An impossibility theorem in game dynamics.

The Nash equilibrium-a combination of choices by the players of a game from which no self-interested player would deviate-is the predominant solution concept in game theory. Even though every game has a Nash equilibrium, it is not known whether there are deterministic behaviors of the players who play a game repeatedly that are guaranteed to converge to a Nash equilibrium of the game from all starting points. If one assumes that the players' behavior is a discrete-time or continuous-time rule whereby the current mixed strategy profile is mapped to the next, this question becomes a problem in the theory of dynamical systems. We apply this theory, and in particular Conley index theory, to prove a general impossibility result: There exist games, for which all game dynamics fail to converge to Nash equilibria from all starting points. The games which help prove this impossibility result are degenerate, but we conjecture that the same result holds, under computational complexity assumptions, for nondegenerate games. We also prove a stronger impossibility result for the solution concept of approximate Nash equilibria: For a set of games of positive measure, no game dynamics can converge to the set of approximate Nash equilibria for a sufficiently small yet substantial approximation bound. Our results establish that, although the notions of Nash equilibrium and its computation-inspired approximations are universally applicable in all games, they are fundamentally incomplete as predictors of long-term player behavior.

Neuroscience Needs Network Science.

The brain is a complex system comprising a myriad of interacting neurons, posing significant challenges in understanding its structure, function, and dynamics. Network science has emerged as a powerful tool for studying such interconnected systems, offering a framework for integrating multiscale data and complexity. To date, network methods have significantly advanced functional imaging studies of the human brain and have facilitated the development of control theory-based applications for directing brain activity. Here, we discuss emerging frontiers for network neuroscience in the brain atlas era, addressing the challenges and opportunities in integrating multiple data streams for understanding the neural transitions from development to healthy function to disease. We underscore the importance of fostering interdisciplinary opportunities through workshops, conferences, and funding initiatives, such as supporting students and postdoctoral fellows with interests in both disciplines. By bringing together the network science and neuroscience communities, we can develop novel network-based methods tailored to neural circuits, paving the way toward a deeper understanding of the brain and its functions, as well as offering new challenges for network science.

ENGOT-EN20/GOG-3083/XPORT-EC-042 - A phase III, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with p53 wild-type, advanced, or recurrent endometrial carcinoma: rationale, methods, and trial design.

BACKGROUND: Patients with advanced/recurrent endometrial cancer have a poor prognosis and limited treatment options. Biomarkers such as tumor protein 53 (TP53) in endometrial cancer can integrate novel strategies for improved and individualized treatment that could impact patient outcomes. In an exploratory analysis of the phase III ENGOT-EN5/GOG-3055/SIENDO study of selinexor maintenance monotherapy 80 mg in advanced/recurrent endometrial cancer, a pre-specified subgroup of patients with TP53 wild type (wt) endometrial cancer showed preliminary activity at long-term follow-up with a generally manageable safety profile (median progression-free survival 27.4 months vs 5.2 months placebo, HR=0.41). PRIMARY OBJECTIVE: To evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent TP53wt endometrial cancer. STUDY HYPOTHESIS: Selinexor administered at 60 mg weekly as maintenance therapy will show manageable safety and maintain efficacy in patients with TP53wt advanced/recurrent endometrial cancer after systemic therapy versus placebo. TRIAL DESIGN: This is a prospective, multicenter, double-blind, placebo-controlled, randomized phase III study designed to evaluate the efficacy and safety of selinexor as a maintenance therapy in patients with advanced or recurrent TP53wt endometrial cancer. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have histologically confirmed endometrial cancer, TP53wt confirmed by next-generation sequencing, completed at least 12 weeks of platinum-based therapy with or without immunotherapy, with confirmed partial response or complete response, and primary Stage IV disease or at first relapse. PRIMARY ENDPOINT: The primary endpoint is investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the intent-to-treat population. SAMPLE SIZE: A total of 220 patients will be enrolled. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is expected to be completed in 2024 with presentation of results in 2025. TRIAL REGISTRATION: NCT05611931.

Brain computation by assemblies of neurons.

