COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study.

BACKGROUND: Individuals with cancer, particularly those who are receiving systemic anticancer treatments, have been postulated to be at increased risk of mortality from COVID-19. This conjecture has considerable effect on the treatment of patients with cancer and data from large, multicentre studies to support this assumption are scarce because of the contingencies of the pandemic. We aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in patients with cancer. METHODS: In this prospective observational study, all patients with active cancer and presenting to our network of cancer centres were eligible for enrolment into the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effects of COVID-19 on patients with cancer. Eligible patients tested positive for severe acute respiratory syndrome coronavirus 2 on RT-PCR assay from a nose or throat swab. We excluded patients with a radiological or clinical diagnosis of COVID-19, without a positive RT-PCR test. The primary endpoint was all-cause mortality, or discharge from hospital, as assessed by the reporting sites during the patient hospital admission. FINDINGS: From March 18, to April 26, 2020, we analysed 800 patients with a diagnosis of cancer and symptomatic COVID-19. 412 (52%) patients had a mild COVID-19 disease course. 226 (28%) patients died and risk of death was significantly associated with advancing patient age (odds ratio 9·42 [95% CI 6·56-10·02]; p<0·0001), being male (1·67 [1·19-2·34]; p=0·003), and the presence of other comorbidities such as hypertension (1·95 [1·36-2·80]; p<0·001) and cardiovascular disease (2·32 [1·47-3·64]). 281 (35%) patients had received cytotoxic chemotherapy within 4 weeks before testing positive for COVID-19. After adjusting for age, gender, and comorbidities, chemotherapy in the past 4 weeks had no significant effect on mortality from COVID-19 disease, when compared with patients with cancer who had not received recent chemotherapy (1·18 [0·81-1·72]; p=0·380). We found no significant effect on mortality for patients with immunotherapy, hormonal therapy, targeted therapy, radiotherapy use within the past 4 weeks. INTERPRETATION: Mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from COVID-19 disease compared with those not on active treatment. FUNDING: University of Birmingham, University of Oxford.

Immune checkpoint blockade: releasing the breaks or a protective barrier to COVID-19 severe acute respiratory syndrome?

The rapid emergence of COVID-19 has sent shockwaves through healthcare systems globally, with cancer patients at increased risk. The interplay of the virus and host immune system has been implicated in the development of ARDS. Immunotherapy agents have the potential to adversely potentiate this phenomenon, requiring careful real-world observation.

Macronutrient content of donor milk from a regional human milk bank: variation with donor mother-infant characteristics.

Better understanding of the variation in macronutrient content of human donor milk (HDM) potentiates targeted nutrition for preterm babies. The present study describes the relationship of maternal age, parity, monthly lactation stage estimate (LSEm), daily volume of milk expressed (Vd), sex, gestation and birth weight z scores with macronutrient content of HDM. Multilevel mother-infant pair ID random intercept models were performed using the predictor variables above on the outcome HDM macronutrient content determined using mid-IR spectroscopy. Mean macronutrient content was also compared by gestational age and small for gestational age (SGA) (z score < -1·28) or appropriate for gestational age (AGA) (z score ≥ -1·28) categories. A total of 2966 samples of donations from 1175 mother-infant pairs to the UK Northwest Human Milk Bank between 2011 and 2017 were analysed. Mean protein, fat, carbohydrate and calculated energy were 0·89 (SD 0·24) g/dl, 2·99 (SD 0·96) g/dl, 7·09 (SD 0·44) g/dl, and 60·37 (SD 8·41) kcal/dl (252·59 (SD 35·19) kJ/dl), respectively. Preterm SGA HDM was significantly higher in protein, fat and energy content than term AGA HDM and significantly lower in carbohydrate content than term AGA HDM after controlling for LSEm, Vd and between-subject effects. Degree of prematurity did not influence macronutrient content. Between-subject effects accounted for more of the variance in macronutrient content than the fixed effects in the model. Despite this, SGA status, as well as prematurity, may be an important determinant of macronutrient content in human milk. As bioavailability of macronutrients from HDM is uncertain, studies evaluating growth and body composition in preterm and SGA babies fed HDM are warranted.

