dual POLE- mutated (POLE mut)/DNA mismatch repair-deficient (MMRd) endometrial cancers (ECs) have unique molecular features. • Single nucleotide variants were more frequent in POLE mut/MMR-proficient and POLE mut/MMRd cases vs POLE wild-type/MMRd cases. • Small insertions and deletions were more frequent in microsatellite instability-high/MMRd EC vs POLE mut or POLE mut/MMRd ECs. • Tumor mutational burden was highest in the dual POLE mut/MMRd cohort. • Recurrences occurred more frequently in the dual POLE mut/MMRd cohort compared to the POLE mut/MMR-proficient cohort. [ABSTRACT FROM AUTHOR]

Aims Methods and Results Conclusion Since the publication of The Cancer Genome Atlas (TCGA) molecular Classification of endometrial carcinomas in 2013, multiple studies have demonstrated the prognostic and therapeutic importance of this. However, there is great variability on whether and how this is undertaken in different institutions, and this is often dependent on resources and availability of molecular testing. Points of controversy include whether molecular classification is needed on all endometrial carcinomas and whether pure molecular testing is undertaken or a surrogate such as the ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) Classifier. Herein we report our experience instigating molecular classification of endometrial carcinomas in Northern Ireland.From 1st March 2023, all endometrial carcinomas diagnosed on biopsy in the four pathology laboratories in Northern Ireland were referred to the central molecular pathology laboratory for genomic analysis using a custom next‐generation sequencing (NGS) panel; the NGS panel included the entire coding regions of polymerase epsilon (POLE) and TP53 genes, as well as microsatellite instability (MSI) analysis. All cases also underwent immunohistochemical staining with oestrogen receptor (ER), p53, and the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. The molecular results were available by the time of surgery (if a hysterectomy was performed) allowing integration into the final pathology report where a TCGA molecular type was assigned. Two hundred and sixty‐seven endometrial carcinomas underwent molecular testing; in five cases, there was insufficient material for testing, leaving 262 cases. The TCGA groups were POLEmut (19; 7.3%), MMRd (63; 24%), p53abn (62; 23.7%), and no specific molecular profile (NSMP) 118 (45%). Seventeen tumours (6.5%) were “multiple‐classifiers”: five POLEmut‐p53abn, two POLEmut‐MMRd, one POLE‐MMRd‐p53abn (all included in the POLEmut TCGA group), and nine MMRd‐p53abn (included in the MMRd group).This represents one of the first population‐based studies investigating the prevalence of the different TCGA molecular groups of endometrial carcinomas in an unselected population. Performing molecular testing on biopsies enables management to be tailored to the molecular group and allows integration of the TCGA group into the report of the final resection specimen. We hope our experience will facilitate other laboratories in undertaking TCGA molecular classification. [ABSTRACT FROM AUTHOR]

Endometrial carcinoma is the most common gynaecological malignancy in the UK and its incidence is increasing worldwide. The classification of endometrial carcinoma (EC) has been based on cell type (histotype) for decades, and this, together with grade, lymphovascular space invasion (LVSI) and stage of the tumor was used for risk assessment, guiding decisions about the extent of surgery and the need for post-surgical adjuvant treatment. There has been, and remains, considerable variation in clinical practice worldwide, with respect to both the extent of surgery (lymph node dissection, omentectomy, pelvic washings) and use of adjuvant therapy (radiation, chemotherapy, or both) for patients with identical risk factors but treated at different centers. Furthermore, EC has tended to be treated as a single disease, irrespective of histotype. In the past five years there has been a significant move to more personalized risk assessment and treatment with the introduction of routine molecular assessment of EC, and diagnosis of molecular subtype. The four EC molecular subtypes differ with respect to molecular pathology, genetic and environmental risk factors, precursor lesions, prognosis and response to specific treatments. This review will discuss the assessment of EC molecular subtype in clinical practice and how this information impacts on risk assessment and treatment. [ABSTRACT FROM AUTHOR]

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Colon cancer with high microsatellite instability is characterized by a high tumor mutational burden and responds well to immunotherapy. Mutations in polymerase ɛ, a DNA polymerase involved in DNA replication and repair, are also associated with an ultra-mutated phenotype. We describe a case where a patient with POLE-mutated and hypermutated recurrent colon cancer was treated with pembrolizumab. Treatment with immunotherapy in this patient also led to the clearance of circulating tumor DNA (ctDNA). ctDNA is beginning to emerge as a marker for minimal residual disease in many solid malignancies, including colon cancer. Its clearance with treatment suggests that the selection of pembrolizumab on the basis of identifying a POLE mutation on next-generation sequencing may increase disease-free survival in this patient.

