Search

Objective: To investigate cell-free DNA (cfDNA) in plasma and ascites and its association with clinical outcomes (paracentesis-free interval, overall survival) and CA125 level in participants with advanced ovarian cancer, treated with palliative intraperitoneal bevacizumab to delay re-accumulation of ascites. Methods: cfDNA was extracted from 0.3 to 1 mL samples from 20/24 participants of the REZOLVE trial. Standard and methylation-specific PCRs were performed to measure 3 biomarkers: total cfDNA (Alu), tumour-derived cfDNA (ctDNA, methylated IFFO1 promoter) and endothelium-derived cfDNA (ec-cfDNA, unmethylated CDH5 promoter). Values were correlated to clinical outcomes. Results: cfDNA was detected in all samples, with higher yield in ascites (mean 669 ng/mL) than plasma (mean 75 ng/mL, p < 0.0001). Ascites had a higher ctDNA proportion than plasma (74 % vs. 20 %, p < 0.0001) and plasma had a higher ec-cfDNA proportion than ascites (24 % vs. 16 %, p < 0.002). High ctDNA proportion (>75 %) in ascites was associated with a significantly shorter paracentesis-free interval (median interval 47.5 versus 84 days, hazard ratio (HR) 2.21, 95 % confidence interval (CI) 0.85 to 5.73, p = 0.039) and ctDNA presence in plasma was unfavourable for survival (median survival 56 versus 242 days, HR 3.21, 95 % CI 1.15 to 9.00, p = 0.008). A significant positive correlation was observed between ctDNA proportion in plasma and CA125 level (p = 0.012). No significant difference in total cfDNA, ctDNA nor ec-cfDNA was observed between participants who were responders versus non-responders. Conclusion: Sufficient cfDNA was detected in both plasma and ascites to study three biomarkers. These samples can provide useful information and should be considered in the design of future ovarian cancer trials.

Introduction People with advanced non-small cell lung cancer (NSCLC) treated with immunotherapies (IT) or targeted therapies (TT) may have improved outcomes in a subset of people who respond, raising unique psychological concerns requiring specific attention. These include the need for people with prolonged survival to reframe their life plans and tolerate uncertainty related to treatment duration and prognosis. A brief intervention for people with advanced cancer, Managing Cancer and Living Meaningfully (CALM), could help people treated with IT or TT address these concerns. However, CALM has not been specifically evaluated in this population. This study aims to evaluate the acceptability and feasibility of CALM in people with advanced NSCLC treated with IT or TT and obtain preliminary evidence regarding its effectiveness in this population.Methods and analysis Twenty people with advanced NSCLC treated with IT or TT will be recruited from Peter MacCallum Cancer Centre, Melbourne, Australia. Participants will complete three to six sessions of CALM delivered over 3–6 months. A prospective, single-arm, mixed-methods pilot study will be conducted. Participants will complete outcome measures at baseline, post-intervention, 3 months and 6 months, including Patient Health Questionnaire, Death and Dying Distress Scale, Functional Assessment of Cancer Therapy General and Clinician Evaluation Questionnaire. The acceptability of CALM will be assessed using patient experiences surveys and qualitative interviews. Feasibility will be assessed by analysis of recruitment rates, treatment adherence and intervention delivery time.Ethics and dissemination Ethics approval has been granted by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/82047/PMCC). Participants with cancer will complete a signed consent form prior to participation, and carers and therapists will complete verbal consent. Results will be made available to funders, broader clinicians and researchers through conference presentations and publications. If CALM is found to be acceptable in this cohort, this will inform a potential phase 3 trial.