The role of nurse prescribers in memory services and their continuing professional development: A review of the literature.

BACKGROUND: Nurse prescribers (NPs) in memory services have a potentially important role in alleviating the burden of dementia on health care, but they require continuing professional development (CPD) specific to their scope of practice. AIMS: To inform development of CPD workshops for mental health NPs working in memory services, a review of the literature was undertaken regarding role and CPD issues of this professional group. DESIGN AND METHODS: Healthcare databases were searched using defined search terms alongside lateral searches. Study characteristics were extracted systematically, with results grouped thematically in the style of a narrative review. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, adapted for current methods (see Supporting Information File S1). RESULTS AND DISCUSSION: Nine articles specifically addressing nurse prescribing in memory services were found. Studies from broader areas were drawn upon. Considerable variation was found for how the role of memory service NPs might be defined, due in part to variation in characteristics of memory services. NPs, other clinical staff and patients have provided positive feedback to the introduction of the role in memory services and elsewhere. However, concerns around prescribing cautiousness of NPs were apparent. Little clinical or economic outcome data were found to compare opinions and experiences to, with none for NPs in memory services. Literature addressing CPD issues for NPs in memory services was nonexistent. Studies from surrounding areas suggest a problem with availability of CPD opportunities for nurse prescribers. CONCLUSION: This review highlights the paucity of literature for this area of inquiry, particularly for clinical, economic and other patient outcome data. RELEVANCE TO CLINICAL PRACTICE: Variation in the little existing evidence suggests development of CPD opportunities should spend time understanding issues at the local level. The gap in the literature in this area may impact policy decisions in the UK and elsewhere.

A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS.

OBJECTIVE: Capecitabine is an oral 5-fluorouracil (5-FU) pro-drug commonly used to treat colorectal carcinoma and other tumours. About 35% of patients experience dose-limiting toxicity. The few proven genetic biomarkers of 5-FU toxicity are rare variants and polymorphisms, respectively, at candidate loci dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS). DESIGN: We investigated 1456 polymorphisms and rare coding variants near 25 candidate 5-FU pathway genes in 968 UK patients from the QUASAR2 clinical trial. RESULTS: We identified the first common DPYD polymorphisms to be consistently associated with capecitabine toxicity, rs12132152 (toxicity allele frequency (TAF)=0.031, OR=3.83, p=4.31×10(-6)) and rs12022243 (TAF=0.196, OR=1.69, p=2.55×10(-5)). rs12132152 was particularly strongly associated with hand-foot syndrome (OR=6.1, p=3.6×10(-8)). The rs12132152 and rs12022243 associations were independent of each other and of previously reported DPYD toxicity variants. Next-generation sequencing additionally identified rare DPYD variant p.Ala551Thr in one patient with severe toxicity. Using functional predictions and published data, we assigned p.Ala551Thr as causal for toxicity. We found that polymorphism rs2612091, which lies within an intron of ENOSF1, was also associated with capecitabine toxicity (TAF=0.532, OR=1.59, p=5.28×10(-6)). ENSOF1 is adjacent to TYMS and there is a poorly characterised regulatory interaction between the two genes/proteins. Unexpectedly, rs2612091 fully explained the previously reported associations between capecitabine toxicity and the supposedly functional TYMS variants, 5'VNTR 2R/3R and 3'UTR 6 bp ins-del. rs2612091 genotypes were, moreover, consistently associated with ENOSF1 mRNA levels, but not with TYMS expression. CONCLUSIONS: DPYD harbours rare and common capecitabine toxicity variants. The toxicity polymorphism in the TYMS region may actually act through ENOSF1.

Visual similarity effects on masked priming.