Copyright of Revista Foco (Interdisciplinary Studies Journal) is the property of Revista Foco and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The Cancer Genome Atlas (TCGA) Research Network described 4 molecular subgroups of endometrial carcinomas with different outcome: 1) POLE ultramutated endometrioid carcinomas which have an indolent behavior; 2) microsatellite instability hypermutated endometrioid carcinomas associated with intermediate prognosis; 3) copy-number low endometrioid carcinomas also with intermediate prognosis; and 4) copy-number high predominantly serous (non-endometrioid) but also serous-like endometrioid carcinomas, almost always carrying TP53 mutations, with poor clinical outcome. After 10 years of comprehensive analysis, it appears that the only real contribution of TCGA to the clinical management of these patients would be limited to the infrequent high-grade, early-stage endometrioid carcinomas with POLE exonuclease domain mutations, as these patients could benefit from a de-escalating treatment; knowledge about the other three subgroups has not changed significantly. The copy-number low (or non-specific genetic profile) which is the most frequent subgroup, is a mixture subgroup where investigators are currently trying to establish prognostic markers; for example, unexpected variations in a relatively small percentage of cases (i.e., CTNNB1 mutated or p53 aberrant low-grade and low-stage endometrioid carcinomas associated with unfavorable prognosis). On the other hand, TCGA has underlined that a small number of grade 3 endometrioid carcinomas, all TP53 mutated, overlap with copy-number high serous carcinomas. Recently, TCGA molecular subgroups have been integrated into the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging classification which incorporates other non-anatomic parameters like histotype, tumor grade, and lymphovascular space invasion. The result is a complicated and non-intuitive classification that makes its clinical application difficult and does not facilitate correspondence with the 2009 FIGO staging. • The Cancer Genome Atlas Research Network described 4 molecular subgroups of endometrial carcinomas with different outcome • High-grade, early-stage EECs with POLE mutations are uncommon. These patients could benefit from a de-escalating treatment • Conventional histopathologic classification should be complemented with, but not replaced by, TCGA classification • Molecular data should not be integrated into the staging, but rather should be collected as complementary information • The 2023 FIGO staging is a complicated and non-intuitive classification that makes its clinical application difficult [ABSTRACT FROM AUTHOR]

We view the (real) Laplace transform through the lens of linear algebra as a continuous analogue of the power series by a negative exponential transformation that switches the basis of power functions to the basis of exponential functions. This approach immediately points to how the complex Laplace transform is a generalisation of the Fourier transform where the pole of the transform realises the linear algebraic intuition. The exponential transformation also motivates the Taylor inversion of the real Laplace transform. [ABSTRACT FROM AUTHOR]

Xiaohong Yao,1 Min Feng,1,2 Wei Wang1,2 1Department of Pathology, West China Second University Hospital, Sichuan University, Sichuan, Chengdu, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Wei Wang, Email bearwin2000@126.comAbstract: Endometrial cancer shows high histological and molecular heterogeneity. The POLE mutation is a significant molecular alteration in endometrial cancer, leading to the identification of a specific subtype known as POLE-mutated endometrial cancer. This subtype exhibits a high tumor mutation burden, abundant lymphocyte infiltration, and a favorable prognosis, making it a promising candidate for immune checkpoint inhibitor therapy. This paper presents a comprehensive review of the clinical and pathological characteristics, outcomes, treatment advancements, pathogenic POLE gene detection, and alternative testing methods for POLE-mutated endometrial cancer.Keywords: endometrial cancer, molecular subtyping, POLE, POLE-mutated endometrial cancer, immunotherapy

Background: Molecular subtyping of endometrial carcinomas (EC) has been shown to classify tumors into prognostically relevant groups. Characterizing EC with a limited number of markers viz., POLE mutations, p53 mutations, and MMR status, can provide valuable information. Design: Paraffin sections of a cohort of 48 EC from a tertiary care center were characterized for the above-mentioned molecular markers and analyzed in the context of survival. Methods: Formalin fixed paraffin embedded tissues from 48 EC were characterized for POLE mutations by Sanger sequencing (exons 9–14), for MMR (MLH1, MH2, MSH6) using immunohistochemistry (IHC) and copy number (high/low) using p53 IHC. Mutational status was integrated along with the clinicopathological details and survival analysis performed. Results: Eleven (22.9%) patients were MMR deficient, 3 (6.3%) had POLE mutation, while 2 (4.1%) had both POLE and P53 mutations (regarded as multiple classifiers). Twelve (25%) patients were found to have P53 mutations, while the remaining 20 (41.7%) had no specific molecular profile (NSMP). Median follow-up duration was 43.5 (2–62) months with 8 recurrences and 9 deaths. Tumors with POLE mutation had the most favorable prognosis followed by the NSMP and the MMR mutated group while the P53 and multiple classifier groups had the worst prognosis in terms of OS (Log-rank p: 0.006) and PFS (Log-rank p: 0.001). Conclusion: The integration of molecular-clinicopathologic data for endometrial cancer classification, through cost-effective, clinically applicable assays appears to be a highly objective tool that can be adopted even in resource-limited settings. It has the potential to cause a shift in the paradigm of EC pathology and management practice. [ABSTRACT FROM AUTHOR]

Endometrioid endometrial carcinoma (EEC) stands as a prevalent gynecologic malignancy in developed regions. However, predicting relapse cases remains challenging, necessitating the identification of a novel biomarker for EEC relapse. The assessment of tumor mutational burden (TMB) is pivotal for immunotherapy in EEC patients. However, both whole-exome sequencing (WES) and targeted sequencing encountered application-related difficulties. In light of this, standardized and simplified techniques for TMB measurement are imperative. In this study, we employed WES on 25 EEC patients (12 relapsed cases and 13 non-relapsed cases) who accepted hysterectomy surgery (CHCAMS cohort). We additionally obtained a total of 391 tumor samples with clinicopathological features from TCGA website to broaden the study cohort. In the CHCAMS cohort, the TTN mutant group showed shorter progression-free survival (p < 0.001) and overall survival (p < 0.001) than TTN wild-type group. Additionally, we discovered that the number of TTN mutations per sample was significantly linked with TMB-WES in CHCAMS cohort and TCGA cohort (p < 0.05). And the number of TTN mutations per sample in POLE mutant group was greater than in the POLE wild-type group (p < 0.0001). In conclusion, TTN mutation may serve as a biomarker for EEC prognosis. TTN mutation is also associated with WES-TMB, and could be a simplified TMB measurement technique. [ABSTRACT FROM AUTHOR]

POLE mutated endometrial carcinomas may represent a subspecific type of tumors harboring a more favorable prognosis. Grade 3 (G3 or high-grade) endometrioid endometrial carcinomas remain a clinical dilemma, with some tumors behaving as the low-grade counterparts and others presenting a more aggressive behavior. To determine the association between POLE mutational status and the overall-survival (OS) and progression-free-survival (PFS) of patients with G3 endometrioid endometrial cancer (EC). We also aimed to determine the prevalence of POLE mutations in G3 endometrioid EC. We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO No: CRD4202340008). We searched the following electronic databases: PubMed/Medline, EMBASE, Cochrane Library, Scopus, and Web of Science. For time-to-event data, the effect of POLE mutation in G3 EC was described using hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Individual patient data for each study was investigated if available from the study authors. If individual patient data were not available, information regarding time-to-event outcomes was extracted using an appropriate methodology. OS and PFS were analyzed using both one-stage and two-stage approaches, the Kaplan-Meier method, and Cox-proportional hazards models. This systematic review and meta-analysis included 19 studies with 3092 patients who had high-grade endometrioid EC. Patients with POLE mutation s had lower risks of death (HR = 0.36, 95% CI 0.26 to 0.50, I2 = 0%, 10 trials) and disease progression (HR = 0.31, 95% CI 0.17 to 0.57, I2 = 33%, 10 trials). The pooled prevalence of POLE mutation was 11% (95% CI 9 to 13, I2 = 68%, 18 studies). POLE mutations in high-grade endometrioid EC are associated with a more favorable prognosis with increased OS and PFS. • Systematic review and meta-analysis of 19 studies (total of 3092 patients) with high-grade endometrioid endometrial cancer. • We found a lower risk of disease progression and death in patients with POLE mutations. • We estimated a pooled prevalence of POLE mutation of 11% (95% CI 9% to 13%, I2 = 68%). [ABSTRACT FROM AUTHOR]

Abstract Pathogenic germline variants in the DNA polymerase genes POLE and POLD1 cause polymerase proofreading-associated polyposis, a dominantly inherited disorder with increased risk of colorectal carcinomas and other tumors. POLE/POLD1 variants may result in high somatic mutation and neoantigen loads that confer susceptibility to immune checkpoint inhibitors (ICIs). To explore the role of POLE/POLD1 germline variants in glioma predisposition, whole-exome sequencing was applied to leukocyte DNA of glioma patients from 61 tumor families with at least one glioma case each. Rare heterozygous POLE/POLD1 missense variants predicted to be deleterious were identified in glioma patients from 10 (16%) families, co-segregating with the tumor phenotype in families with available DNA from several tumor patients. Glioblastoma patients carrying rare POLE variants had a mean overall survival of 21 months. Additionally, germline variants in POLD1, located at 19q13.33, were detected in 2/34 (6%) patients with 1p/19q-codeleted oligodendrogliomas, while POLE variants were identified in 2/4 (50%) glioblastoma patients with a spinal metastasis. In 13/15 (87%) gliomas from patients carrying POLE/POLD1 variants, features of defective polymerase proofreading, e.g. hypermutation, POLE/POLD1-associated mutational signatures, multinucleated cells, and increased intratumoral T cell response, were observed. In a CRISPR/Cas9-derived POLE-deficient LN-229 glioblastoma cell clone, a mutator phenotype and delayed S phase progression were detected compared to wildtype POLE cells. Our data provide evidence that rare POLE/POLD1 germline variants predispose to gliomas that may be susceptible to ICIs. Data compiled here suggest that glioma patients carrying POLE/POLD1 variants may be recognized by cutaneous manifestations, e.g. café-au-lait macules, and benefit from surveillance colonoscopy.

Vortex crystals are quasiregular arrays of like-signed vortices in solid-body rotation embedded within a uniform background of weaker vorticity. Vortex crystals are observed at the poles of Jupiter and in laboratory experiments with magnetized electron plasmas in axisymmetric geometries. We show that vortex crystals form from the free evolution of randomly excited two-dimensional turbulence on an idealized polar cap. Once formed, the crystals are long lived and survive until the end of the simulations (300 crystal-rotation periods). We identify a fundamental length scale, Lγ=(U/γ)1/3, characterizing the size of the crystal in terms of the mean-square velocity U of the fluid and the polar parameter γ=fp/a2p, with fp the Coriolis parameter at the pole and ap the polar radius of the planet.

Abstract Background In this study, we evaluated the potential of DNA polymerase epsilon (POLE) and DNA polymerase delta 1 (POLD1) as prognostic biomarkers for immune checkpoint inhibitor (ICI) treatment in patients with advanced stage non‐small cell lung cancer (NSCLC). Methods Disease stage, PD‐L1 positivity, histological subtypes, POLE/POLD1 mutation status, tumor mutation burden (TMB), and response to ICIs in NSCLC cases were derived from AACR GENIE dataset (n = 24 120), TCGA‐Pan Lung Cancer dataset (n = 1144), AACR GENIE BPC NSCLC v2.0‐public (n = 2004), and Memorial Sloan Kettering‐Integrated Mutation Profiling of Actionable Cancer Targets dataset (n = 350). The smoking history from TCGA and AACR GENIE datasets was grouped into current, former or never‐smokers. Results POLE and POLD1 genetic alterations were identified in 5% and 2.6% of NSCLC patients, respectively. Current smokers had 9% and 4% of POLE/POLD1 mutations, respectively, versus 1.7% for both POLE and POLD1 mutations prevalence in never‐smokers. POLE/POLD1 mutations were associated with elevated mutation counts than those with wild‐type (median mutation counts 16 vs. 7, p 18 (p 18 can be a composite biomarker for selecting NSCLC patients with survival benefits to ICI treatment.

Asynchronous motors have become part of everyday life. There are various types and shapes, and they are found in all machines that are used to process materials. Recently, these motors have been mainly controlled by frequency regulators, that is, electronics that extract the desired performance from them. Not infrequently, the dimensions of these engines are reduced to the extreme, for the reason that they could fit into the requirements of the machines. As such, they are subject to breakdowns, and very often we are in a situation where we need a lot of time to procure and replace them. This causes very high costs in production, so in order to reduce them, winding of asynchronous motors is resorted to. In this context, the goal of the work was to examine whether rewinding, which was done according to all technical principles, affects the quality of the motor, that is, whether such a motor will still be able to perform its intended functions. The main idea was to accurately calculate the required wire cross-section and replace that calculated wire cross-section with two other wire cross-sections that are close to the calculated wire cross-section. The replacement was made for the reason that this most often happens in rewinding centers where they do not have the calculated cross-section of the wire, but replace the calculated cross-section with the cross-sections they have on hand. After this, we recorded the loads of individual parts of the engine using a thermal imaging camera and made the necessary conclusions. [ABSTRACT FROM AUTHOR]

The article examines the engagement of Jews in the Polish army during the interwar period, with particular attention to the nascent Second Polish Republic. The inception of Jewish involvement in Polish military units can be traced back to World War I, where a considerable number participated in the Polish Legions aligned with Austria-Hungary and later in the Polish army during the Polish-Bolshevik War. The cessation of hostilities marked the transition of the army to peacetime operations and the gradual implementation of general military conscription. Commencing in 1921, Jews were conscripted into the army, constituting approximately 4 to 7% of the total force in different years. Attempts by Jews to evade military service were not uncommon, often involving the bribery of officers in district recruitment units or personnel in medical examination commissions. However, if deemed suitable for service, they were obligated to report to designated locations for deployment. The majority of Jewish recruits were assigned to infantry, cavalry, and artillery units, with only a minority serving in sanitary, engineering, and sapper troops. Aviation, gendarmerie, Border Guard Corps cavalry, communications units, and armored troops saw minimal Jewish representation. It is noteworthy that within the army, Jews sought opportunities for temporary release from service or assumed specific roles to circumvent military training. While within military units, Jews often maintained a certain separation from other groups, and their interactions with representatives of other nationalities ranged from amicable to openly antagonistic. Hostile relations were more frequently observed with the Polish contingent, while interactions with other nationalities generally tended towards friendliness, albeit not without occasional minor misunderstandings. Instances of conflicts among Jews from different regions of Poland surfaced, primarily driven by ideological and religious disparities. During their service, Jews exhibited qualities of obedience, adherence to orders, and minimal conflicts with officers, adhering to principles of subordination. Nonetheless, commanders underscored that this outward compliance was often illusory and motivated primarily by the fear of reprisals. Despite societal perceptions associating Jews with Soviet ideals, there was an absence of overt political expression or propaganda within the army. Nevertheless, a lingering uncertainty among commanders persisted regarding the loyalty of Jews in the event of war. [ABSTRACT FROM AUTHOR]

Copyright of Culture Context / Konteksty Kultury is the property of Jagiellonian University Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Endometrial cancer (EC) is the most frequent gynecological cancer. The ESGO/ESTRO/ESP 2020 guidelines identify prognostic groups based on morpho-molecular characteristics. This study aims to evaluate the clinical applicability of NGS analysis to define an appropriate risk class and to improve the diagnostic and prognostic stratification of ECs. Cases of serous carcinoma (OHEC) and high- (HGEC) and low-grade (LGEC) endometrioid carcinoma diagnosed with the morphological and immunohistochemical (IHC) protocols were considered. After a standardized pre-analytical phase, tumor DNA was semi-automatically extracted and analyzed using NGS with a panel of 14 genes. A total of 63 cases were considered. NGS analysis was successful in 60 cases; all of these were classified according to the new diagnostic algorithm. The molecular risk classification showed a good correlation with the morphological (k = 0.8). The study showed that the protocols of the pre-analytical and analytical phases used are robust and can lead to molecular results that fall within the standards required, which can be used in clinical practice for more precise diagnostic–therapeutic management of patients. The implementation of the classification is particularly relevant for better prognostic stratification of HGECs. In addition, the identification of a suspicious VUS in POLE questions the classification of truncating variants. [ABSTRACT FROM AUTHOR]

Pathogenic germline variants in the DNA polymerase genes POLE and POLD1 cause polymerase proofreading-associated polyposis, a dominantly inherited disorder with increased risk of colorectal carcinomas and other tumors. POLE/POLD1 variants may result in high somatic mutation and neoantigen loads that confer susceptibility to immune checkpoint inhibitors (ICIs). To explore the role of POLE/POLD1 germline variants in glioma predisposition, whole-exome sequencing was applied to leukocyte DNA of glioma patients from 61 tumor families with at least one glioma case each. Rare heterozygous POLE/POLD1 missense variants predicted to be deleterious were identified in glioma patients from 10 (16%) families, co-segregating with the tumor phenotype in families with available DNA from several tumor patients. Glioblastoma patients carrying rare POLE variants had a mean overall survival of 21 months. Additionally, germline variants in POLD1, located at 19q13.33, were detected in 2/34 (6%) patients with 1p/19q-codeleted oligodendrogliomas, while POLE variants were identified in 2/4 (50%) glioblastoma patients with a spinal metastasis. In 13/15 (87%) gliomas from patients carrying POLE/POLD1 variants, features of defective polymerase proofreading, e.g. hypermutation, POLE/POLD1-associated mutational signatures, multinucleated cells, and increased intratumoral T cell response, were observed. In a CRISPR/Cas9-derived POLE-deficient LN-229 glioblastoma cell clone, a mutator phenotype and delayed S phase progression were detected compared to wildtype POLE cells. Our data provide evidence that rare POLE/POLD1 germline variants predispose to gliomas that may be susceptible to ICIs. Data compiled here suggest that glioma patients carrying POLE/POLD1 variants may be recognized by cutaneous manifestations, e.g. café-au-lait macules, and benefit from surveillance colonoscopy. [ABSTRACT FROM AUTHOR]

Molecular classification was introduced in endometrial cancer staging following the transition of the International Federation of Gynecology and Obstetrics (FIGO) 2008 to FIGO2023. In the early stages, p53 abnormal endometrial carcinoma with myometrial involvement was upstaged to stage IIC m , in addition to the downstaging of POLE mutation endometrial cancer to stage IA m. This study compared the goodness of fit and discriminatory ability of FIGO2008, FIGO2023 without molecular classification (FIGO2023), and FIGO2023 with molecular classification (FIGO2023 m); no study has been externally validated to date. The study included 265 patients who underwent initial surgery at the National Cancer Center Hospital between 1997 and 2019 and were pathologically diagnosed with endometrial cancer. The three classification systems were compared using Harrell's concordance index (C-index), Akaike information criterion (AIC), and time-dependent receiver operating characteristic (ROC) curves. A higher C-index score and a lower AIC value indicated a more accurate model. Among the three classification systems, FIGO2023 m had the lowest AIC value (FIGO2023 m : 455.925; FIGO2023: 459.162; FIGO2008: 457.901), highest C-index (FIGO2023 m : 0.768; FIGO2023: 0.743; FIGO2008: 0.740), and superior time-dependent ROC curves within 1 year after surgical resection. In the stage IIIC, patients with p53 abnormalities had considerably lower 5-year overall survival than those with a p53 wild-type pattern (24.3% vs. 83.7%, p = 0.0005). FIGO2023 m had the best discriminatory ability compared with FIGO2008 and FIGO2023. Even in advanced stages, p53 status was a poor prognostic factor. When feasible, molecular subtypes can be added to the staging criteria to allow better prognostic prediction in all stages. • FIG O2023 m classification had the best discriminatory ability compared with FIGO2008 and FIGO2023. • The presence of StageIA mPOLEmut , and Stage IIC mp53abn impacts prognostic outcome. • We suggest the possibility that p53 abnormalities contribute to prognostic outcomes even in Stage IIIC. • Adding molecular subtype to staging can improve prognosis prediction especially for Stage I and II. [ABSTRACT FROM AUTHOR]

Abstract In order to more accurately and efficiently determine the loss and heating state of the magnetic pole area of a tubular hydro‐generator, this study establishes a comprehensive 3D electromagnetic field–thermal network analysis model of its pole area and implements calculations according to its rated symmetrical operating conditions. A 36 MW large tubular hydro‐generator is used as an example. Based on the measured results of the pole temperature and the use of the calculation hardware, the results are compared with the traditional electric circuit‐magnetic circuit‐thermal circuit method and 3D electromagnetic field‐temperature field finite‐element method. It is shown that the 3D electromagnetic field–thermal network model established in this study has several advantages, including high calculation accuracy, short calculation time, and low hardware consumption. These results have important value in improving the electromagnetic–temperature analysis and design of poles in large hydro‐generators.

Simple Summary: While a significant number of ECs are successfully treated without recurrence, some cases of EC still result in death even in their early stages. Incorporating molecular classification enhances prognostic accuracy, aiding tailored treatments. This approach has been utilized by the 2021 ESGO/ESTRO/ESP guidelines, the 2022 ESMO guidelines, and the updated 2023 FIGO classification. Our study employed POLE ddPCR, a cost-effective and easy-to-perform test, as an alternative to POLE NGS for molecular classification. This classification was further enriched by the established prognostic marker, L1CAM, resulting in molecular L1CAM classification. The NSMP group was the largest heterogeneous subgroup. Efforts have been made to find additional markers for further subclassification. When we further categorized the NSMP group, which demonstrates an intermediate prognosis between the POLEmut/MMR-D group and the p53abn group, we were able to distinguish the NSMP-L1CAM-positive subgroup, which exhibited a prognosis similar to the p53-mutated subgroup in terms of poorer outcomes. In multivariate analysis, the molecular L1CAM classification showed an independent prognostic factor for recurrence-free survival and overall survival. Aim: In order to enhance risk stratification in early-stage endometrial cancer (EC), we conducted molecular classification using surrogate markers, including the POLE droplet digital polymerase chain reaction (ddPCR) and L1CAM immunohistochemistry (IHC). Method: We analyzed archival tumor tissue from 183 early-stage EC patients. POLE pathogenic mutations of P286R, V411L, S297F, A456P, and S459F within exons 9, 13, and 14 were detected using a ddPCR, while the mismatch repair (MMR) status was determined by MMR protein IHC and MSI tests. Additionally, we conducted IHC for p53 and L1CAM. Results: The 183 ECs were categorized into four subgroups: POLE-mutated (15.9%), MMR-deficient (29.0%), p53-abnormal (8.7%), and non-specific molecular profile (NSMP, 46.4%). We further subcategorized the NSMP subgroup into NSMP-L1CAMneg (41.5%) and NSMP-L1CAMpos (4.9%), which we refer to as the molecular L1CAM classification. The molecular L1CAM classification was an independent prognostic factor for recurrence-free survival (RFS) and overall survival (OS) (p < 0.001, each). Conclusion: Integrating molecular L1CAM classification can enhance risk stratification in early-stage EC, providing valuable prognostic information to guide treatment decisions and improve patient outcomes. POLE ddPCR might be a cost-effective and easy-to-perform test as an alternative to POLE NGS. [ABSTRACT FROM AUTHOR]

Germline variations in the DNA polymerase genes, POLE and POLD1, can lead to a hereditary cancer syndrome that is characterized by frequent gastrointestinal polyposis and multiple primary malignant tumors. However, because of its rare occurrence, this disorder has not been extensively studied. In this report, we present the case of a 22-year-old female patient who had been diagnosed with gastrointestinal polyposis, breast fibroadenoma, multiple primary colorectal cancers, and glioblastoma (grade IV) within a span of 4 years. Next-generation sequencing analysis revealed a germline variant in POLD1 (c.1816C>A; p.L606M). In silico analysis using protein functional predicting software, including SIFT, Polyphen, GERP++, and CADD, further confirmed the pathogenicity of POLD1 p.L606M (classified as ACMG grade Class 4). In line with polymerase deficiency, both rectal cancer and glioblastoma tissues exhibited a high tumor mutation burden, with 16.9 muts/Mb and 347.1 muts/Mb, respectively. Interestingly, the patient has no family history of cancer, and gene examination of both parents confirms that this is a de novo germline variant. Therefore, molecular screening for POLD1 may be necessary for patients with such a cancer spectrum, regardless of their family history. [ABSTRACT FROM AUTHOR]

This study aimed to explore the practical organisational aspects and difficulties in the implementation of the molecular classification of endometrial carcinoma (EC), and to demonstrate its potential impact in prognostic risk group classification. We conducted a multicentre, retrospective cohort study of 230 patients with EC diagnosed between 2019 and 2022. Sample processing, clinicopathological, treatment and follow-up data were collected. Molecular classification was obtained by p53 and mismatch repair proteins immunohistochemistry, and POLE next-generation sequencing. Implementation was achieved through centralization of molecular analysis. In practice, it was possible to optimise turnaround times of complete integrative reports for hysterectomy specimens to a median time of 18 workdays. If genetic study was started in endometrial biopsies before surgery, 82.0% were available at the time of multidisciplinary tumour board, compared to 8.4% if performed in hysterectomy. ECs were classified as follows: 37.8% no specific molecular profile, 31.7% p53 abnormal, 24.3% mismatch repair deficient, and 6.1% POLE mutant. Integration of these results with traditional clinicopathologic factors led to a change in prognostic risk group in 15 (6.5%) patients, most being initially allocated to high-intermediate (n = 8) and low (n = 5) risk groups. Eight patients changed to a higher risk, and 7 to a lower risk group, whereas 2 remained in the same group. Centralization of EC molecular classification is a feasible option for countries with limited resources. Optimization of workflows may be achieved by earlier analysis in biopsies and prioritisation of patients whose results imply changes in risk group classification. [Display omitted] • Centralization of molecular classification is a feasible option for countries with sparse molecular facilities. • Starting molecular analysis in endometrial biopsy assures earlier results, in time for adjuvant treatment decision. • 2020 ESGO/ESTRO/ESP risk group classification changed in 6.5% of patients, when molecular classification is considered. • Molecular analysis should be prioritized for high-intermediate risk group and low-grade endometrioid with p53 abnormal. [ABSTRACT FROM AUTHOR]

Classification of endometrial carcinomas (EC) based solely on histological features is not sufficient for the prognostic and therapeutic guidance of patients. Furthermore, the existence of EC in which the histological type cannot be determined clearly and the poor reproducibility of histological typing have led to difficulties in clinical management. However, molecular classification of EC is very promising because of the high reproducibility and good correlation with clinical outcome. Within the scope of "the Cancer Genome Atlas Project", EC were divided into four different genomic subtypes, and molecular classification models for EC were developed based on these molecular subcategories. The prognostic differences between these molecular subgroups and the benefit for guidance for adjuvant therapy have been clearly demonstrated in studies. In this article, the importance of molecular classification for EC is discussed and its use in clinical practice is reviewed. [ABSTRACT FROM AUTHOR]

Introduction. Endometrial cancer is one of the most frequent gynecological cancers. Over the years, there has been more and more interest in the molecular characteristics of endometrial tumors that led to the molecular classification in 2013 of the endometrial cancer, with four molecular subtypes, with specific prognosis and treatment. Materials and method. We performed a narrative literature review in order to establish the changes that have been brought by the implementation of the molecular classification for endometrial cancer. We used the PubMed database, with a defined timed interval from 2013 to 2023, using the following keywords: "endometrial cancer", "molecular classification", "endometrial cancer management". We selected the most appropriate articles which reflect our topic. Results. International societies have widely adopted the molecular classification and included it in algorithms in order to determine a risk classification. Further, staging and treatment options are based on these specific risk groups, which has led to shifts and changes to the way certain tumors were treated until now. Also, molecular classification has led the way to personalized treatment concerning adjuvant therapy. Conclusions. The introduction of molecular classification in clinical practice has made significant changes in endometrial cancer management, and important studies are ongoing, with the purpose of finding more therapeutic resources for every endometrial cancer subtype. [ABSTRACT FROM AUTHOR]

Objective: To summarize the clinicopathological characteristics of uterine serous carcinoma (USC), and to investigate its molecular classification and human epidermal growth factor receptor 2 (HER2) expression. Methods: The clinical data of 20 USC patients were collected. HE, immunohistochemistry, Sanger sequencing and FISH were used to detect in USC patients, and the molecular typing and HER2 expression were analyzed. Results: USC accounted for 8% of endometrial cancers, with FIGO stage Ⅰ in 5 cases (25%), stage Ⅱ in 1 case (5%), stage Ⅲ in 9 cases (45%), and stage Ⅳ in 5 cases (25%). Three histological structures of papilla, glandular and solid were seen in the carcinoma tissue. The nipple is wide or small, the cells are easy to fall off, the edge is not smooth and the glandular lumen is mostly fissured. The cytoplasm was clear or eosinophilic and vascular invasion was observed in 13 cases (65%). The positive rates of ER, PR, Vimentin, WT1 and P16 were 40%, 25%, 10%, 35% and 100%, respectively, and the positive rates of Ki-67 were 30%-80%. POLE mutation was not detected in 20 UCS patients, MLH1, PMS2, MSH2 and MSH6 were all positive. There were 16 cases (75%) with P53 missense mutation and 4 cases (25%) with nonsense mutation. HER2 3+ was labeled by immunohistochemistry in 5 cases (25%), and amplified signal was detected by FISH in 4 cases. Conclusions: The incidence of USC was low and the pathological morphology of USC was diverse. Immunohistochemical staining was helpful for its diagnosis. The molecular typing of USC was abnormal P53, and HER2 was expected to be a therapeutic target. [ABSTRACT FROM AUTHOR]

In order to more accurately and efficiently determine the loss and heating state of the magnetic pole area of a tubular hydro‐generator, this study establishes a comprehensive 3D electromagnetic field–thermal network analysis model of its pole area and implements calculations according to its rated symmetrical operating conditions. A 36 MW large tubular hydro‐generator is used as an example. Based on the measured results of the pole temperature and the use of the calculation hardware, the results are compared with the traditional electric circuit‐magnetic circuit‐thermal circuit method and 3D electromagnetic field‐temperature field finite‐element method. It is shown that the 3D electromagnetic field–thermal network model established in this study has several advantages, including high calculation accuracy, short calculation time, and low hardware consumption. These results have important value in improving the electromagnetic–temperature analysis and design of poles in large hydro‐generators. [ABSTRACT FROM AUTHOR]

The design of machines with permanent magnets is actively developing day by day and is often used in wind energy. The main advantages of such variable speed drives are high efficiency, high power density and torque density. When designing a wind generator with two rotors and permanent magnets, it is necessary to solve such a problem as the correct choice of the number of poles and slots to increase efficiency and minimize the cost of the machine. In this work, an improved spotted hyena optimization algorithm is used to obtain the optimal combination of slots and poles. This optimization algorithm makes it possible to obtain the number of fractional slots per pole and evaluate the operating efficiency of a wind generator with a double rotor and ferrite magnets. At the first stage of machine design, various combinations of slots are installed. Next, the optimal combination is selected from various slot-pole combinations, taking into account the Enhanced Spotted Hyena Optimization (ESHO) algorithm, in which a multi-objective function is configured. Accordingly, the multi-objectives are the integration of reverse electromotive force, output torque, gear torque, flux linkage, torque ripple along with losses. Analysis of the results obtained shows that the proposed algorithm for determining the optimal slot combination is more efficient than other slot combinations. It has also been found that the choice of slot and pole combination is critical to the efficient operation of permanent magnet machines.