Assemblies are large populations of neurons believed to imprint memories, concepts, words, and other cognitive information. We identify a repertoire of operations on assemblies. These operations correspond to properties of assemblies observed in experiments, and can be shown, analytically and through simulations, to be realizable by generic, randomly connected populations of neurons with Hebbian plasticity and inhibition. Assemblies and their operations constitute a computational model of the brain which we call the Assembly Calculus, occupying a level of detail intermediate between the level of spiking neurons and synapses and that of the whole brain. The resulting computational system can be shown, under assumptions, to be, in principle, capable of carrying out arbitrary computations. We hypothesize that something like it may underlie higher human cognitive functions such as reasoning, planning, and language. In particular, we propose a plausible brain architecture based on assemblies for implementing the syntactic processing of language in cortex, which is consistent with recent experimental results.

Anti-Tumor Immunity and Preoperative Radiovaccination: Emerging New Concepts in the Treatment of Breast Cancer.

Neoadjuvant chemotherapy (NACT) for certain breast cancer (BC) subtypes confers significant tumor regression rates and a survival benefit for patients with a complete pathologic response. Clinical and preclinical studies have demonstrated that immune-related factors are responsible for better treatment outcomes, and thus, neoadjuvant immunotherapy (IO) has emerged as a means to further improve patient survival rates. Innate immunological "coldness", however, of specific BC subtypes, especially of the luminal ones, due to their immunosuppressive tumor microenvironment, hinders the efficacy of immune checkpoint inhibitors. Treatment policies aiming to reverse this immunological inertia are, therefore, needed. Moreover, radiotherapy (RT) has been proven to have a significant interplay with the immune system and promote anti-tumor immunity. This "radiovaccination" effect could be exploited in the neoadjuvant setting of BC and significantly enhance the effects of the already established clinical practice. Modern stereotactic irradiation techniques directed to the primary tumor and involved lymph nodes may prove important for the RT-NACT-IO combination. In this review, we provide an overview and critically discuss the biological rationale, clinical experience, and ongoing research underlying the interplay between neoadjuvant chemotherapy, anti-tumor immune response, and the emerging role of RT as a preoperative adjunct with immunological therapeutic implications in BC.

The Role of EMT-Related lncRNAs in Ovarian Cancer.

Ovarian cancer (OC) is one of the deadliest cancers worldwide; late diagnosis and drug resistance are two major factors often responsible for high morbidity and treatment failure. Epithelial-to-mesenchymal transition (EMT) is a dynamic process that has been closely linked with cancer. Long non-coding RNAs (lncRNAs) have been also associated with several cancer-related mechanisms, including EMT. We conducted a literature search in the PubMed database in order to sum up and discuss the role of lncRNAs in regulating OC-related EMT and their underlying mechanisms. Seventy (70) original research articles were identified, as of 23 April 2023. Our review concluded that the dysregulation of lncRNAs is highly associated with EMT-mediated OC progression. A comprehensive understanding of lncRNAs' mechanisms in OC will help in identifying novel and sensitive biomarkers and therapeutic targets for this malignancy.

Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: final long-term results of the Hellenic Cooperative Oncology Group Phase III HE10/05 Trial.

BACKGROUND: Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation. METHODS: Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease. RESULTS: At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms. CONCLUSIONS: Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000151033.

Bridging the Gap Between Neurons and Cognition Through Assemblies of Neurons.

During recent decades, our understanding of the brain has advanced dramatically at both the cellular and molecular levels and at the cognitive neurofunctional level; however, a huge gap remains between the microlevel of physiology and the macrolevel of cognition. We propose that computational models based on assemblies of neurons can serve as a blueprint for bridging these two scales. We discuss recently developed computational models of assemblies that have been demonstrated to mediate higher cognitive functions such as the processing of simple sentences, to be realistically realizable by neural activity, and to possess general computational power.

Circulating miRNA Expression Profiles and Machine Learning Models in Association with Response to Irinotecan-Based Treatment in Metastatic Colorectal Cancer.