We investigated the role of the visual similarity of masked primes to targets in a lexical decision experiment. In the primes, some letters in the target (e.g., A in ABANDON) had either visually similar letters (e.g., H), dissimilar letters (D), visually similar digits (4), or dissimilar digits (6) substituted for them. The similarities of the digits and letters to the base letter were equated and verified in a two-alternative forced choice (2AFC) perceptual identification task. Using targets presented in lowercase (e.g., abandon) and primes presented in uppercase, visually similar digit primes (e.g., 484NDON) produced more priming than did visually dissimilar digit primes (676NDON), but little difference was found between the visually similar and dissimilar letter primes (HRHNDON vs. DWDNDON). These results were explained in terms of task-driven competition between the target letter and the visually similar letter.

Preterm Formula, Fortified or Unfortified Human Milk for Very Preterm Infants, the PREMFOOD Study: A Parallel Randomised Feasibility Trial.

OBJECTIVE: Uncertainty exists regarding optimal supplemental diet for very preterm infants if the mother's own milk (MM) is insufficient. We evaluated feasibility for a randomised controlled trial (RCT) powered to detect important differences in health outcomes. METHODS: In this open, parallel, feasibility trial, we randomised infants 25+0-31+6 weeks of gestation by opt-out consent to one of three diets: unfortified human milk (UHM) (unfortified MM and/or unfortified pasteurised human donor milk (DM) supplement), fortified human milk (FHM) (fortified MM and/or fortified DM supplement), and unfortified MM and/or preterm formula (PTF) supplement from birth to 35+0 weeks post menstrual age. Feasibility outcomes included opt-outs, adherence rates, and slow growth safety criteria. We also obtained anthropometry, and magnetic resonance imaging body composition data at term and term plus 6 weeks (opt-in consent). RESULTS: Of 35 infants randomised to UHM, 34 to FHM, and 34 to PTF groups, 21, 19, and 24 infants completed imaging at term, respectively. Study entry opt-out rate was 38%; 6% of parents subsequently withdrew from feeding intervention. Two infants met predefined slow weight gain thresholds. There were no significant between-group differences in term total adipose tissue volume (mean [SD]: UHM: 0.870 L [0.35 L]; FHM: 0.889 L [0.31 L]; PTF: 0.809 L [0.25 L], p = 0.66), nor in any other body composition measure or anthropometry at either timepoint. CONCLUSIONS: Randomisation to UHM, FHM, and PTF diets by opt-out consent was acceptable to parents and clinical teams, associated with safe growth profiles and no significant differences in body composition. Our data provide justification to proceed to a larger RCT.

Effectiveness of Interventions for Preventing People With Dementia Exiting or Getting Lost.

BACKGROUND AND OBJECTIVES: People with dementia are at risk of exiting premises unsupervised, eloping, or getting lost, potentially leading to harmful or distressing consequences. This review aimed to estimate the effectiveness of interventions for preventing people with dementia from exiting or getting lost. RESEARCH DESIGN AND METHODS: A systematic review of English sources was undertaken. Health care (EMBASE, BNI, Medline, PubMed, CINAHL, PsycINFO, AMED, HTA, CENTRAL) and gray literature (OpenGrey) databases were searched using prespecified search terms. Additional studies were identified by hand-searching bibliographies of relevant reviews and included studies. Wide inclusion criteria were set to capture a range of intervention types. Data extraction and risk of bias assessment were completed independently by two reviewers. Methods were preregistered on PROSPERO. RESULTS: Individual and overall risk of bias was too high for statistical meta-analyses. A narrative synthesis was therefore performed. Twenty-five studies with 814 participants were included, investigating a range of nonpharmacological interventions aiming to prevent exiting, facilitate retrieval, educate participants, or a combination of these. Seventeen (68%) of the included studies had critical risks of internal bias to outcomes, providing no useful evidence for the effectiveness of their respective interventions. The remaining 8 (32%) studies had serious risks of bias. Narrative synthesis of results yielded no overall robust evidence for the effectiveness of any interventions. DISCUSSION AND IMPLICATIONS: No evidence was found to justify the recommendation of any interventions included in this review. Future studies should focus on high-quality, controlled study designs.

Phonological encoding in the oral but not manual Stroop task: Evidence for the role of a speech production process.