Introduction Epidemiological evidence supports an association between higher levels of physical activity and improved cancer survival. Trial evidence is now needed to demonstrate the effect of exercise in a clinical setting. The Exercise during CHemotherapy for Ovarian cancer (ECHO) trial is a phase III, randomised controlled trial, designed to determine the effect of exercise on progression-free survival and physical well-being for patients receiving first-line chemotherapy for ovarian cancer.Methods and analysis Participants (target sample size: n=500) include women with newly diagnosed primary ovarian cancer, scheduled to receive first-line chemotherapy. Consenting participants are randomly allocated (1:1) to either the exercise intervention (plus usual care) or usual care alone, with stratification for recruitment site, age, stage of disease and chemotherapy delivery (neoadjuvant vs adjuvant). The exercise intervention involves individualised exercise prescription with a weekly target of 150 minutes of moderate-intensity, mixed-mode exercise (equivalent to 450 metabolic equivalent minutes per week), delivered for the duration of first-line chemotherapy through weekly telephone sessions with a trial-trained exercise professional. The primary outcomes are progression-free survival and physical well-being. Secondary outcomes include overall survival, physical function, body composition, quality of life, fatigue, sleep, lymphoedema, anxiety, depression, chemotherapy completion rate, chemotherapy-related adverse events, physical activity levels and healthcare usage.Ethics and dissemination Ethics approval for the ECHO trial (2019/ETH08923) was granted by the Sydney Local Health District Ethics Review Committee (Royal Prince Alfred Zone) on 21 November 2014. Subsequent approvals were granted for an additional 11 sites across Queensland, New South Wales, Victoria and the Australian Capital Territory. Findings from the ECHO trial are planned to be disseminated via peer-reviewed publications and international exercise and oncology conferences.Trial registration number Australian New Zealand Clinical Trial Registry (ANZCTRN12614001311640; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367123&isReview=true).

Background Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs.Methods Patients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed.Results A total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB (>10 mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p

BackgroundWhile multiple clinical trials have demonstrated benefits of early palliative care for people with cancer, access to these services is frequently very late if at all. Establishing evidence-based, disease-specific ‘triggers’ or times for the routine integration of early palliative care may address this evidence-practice gap.AimTo test the feasibility of using defined triggers for the integration of standardised, early palliative (STEP) care across three advanced cancers.MethodPhase II, multi-site, open-label, parallel-arm, randomised trial of usual best practice cancer care +/- STEP Care conducted in four metropolitan tertiary cancer services in Melbourne, Australia in patients with advanced breast, prostate and brain cancer. The primary outcome was the feasibility of using triggers for times of integration of STEP Care, defined as enrolment of at least 30 patients per cancer in 24 months. Triggers were based on hospital admission with metastatic disease (for breast and prostate cancer), or development of disease recurrence (for brain tumour cohort). A mixed method study design was employed to understand issues of feasibility and acceptability underpinning trigger points.ResultsThe triggers underpinning times for the integration of STEP care were shown to be feasible for brain but not breast or prostate cancers, with enrolment of 49, 6 and 10 patients across the three disease groups respectively. The varied feasibility across these cancer groups suggested some important characteristics of triggers which may aid their utility in future work.ConclusionsAchieving the implementation of early palliative care as a standardized component of quality care for all oncology patients will require further attention to defining triggers. Triggers which are 1) linked to objective points within the illness course (not dependent on recognition by individual clinicians), 2) Identifiable and visible (heralded through established service-level activities) and 3) Not reliant upon additional screening measures may enhance their feasibility.

Purpose: Endometrial cancer is associated with the highest comorbid disease burden of any cancer. The aim of this trial was to assess the feasibility and safety of an allied health intervention during adjuvant treatment. Methods: A mixed-methods pilot randomized (2:1) controlled trial with concealed allocation and assessor-blinding. Eligibility criteria: adjuvant endometrial cancer treatment scheduled, disease stage I-IIIC1, ECOG 0-2 and able to perform unsupervised physical activity (PA). Participants received usual care and 8 sessions of weekly, individualized, lifestyle education (diet and PA) with behavior change and social support (intervention group), delivered predominantly by telehealth, or usual care alone. Feasibility outcomes: recruitment and consent rates, decline reasons, program acceptability, intervention adherence and retention. Results: 22/44 eligible patients (50%, 95%CI: 36%, 64%) were recruited over 10 months (14 intervention, 8 usual care). The recruitment rate was 2.2 patients/month (95%CI: 1.4, 3.3). Patients who declined had too much going on (7/22, 32%) or were not interested (6/22, 27%). Mean (SD) age and BMI were 63.2 years (6.8) and 31.9 kg/m 2 (6.7). A majority were FIGO stage I (15/22, 68%) and received vaginal brachytherapy (14/22, 64%). Adherence was high, 11/14 (79%, 95%CI: 52%, 92%) participants attended >70% of scheduled sessions. Retention was 100% (95%CI: 85%, 100%) at 9 weeks, however completion of objective measures was impacted by COVID-19 restrictions. Telehealth and online questionnaires enabled participation. No serious adverse events occurred. Conclusion: The intervention was acceptable to participants with high levels of adherence and retention. Trial findings will be used to design a future RCT. Trial registration: The trial was registered on www.anzctr.org.au (ACTRN12619000631101) 29/04/2019.