Colorectal cancer represents a leading cause of cancer-related morbidity and mortality. Despite improvements, chemotherapy remains the backbone of colorectal cancer treatment. The aim of this study is to investigate the variation of circulating microRNA expression profiles and the response to irinotecan-based treatment in metastatic colorectal cancer and to identify relevant target genes and molecular functions. Serum samples from 95 metastatic colorectal cancer patients were analyzed. The microRNA expression was tested with a NucleoSpin miRNA kit (Machnery-Nagel, Germany), and a machine learning approach was subsequently applied for microRNA profiling. The top 10 upregulated microRNAs in the non-responders group were hsa-miR-181b-5p, hsa-miR-10b-5p, hsa-let-7f-5p, hsa-miR-181a-5p, hsa-miR-181d-5p, hsa-miR-301a-3p, hsa-miR-92a-3p, hsa-miR-155-5p, hsa-miR-30c-5p, and hsa-let-7i-5p. Similarly, the top 10 downregulated microRNAs were hsa-let-7d-5p, hsa-let-7c-5p, hsa-miR-215-5p, hsa-miR-143-3p, hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-142-5p, hsa-miR-148a-3p, hsa-miR-122-5p, and hsa-miR-17-5p. The upregulation of microRNAs in the miR-181 family and the downregulation of those in the let-7 family appear to be mostly involved with non-responsiveness to irinotecan-based treatment.

STDP Forms Associations between Memory Traces in Networks of Spiking Neurons.

Memory traces and associations between them are fundamental for cognitive brain function. Neuron recordings suggest that distributed assemblies of neurons in the brain serve as memory traces for spatial information, real-world items, and concepts. However, there is conflicting evidence regarding neural codes for associated memory traces. Some studies suggest the emergence of overlaps between assemblies during an association, while others suggest that the assemblies themselves remain largely unchanged and new assemblies emerge as neural codes for associated memory items. Here we study the emergence of neural codes for associated memory items in a generic computational model of recurrent networks of spiking neurons with a data-constrained rule for spike-timing-dependent plasticity. The model depends critically on 2 parameters, which control the excitability of neurons and the scale of initial synaptic weights. By modifying these 2 parameters, the model can reproduce both experimental data from the human brain on the fast formation of associations through emergent overlaps between assemblies, and rodent data where new neurons are recruited to encode the associated memories. Hence, our findings suggest that the brain can use both of these 2 neural codes for associations, and dynamically switch between them during consolidation.

One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene.

BACKGROUND: Gene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations. METHODS: To further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case-control analysis. RESULTS: Herein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively. CONCLUSION: Studying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

BRCA1 and BRCA2 germline testing in Cretan isolates reveals novel and strong founder effects.

Germline BRCA1 and BRCA2 loss-of-function variants have been linked to increased breast and ovarian cancer risk, with more than 5,000 distinct pathogenic variants being reported worldwide. Among individuals of Greek descent, the BRCA1/2 variant spectrum is heterogeneous, but characterized by strong founder effects. As patients from certain geographical regions of Greece (like Crete) were underrepresented in previous studies, we hypothesized that isolated Cretans, a southern Greece islanders' population with distinct demographic, cultural and genetic features, could harbor founder BRCA1/2 mutations. A total of 304 breast or/and ovarian cancer patients of Cretan descent, fulfilling NCCN criteria for genetic testing, were tested by NGS or Sanger sequencing, followed by MLPA. Haplotype analysis was subsequently performed to investigate potential founder effects of recurrent alleles. Overall, 16.5% (50/304) of the tested patients carried 22 different pathogenic variants; 48% in BRCA1, 52% in BRCA2. Three variants, namely two in BRCA2 (Δexons 12 and 13 and c.7806-2A>T) and one in BRCA1 (c.5492del), constituting approximately half (48%) of all detected pathogenic variants, were shown to have a founder effect, with all carriers sharing common haplotypes. Remarkably, these variants were confined to Cretans and have not been identified in other regions of Greece. The high prevalence of specific BRCA1/2 pathogenic variants among Cretans, provides the possibility of cost- and time-efficient screening of the Cretan population. Integrating this knowledge in local public health services may have a significant impact on cancer prevention, and may serve as a starting point for the implementation of testing on a population level.

PALB2 c.2257C>T truncating variant is a Greek founder and is associated with high breast cancer risk.

PALB2 loss-of-function variants play an important role in breast, pancreatic and possibly, ovarian and gastric cancer susceptibility. Their frequency can be influenced by founder effects, already described in some populations. Herein, we have assessed the possible founder effect of PALB2 c.2257C>T (p.Arg753*) truncating variant among Greek breast cancer patients, while investigating possible correlations with cancer diagnoses. Following a lead deriving from a background study of highly selected Greek breast cancer patients, a total of 2496 breast and 697 ovarian cancer patients were directly genotyped for the PALB2 c.2257C>T truncating variant. Consequently, haplotype analysis was conducted on identified carriers, using seven microsatellite markers. The prevalence of the PALB2 variant was 0.24% (6/2496) and 0.14% (1/697) among breast and ovarian cases, respectively. Family history seems to be an important factor for the variant identification, although not reaching statistical significance. Microsatellite analysis on 12 carriers revealed a common shared haplotype, spanning a chromosomal region of ~1.2 Mb; the variant was possibly introduced in the Greek population ~1600 years ago. The variant confers high breast cancer risk, as illustrated by comparison with publicly available control groups. Genetic testing for PALB2, especially for the Greek founder c.2257C>T truncating variant, should be seriously considered in Greek breast cancer cases, since such findings could assist appropriate clinical management for the patients and their families.

Epidemiological characteristics, clinical outcomes and management patterns of metastatic breast cancer patients in routine clinical care settings of Greece: Results from the EMERGE multicenter retrospective chart review study.

BACKGROUND: The "EMERGE" study, aimed to capture real-life management patterns and outcomes in metastatic breast cancer (MBC) in Greece, also accounting for hormone (HR) and human epidermal growth factor receptor 2 (HER2) status. METHODS: "EMERGE" was a multicenter, retrospective cohort study of adult MBC patients diagnosed between 01-Janaury-2010 and 30-June-2012, either de novo or having progressed from a non-metastatic state. Patient data, including treatment patterns and outcomes, were mainly abstracted through medical chart review. RESULTS: 386 patients were enrolled by 16 hospital-based oncologists between 12-March-2013 and 31-March-2015. The median look-back period was 29.1 months. At MBC diagnosis, 56.1% of the patients were HR+/HER2-, 16.6% HR+/HER2+, 14.5% HR-/HER2-, and 12.8% HR-/HER2+. In the first line setting, chemotherapy, targeted therapy and endocrine therapy were received by 76.7, 52.4, and 28.3% of the overall population, and by 66.5/36.2/42.0%, 80.4/80.4/28.6%, 88.4/90.7/0.0, and 95.6%/56.5/6.5% of the HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2- subpopulations, respectively. In the overall population, the disease progression incidence rate was 0.57 [95% confidence interval (CI): 0.48-0.67] per person-year; median progression-free survival (PFS) was 22.4 (95% CI: 20.4-24.7) and overall survival (OS) was 45.0 (95% CI: 40.9-55.0) months. Median PFS was 24.6 (95% CI: 21.3-27.9) in HR+/HER2-, 19.7 (95% CI: 12.9-25.9) in HR+/HER2+, 23.0 (95% CI: 16.6-29.7) in HR-/HER2+ and 18.3 (95% CI: 10.0-24.7) months in HR-/HER2- subpopulations. A multivariable Cox proportional hazards model, adjusted among other factors for age and duration of diagnosis, HR and HER2 status, demonstrated that in the overall population PFS was better among those receiving first line endocrine therapy (hazard ratio: 0.70; 95%CI: 0.51-0.95; p = 0.024). CONCLUSIONS: "EMERGE" demonstrates differences between HR/HER2 subtypes in clinical outcomes and divergence from evidence-based guideline recommendations for MBC management, especially as it pertains to the HR+/HER2- patients in which chemotherapy was favored over endocrine therapy in the first line setting. STUDY REGISTRATION: The study has been registered on the electronic Registry of Non-Interventional Studies (RNIS) posted on the website of the Hellenic Association of Pharmaceutical Companies (SFEE): https://www.dilon.sfee.gr/studiesp_d.php?meleti_id=NIS-OGR-XXX-2012/1.

Sex: The power of randomization.

In evolutionary biology, randomness has been perceived as a force that, in and of itself, is capable of inventing: mutation creates new genetic information at random across the genome which leads to phenotypic change, which is then subject to selection. However, in science in general and in computer science in particular, the widespread use of randomness takes a different form. Here, randomization allows for the breaking of pattern, as seen for example in its removal of biases (patterns) by random sampling or random assignment to conditions. Combined with various forms of evaluation, this breaking of pattern becomes an extraordinarily powerful tool, as also seen in many randomized algorithms in computer science. Here we show that this power of randomness is harnessed in nature by sex and recombination. In a finite population, and under the assumption of interactions between genetic variants, sex and recombination allow selection to test how well an allele will perform in a sample of combinations of interacting genetic partners drawn at random from all possible such combinations; consequently, even a small number of tests of genotypes such as takes place in a finite population favors alleles that will most likely perform well in a vast number of yet unrealized genetic combinations. This power of randomization is not manifest in asexual populations.

MiR-218 and miR-100 polymorphisms as markers of irinotecan-based chemotherapy response in metastatic colorectal cancer.

PURPOSE: Colorectal cancer is the fourth cause of cancer-related death. Drug toxicity and resistance remain concerns of major importance. miR-100 and miR-218 are micro-RNAs that regulate cellular proliferation, differentiation and apoptosis acting as oncogenes and tumour suppressors; their functions and have been linked with toxicity development and drug resistance. METHODS: We investigated the correlation between rs11134527 miR-218 and rs1834306 miR-100 polymorphisms and irinotecan-based regimens with regard to drug efficacy and toxicity. A total of 105 mCRC patients receiving irinotecan-based regimens were included in our study and assessed in terms of toxicity development and response to treatment. Rs11134527 miR-218 and rs1834306 miR-100 polymorphism genotyping in the peripheral blood was performed with PCR-RFLP. RESULTS: Neither rs11134527 miR-218 nor rs1834306 miR-100 are associated with toxicity risk to treatment regimens. GA/AA genotypes of rs11134527 and CT/TT genotypes of rs1834306 were associated with a significantly reduced time-to-progression (TTP) and overall survival (OS). CONCLUSIONS: GA/AA genotypes of rs11134527 miR-218 and CT/TT genotypes of rs1834306 miR-100 polymorphisms could serve as prognostic biomarkers of TTP and OS. Carriers of the A allele of the miR-218 rs11134527 and T allele of the miR-100 rs1834306 polymorphisms are more likely not to respond to irinotecan-based therapies. However, further studies in larger patient populations are required.

Assessing the landscape of ovarian serous borderline tumors.

AIM: To compare distinct clinicopathological features between atypical proliferative serous tumors and non-invasive low-grade ovarian serous carcinomas. METHODS: Our study group comprised 203 cases of serous borderline tumors sub-classified as atypical proliferative serous tumors or as non-invasive low-grade serous carcinomas. All pathological features related to borderline tumors were re-evaluated by two gynecological pathologists. Data concerning recurrences and survival were retrieved from the medical records of the patients. RESULTS: When comparing atypical proliferative serous tumors to non-invasive low-grade serous carcinomas, the latter were statistically related to advanced stage at diagnosis, bilateral disease, exophytic pattern of growth, microinvasive carcinoma, and the presence of invasive implants. In univariate analysis, recurrences were statistically related to the exophytic pattern of growth, to microinvasion, and to the presence of implants (both invasive and non-invasive). Nevertheless, in multivariate analysis, only microinvasion and the presence of invasive implants were related to recurrence. Women who eventually succumbed to the disease were only those with invasive implants. Their ovarian tumor was either a non-invasive low-grade serous carcinoma or an atypical proliferative serous tumor with 'minimal' micropapillary pattern. Neither lymph node involvement nor endosalpingiosis seemed to influence the course of the disease. CONCLUSIONS: The results of our study underline the increased possibility of non-invasive low-grade serous carcinomas to be related with features indicative of aggressive behavior as opposed to atypical proliferative serous tumors. Nevertheless, irrespective of tumor histology, the presence of invasive implants and microinvasion were the only independent prognostications of recurrence.

The impact of programmed cell death-ligand 1 (PD-L1) and CD8 expression in grade 3 endometrial carcinomas.

BACKGROUND: To evaluate the expression of programmed cell death-ligand 1 (PD-L1) and CD8 in high-grade endometrial carcinomas and relate it to several clinicopathological parameters. METHODS: One hundred and one (101) patients with high-grade endometrial carcinomas who were completely surgically staged were included in this study. PD-L1 and CD8 + expression was evaluated by immunohistochemistry. RESULTS: In our cohort, 47 women (46.5%) had endometrioid carcinomas and 54 patients (53.5%) were diagnosed with non-endometrioid cancers. In endometrioid carcinomas, there was a significantly higher rate of positivity for PD-L1 expression (p = 0.042) and of intraepithelial CD8 + cell counts (p = 0.004) as opposed to non-endometrioid cancers. There were no significant relationships with any of the other clinicopathological features under study. Univariate and multivariate analysis revealed that only high intraepithelial CD8 + counts (p = 0.01) was associated with longer progression-free survival. Tumors positive for PD-L1 and high intraepithelial CD8 expression were mainly of endometrioid histology, whilst PD-L1-positive/CD8 low and PD-L1-negative/CD8 low tumors were mostly non-endometrioid carcinomas (p = 0.01). PD-L1 negative/CD8 high tumors had the longest progression-free survival (p = 0.032). CONCLUSIONS: In grade 3 endometrial carcinomas, both of endometrioid and non-endometrioid type, high intraepithelial CD8 + counts represent an independent favorable prognostic factor and when related to PD-L1-negative tumors, a longer progression-free survival can be predicted. Immunotherapy could probably be considered for PD-L1-positive/CD8 + high tumors, which were mostly of endometrioid histology.

Contribution of RAD51D germline mutations in breast and ovarian cancer in Greece.

RAD51D gene's protein product is known to be involved in the DNA repair mechanism by homologous recombination. RAD51D germline mutations have been recently associated with ovarian and breast cancer (OC and BC, respectively) predisposition. Our aim was to evaluate the frequency of hereditary RAD51D mutations in Greek patients. To address this, we have screened for RAD51D germline mutations 609 BRCA1- and BRCA2-negative patients diagnosed with OC, unselected for age or family history, and 569 BC patients diagnosed under 55 years and with an additional relative with BC or OC. We identified four pathogenic mutations in four unrelated individuals with family history of BC and/or OC. Three of the RAD51D carriers had developed BC, while the other one was an OC patient, thus accounting for a mutation frequency of 0.16% in the OC cohort and 0.53% in the BC cohort. One of the detected mutations is novel (c.738 + 1G > A), whereas the rest had been detected previously (p.Gln151Ter, p.Arg186Ter, and p.Arg300Ter). It is noteworthy that the 4 carrier families had 13 BC cases and only 4 OC cases. Our data support that RAD51D should be implemented into the comprehensive multigene panel, as mutation carriers may benefit from the administration of PARP inhibitors.

From Nash Equilibria to Chain Recurrent Sets: An Algorithmic Solution Concept for Game Theory.

In 1950, Nash proposed a natural equilibrium solution concept for games hence called Nash equilibrium, and proved that all finite games have at least one. The proof is through a simple yet ingenious application of Brouwer's (or, in another version Kakutani's) fixed point theorem, the most sophisticated result in his era's topology-in fact, recent algorithmic work has established that Nash equilibria are computationally equivalent to fixed points. In this paper, we propose a new class of universal non-equilibrium solution concepts arising from an important theorem in the topology of dynamical systems that was unavailable to Nash. This approach starts with both a game and a learning dynamics, defined over mixed strategies. The Nash equilibria are fixpoints of the dynamics, but the system behavior is captured by an object far more general than the Nash equilibrium that is known in dynamical systems theory as chain recurrent set. Informally, once we focus on this solution concept-this notion of "the outcome of the game"-every game behaves like a potential game with the dynamics converging to these states. In other words, unlike Nash equilibria, this solution concept is algorithmic in the sense that it has a constructive proof of existence. We characterize this solution for simple benchmark games under replicator dynamics, arguably the best known evolutionary dynamics in game theory. For (weighted) potential games, the new concept coincides with the fixpoints/equilibria of the dynamics. However, in (variants of) zero-sum games with fully mixed (i.e., interior) Nash equilibria, it covers the whole state space, as the dynamics satisfy specific information theoretic constants of motion. We discuss numerous novel computational, as well as structural, combinatorial questions raised by this chain recurrence conception of games.