The present study investigated how response mode (oral vs. manual) modulates the Stroop effect using a picture variant of the Stroop task in which participants named orally, or identified with a manual keypress, line drawings of animals (e.g., camel). Consistent with previous color-response Stroop studies, relative to the nonlinguistic neutral distractor (a row of "#" symbols), incongruent distractors (e.g., GIRAFFE) interfered with responding to pictures, and that interference was reduced for the manual, compared with the oral, response. Additionally, pseudoword distractors with no phonological overlap with the picture name (e.g., NUST-camel) interfered with the oral, but not the manual, response. The novel finding is that relative to this pseudoword distractor, the oral response was facilitated when the distractor shared the onset segment with the picture name, regardless of orthographic overlap (e.g., CUST-camel = KUST-camel < NUST-camel); in contrast, for the manual response, there was no difference between the three pseudoword distractor conditions. These results are explained in terms of phonological encoding, a speech production process involved in computing a phonetic plan for generating an oral, but not a manual, response. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

No Negative Priming Effect in the Manual Stroop Task.

The negative priming effect is an increase in interference when the response to the target on the current trial corresponds to the response to the distractor word on a preceding trial. Contrary to the commonly held belief that the negative priming effect is ubiquitous in the Stroop task, in the original study by Neill (1977), negative priming was found only in the oral, and not the manual Stroop task. The present paper makes three empirical observations. First, we replicate the discrepancy in the finding of the negative priming effect in the oral versus manual Stroop tasks tested under identical conditions, where response mode could be the only the causal factor. Second, we point out that previous manual Stroop experiments reporting the negative priming effect confounded the effect of response repetition. Third, we report the analysis of the negative priming effect at the level of whole RT distribution, which revealed that the effect was absent throughout the RT distribution in the manual task, and it was of constant size across the RT distribution in the oral task. Implications of the results for conflict control in the Stroop task is discussed.

The semantic Stroop effect is controlled by endogenous attention.

Using the oral and manual Stroop tasks we tested the claim that retrieval of meaning from a written word is automatic, in the sense that it cannot be controlled. The semantic interference effect (greater interference caused by color-related words than color-neutral words) was used as the index of semantic activation. To manipulate the level of attentional control over the task of reading, the proportion of nonreadable, neutral trials (a row of #s) was varied (75% vs. 25%). In all four experiments a high-neutral proportion magnified the interference caused by word distractors. With the color-associated words presented in incongruent color (e.g., LEMON in blue), the semantic Stroop effect was weak and did not interact with neutral proportion (Experiment 1 and 2). Experiment 3 and 4 used color names (e.g., GREEN) not in the response set, and here the semantic interference effect was more robust, and the effect was magnified in the high-neutral proportion condition. We take these results to argue that semantic retrieval is controlled by endogenous attention in the Stroop task. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition.

High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutated POLE exonuclease domain-mutant ECs (POLE-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated in POLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in POLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8+ (90% and 69%), PD-1+ (73% and 69%) and PD-L1+ immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8+ cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-rich POLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.

Development of Early Adiposity in Infants of Mothers With Gestational Diabetes Mellitus.

OBJECTIVE: Infants born to mothers with gestational diabetes mellitus (GDM) are at greater risk of later adverse metabolic health. We examined plausible candidate mediators, adipose tissue (AT) quantity and distribution and intrahepatocellular lipid (IHCL) content, comparing infants of mothers with GDM and without GDM (control group) over the first 3 postnatal months. RESEARCH DESIGN AND METHODS: We conducted a prospective longitudinal study using MRI and spectroscopy to quantify whole-body and regional AT volumes, and IHCL content, within 2 weeks and 8-12 weeks after birth. We adjusted for infant size and sex and maternal prepregnancy BMI. Values are reported as the mean difference (95% CI). RESULTS: We recruited 86 infants (GDM group 42 infants; control group 44 infants). Mothers with GDM had good pregnancy glycemic control. Infants were predominantly breast-fed up to the time of the second assessment (GDM group 71%; control group 74%). Total AT volumes were similar in the GDM group compared with the control group at a median age of 11 days (-28 cm(3) [95% CI -121, 65], P = 0.55), but were greater in the GDM group at a median age of 10 weeks (247 cm(3) [56, 439], P = 0.01). After adjustment for size, the GDM group had significantly greater total AT volume at 10 weeks than control group infants (16.0% [6.0, 27.1], P = 0.002). AT distribution and IHCL content were not significantly different at either time point. CONCLUSIONS: Adiposity in GDM infants is amplified in early infancy, despite good maternal glycemic control and predominant breast-feeding, suggesting a potential causal pathway to later adverse metabolic health. Reduction in postnatal adiposity may be a therapeutic target to reduce later health risks.

Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis.

Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.

Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study.

BACKGROUND: Precision cancer medicine depends on defining distinct tumour subgroups using biomarkers that may occur at very modest frequencies. One such subgroup comprises patients with exceptionally mutated (ultramutated) cancers caused by mutations that impair DNA polymerase epsilon (POLE) proofreading. METHODS: We examined the association of POLE proofreading domain mutation with clinicopathological variables and immune response in colorectal cancers from clinical trials (VICTOR, QUASAR2, and PETACC-3) and colorectal cancer cohorts (Leiden University Medical Centre 1 and 2, Oslo 1 and 2, Bern, AMC-AJCC-II, and Epicolon-1). We subsequently investigated its association with prognosis in stage II/III colorectal cancer by Cox regression of pooled individual patient data from more than 4500 cases from these studies. FINDINGS: Pathogenic somatic POLE mutations were detected in 66 (1·0%) of 6517 colorectal cancers, and were mutually exclusive with mismatch repair deficiency (MMR-D) in the 6277 cases for whom both markers were determined (none of 66 vs 833 [13·4%] of 6211; p<0·0001). Compared with cases with wild-type POLE, cases with POLE mutations were younger at diagnosis (median 54·5 years vs 67·2 years; p<0·0001), were more frequently male (50 [75·8%] of 66 vs 3577 [55·5%] of 6445; p=0·0010), more frequently had right-sided tumour location (44 [68·8%] of 64 vs 2463 [39·8%] of 6193; p<0·0001), and were diagnosed at an earlier disease stage (p=0·006, χ2 test for trend). Compared with mismatch repair proficient (MMR-P) POLE wild-type tumours, POLE-mutant colorectal cancers displayed increased CD8+ lymphocyte infiltration and expression of cytotoxic T-cell markers and effector cytokines, similar in extent to that observed in immunogenic MMR-D cancers. Both POLE mutation and MMR-D were associated with significantly reduced risk of recurrence compared with MMR-P colorectal cancers in multivariable analysis (HR 0·34 [95% CI 0·11-0·76]; p=0·0060 and 0·72 [0·60-0·87]; p=0·00035), although the difference between the groups was not significant. INTERPRETATION: POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. This association underscores the importance of rare biomarkers in precision cancer medicine, but also raises important questions about how to identify and implement them in practice. FUNDING: Cancer Research UK, Academy of Medical Sciences, Health Foundation, EU, ERC, NIHR, Wellcome Trust, Dutch Cancer Society, Dutch Digestive Foundation.

Five endometrial cancer risk loci identified through genome-wide association analysis.

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche.

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer.

PURPOSE: Recent studies have shown that 7% to 12% of endometrial cancers are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response, and clinical outcome in cancer, we investigated whether POLE-mutant endometrial cancers showed evidence of increased immunogenicity. EXPERIMENTAL DESIGN: We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined endometrial cancer cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA endometrial cancer series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant endometrial cancers. RESULTS: Compared with other endometrial cancers, POLE mutants displayed an enhanced cytotoxic T-cell response, evidenced by increased numbers of CD8(+) tumor-infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T-cell gene signature, and strong upregulation of the T-cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF, and granzyme B. This was accompanied by upregulation of T-cell exhaustion markers, consistent with chronic antigen exposure. In silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neoepitopes than other endometrial cancers, providing a potential explanation for our findings. CONCLUSIONS: Ultramutated POLE proofreading-mutant endometrial cancers are characterized by a robust intratumoral T-cell response, which correlates with, and may be caused by an enrichment of antigenic neopeptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers.