BRCA loss of function including BRCA1 DNA-methylation, but not BRCA-unrelated homologous recombination deficiency, is associated with platinum hypersensitivity in high-grade ovarian cancer.

Background: In high-grade ovarian cancer (HGOC), determination of homologous recombination deficiency (HRD) status is commonly used in routine practice to predict response to platinum-based therapy or poly (ADP-ribose) polymerase inhibitors (PARPi). Here we tested the hypothesis that BRCA loss of function (LOF) due to epigenetic or genetic aberrations is a better predictor for the clinical outcome than HRD. One hundred thirty-one HGOC tissues were tested for BRCA DNA-methylation, BRCA mutations, HRD and BRCA1 mRNA expression, followed by a comprehensive survival analysis.

Comprehensive analysis of constitutional mismatch repair deficiency-associated non-Hodgkin lymphomas in a global cohort.

Background: Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare childhood cancer predisposition syndrome associated with a broad spectrum of malignancies, including non-Hodgkin lymphomas (NHL). Most patients die due to cancer before the age of 20 years. Limited data exist on CMMRD-associated lymphomas and their outcome.

Short Mindfulness Meditations During Breaks and After Work in Everyday Nursing Care: A Simple Strategy for Promoting Daily Recovery, Mood, and Attention?

Background: Nurses experience high job demands, which makes recovery particularly necessary to maintain well-being and performance. However, these demands also make recovery challenging. Short mindfulness meditations could potentially help alleviate this paradox.

Report of the sixth meeting of the European Consortium 'Care for CMMRD' (CCMMRD), Paris, France, November 16th 2022.

Biallelic germline pathogenic variants in one of the four mismatch repair genes (MSH2, MSH6, MLH1 and PMS2) cause a very rare, highly penetrant, childhood-onset cancer syndrome, called constitutional mismatch repair deficiency (CMMRD). The European consortium "Care for CMMRD" (C4CMMRD) was founded in Paris in 2013 to facilitate international collaboration and improve our knowledge of this rare cancer predisposition syndrome. Following initial publications on diagnostic criteria and surveillance guidelines for CMMRD, several partners collaborating within the C4CMMRD consortium have worked on and published numerous CMMRD-related clinical and biological projects.

Myelin dystrophy impairs signal transmission and working memory in a multiscale model of the aging prefrontal cortex.

Normal aging leads to myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are positively correlated with degree of cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory.

Stratification of Homologous Recombination Deficiency-Negative High-Grade Ovarian Cancer by the Type of Peritoneal Spread into Two Groups with Distinct Survival Outcomes.

Background: Homologous recombination deficiency (HRD) has evolved into a major diagnostic marker in high-grade ovarian cancer (HGOC), predicting the response to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and also platinum-based therapy. In addition to HRD, the type of peritoneal tumor spread influences the treatment response and patient survival; miliary type tumor spread has a poorer predicted outcome than non-miliary type tumor spread.

Methods: Known methods for HRD assessment were adapted for our technical requirements and the predictive-value integrated genomic instability score (PIGIS) for HRD assessment evolved as an outcome.

Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.

Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are distinct cancer syndromes caused, respectively, by mono- and bi-allelic germline mismatch repair (MMR) variants. LS predisposes to mainly gastrointestinal and genitourinary cancers in adulthood. CMMRD predisposes to brain, haematological, and LS-spectrum cancers from childhood.

A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency.

Background: Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis is often hampered by the identification of mismatch repair (MMR) variants of unknown significance and difficulties in PMS2 analysis, the most frequently mutated gene in CMMRD. We present the validation of a robust functional tool for CMMRD diagnosis and the characterization of microsatellite instability (MSI) patterns in blood and tumors.

The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2.

Purpose: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies.

Methods: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.

Is the CTS5 a helpful decision-making tool in the extended adjuvant therapy setting?

Purpose: The Clinical Treatment Score post-5 years (CTS5) is an easy-to-use tool estimating the late distant recurrence (LDR) risk in patients with hormone receptor-positive breast cancer after 5 years of endocrine therapy (ET). Apart from evaluating the prognostic value and calibration accuracy of CTS5, the aim of this study is to clarify if this score is able to identify patients at higher risk for LDR who will benefit from extended ET.

Methods: Prognostic power, calibration, and predictive value of the CTS5 was tested in patients of the prospective ABCSG-06 and -06a trials (n = 1254 and 860 patients, respectively).

Emergence of immune-related adverse events correlates with pathological complete response in patients receiving pembrolizumab for early triple-negative breast cancer.

Based upon results of the KEYNOTE-522 trial and following approval by regulatory authorities, the addition of pembrolizumab to chemotherapy is now the standard-of-care for the treatment of early triple-negative breast cancer (eTNBC) (Clinical stage II-III). Pembrolizumab is a programmed cell death protein 1 monoclonal antibody, known to cause immune-related adverse events (irAEs) in a significant subset of patients. Real-world data on incidence, type and treatment strategies of irAEs in the setting of eTNBC treatment are sparse.

Differential immunomodulatory effects of epirubicin/cyclophosphamide and docetaxel in breast cancer patients.

Background: Epirubicin/cyclophosphamide (EC) and docetaxel (D) are commonly used in a sequential regimen in the neoadjuvant treatment of early, high-risk or locally advanced breast cancer (BC). Novel approaches to increase the response rate combine this treatment with immunotherapies such as PD-1 inhibition. However, the expected stimulatory effect on lymphocytes may depend on the chemotherapy backbone.

The Impact of Adjuvant Radiotherapy on Immediate Prepectoral Implant-Based Breast Reconstruction.

Background: Immediate prepectoral implant-based breast reconstruction (IBBR) rates have increased in recent years owing to improved cosmetic and psychological benefits. However, there is a lack of studies regarding complications rates following adjuvant radiotherapy (RT) among patients undergoing immediate prepectoral IBBR.

Methods: We conducted a retrospective monocentric analysis of a cohort of consecutively treated patients who underwent NSM following immediate prepectoral IBBR at our institution between March 2017 and November 2021.

Myelin dystrophy in the aging prefrontal cortex leads to impaired signal transmission and working memory decline: a multiscale computational study.

Normal aging leads to myelin alternations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are often correlated with cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory.

Ptotic versus Nonptotic Breasts in Nipple-sparing Mastectomy and Immediate Prepectoral Breast Reconstruction.

Unlabelled: In recent years, nipple-sparing mastectomy followed by implant-based breast reconstruction has gained popularity due to improved cosmetic and psychological benefits. However, patients with ptotic breasts remain the main challenge for surgeons, owing to the potential risk of postoperative complications.

Methods: A retrospective chart review was performed for patients who underwent nipple-sparing mastectomy and prepectoral implant-based breast reconstruction between March 2017 and November 2021.

Analysis of 200 unrelated individuals with a constitutional NF1 deep intronic pathogenic variant reveals that variants flanking the alternatively spliced NF1 exon 31 [23a] cause a classical neurofibromatosis type 1 phenotype while altering predominantly NF1 isoform type II.

Neurofibromatosis type 1 results from loss-of-function NF1 pathogenic variants (PVs). Up to 30% of all NF1 PVs disrupt mRNA splicing, including deep intronic variants. Here, we retrospectively investigated the spectrum of NF1 deep intronic PVs in a cohort of 8,090 unrelated individuals from the University of Alabama at Birmingham (UAB) dataset with a molecularly confirmed neurofibromatosis type 1.

Neuronal properties of pyramidal cells in lateral prefrontal cortex of the aging rhesus monkey brain are associated with performance deficits on spatial working memory but not executive function.

Age-related declines in cognitive abilities occur as early as middle-age in humans and rhesus monkeys. Specifically, performance by aged individuals on tasks of executive function (EF) and working memory (WM) is characterized by greater frequency of errors, shorter memory spans, increased frequency of perseverative responses, impaired use of feedback and reduced speed of processing. However, how aging precisely differentially impacts specific aspects of these cognitive functions and the distinct brain areas mediating cognition are not well understood.

Altered task demands lead to a division of labour for sensory and cognitive processing in the middle temporal area.

Neurons in the primate middle temporal (MT) area signal information about visual motion and work together with the lateral prefrontal cortex (LPFC) to support memory-guided comparisons of visual motion direction. These areas are reciprocally connected, and both contain neurons that signal visual motion direction in the strength of their responses. Previously, LPFC was shown to display marked changes in stimulus coding with altered task demands, including changes in selectivity for motion direction, trial-to-trial variability in responses and comparison effects.

Neuronal properties of pyramidal cells in lateral prefrontal cortex of the aging rhesus monkey brain are associated with performance deficits on spatial working memory but not executive function.

Age-related declines in cognitive abilities occur as early as middle-age in humans and rhesus monkeys. Specifically, performance by aged individuals on tasks of executive function (EF) and working memory (WM) is characterized by greater frequency of errors, shorter memory spans, increased frequency of perseverative responses, impaired use of feedback and reduced speed of processing. However, how aging precisely differentially impacts specific aspects of these cognitive functions and the distinct brain areas mediating cognition are not well understood.

Fistula-Associated Anal Adenocarcinoma: A 20-Year Single-Center Experience.

Background: Fistula-associated anal adenocarcinoma (FAAC) is a rare consequence in patients with long-standing perianal fistulas. A paucity of data are available for this patient collective, making clinical characterization and management of this disease difficult.

Objective: This study aimed to describe a single-center experience with FAAC patients, their clinical course, and histopathological and molecular pathological characterization.

Study of the N=32 and N=34 Shell Gap for Ti and V by the First High-Precision Multireflection Time-of-Flight Mass Measurements at BigRIPS-SLOWRI.

The atomic masses of ^{55}Sc, ^{56,58}Ti, and ^{56-59}V have been determined using the high-precision multireflection time-of-flight technique. The radioisotopes have been produced at RIKEN's Radioactive Isotope Beam Factory (RIBF) and delivered to the novel designed gas cell and multireflection system, which has been recently commissioned downstream of the ZeroDegree spectrometer following the BigRIPS separator. For ^{56,58}Ti and ^{56-59}V, the mass uncertainties have been reduced down to the order of 10 keV, shedding new light on the N=34 shell effect in Ti and V isotopes by the first high-precision mass measurements of the critical species ^{58}Ti and ^{59}V.

Extended p_{3/2} Neutron Orbital and the N=32 Shell Closure in ^{52}Ca.

The one-neutron knockout from ^{52}Ca in inverse kinematics onto a proton target was performed at ∼230  MeV/nucleon combined with prompt γ spectroscopy. Exclusive quasifree scattering cross sections to bound states in ^{51}Ca and the momentum distributions corresponding to the removal of 1f_{7/2} and 2p_{3/2} neutrons were measured. The cross sections, interpreted within the distorted-wave impulse approximation reaction framework, are consistent with a shell closure at the neutron number N=32, found as strong as at N=28 and N=34 in Ca isotopes from the same observables.