Acquired resistance limits the efficacy of PARP inhibitors (PARPi) in high grade serous ovarian cancer (HGSOC). Here, the authors show that inhibition of RNA polymerase I transcription using CX-5461 increases the therapeutic efficacy of PARPi and overcomes PARPi resistance in PDX models of HGSOC.

Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.

Background In this study, we assessed the activity of durvalumab, an antibody to programmed death ligand-1, in two cohorts of women with advanced endometrial cancers (AEC)—mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR).Methods A multicenter phase two study was performed in women with AEC with pMMR tumor progressing after one to three lines of chemotherapy and women with AEC with dMMR tumor progressing after zero to three lines of chemotherapy. Mismatch repair status was based on immunohistochemistry expression. All women received durvalumab 1500 mg given every 4 weeks until progression or unacceptable toxicity. The primary endpoint was objective tumor response by RECIST V.1.1 modified for immune-based therapeutics.Results Seventy-one women were recruited: 35 dMMR and 36 pMMR. Median follow-up was 19 vs 21 months in dMMR versus pMMR, respectively. Median age was 67 years. Histology in dMMR versus pMMR included endometrioid (94% vs 57%) and serous (0% vs 31%) and was high grade in 26% vs 74%. The objective tumor response rate (OTRR) in the dMMR cohort was 47% (17/36, 95% CI 32 to 63), including 6 complete responses and 11 partial responses (PRs)) vs 3% in the pMMR cohort (1/35, 95% CI 1 to 15, PR). In the dMMR cohort, durvalumab was the first-line therapy in 58% (OTRR 57%) and the second-line therapy in 39% (OTRR 38%). Median progression-free survival was 8.3 months in the dMMR cohort vs 1.8 months in the pMMR cohort. The 12-month overall survival (OS) rate was 71% in dMMR vs 51% in pMMR, with median OS not reached for dMMR vs 12 months for pMMR. Immune-related adverse events occurred in 14 women, mostly grades 1–2.Conclusion Durvalumab monotherapy showed promising activity and acceptable safety in AEC with dMMR regardless of prior lines of chemotherapy, but activity was limited in AEC with pMMR.Trial registration numbers ANZGOG1601, ACTRN12617000106336, and NCT03015129.

Whether mucinous ovarian carcinoma (MOC) arises from cells at the ovary or from metastases from other primary sites is an unanswered question. Here, Cheasley et al perform a genetic analysis of the disease, showing that MOC arises at the ovary.

Abstract Background Current international consensus is that ‘early’ referral to palliative care services improves cancer patient and family carer outcomes; however, in practice, these referrals are not routine. Uncertainty about the ‘best time’ to refer has been highlighted as contributing to care variation. Previous work has identified clear disease-specific transition points in the cancer illness which heralded subsequent poor prognosis (less than 6 months) and which, we contest, represent times when palliative care should be routinely introduced as a standardised approach, if not already in place, to maximise patient and carer benefit. This protocol details a trial that will test the feasibility of a novel standardised outpatient model of early palliative care [Standardised Early Palliative Care (STEP Care)] for advanced cancer patients and their family carers, with referrals occurring at the defined disease-specific evidence-based transition points. The aims of this study are to (1) determine the feasibility of conducting a definitive phase 3 randomised trial, which evaluates effectiveness of STEP Care (compared to usual best practice cancer care) for patients with advanced breast or prostate cancer or high grade glioma; (2) examine preliminary efficacy of STEP Care on patient/family caregiver outcomes, including quality of life, mood, symptoms, illness understanding and overall survival; (3) document the impact of STEP Care on quality of end-of-life care; and (4) evaluate the timing of palliative care introduction according to patients, families and health care professionals. Methods Phase 2, multicenter, open-label, parallel-arm, randomised controlled trial (RCT) of STEP Care plus standard best practice cancer care versus standard best practice cancer care alone. Discussion The research will test the feasibility of standardised palliative care introduction based on illness transitions and provide guidance on subsequent development of phase 3 studies of integration. This will directly address the current uncertainty about palliative care timing. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12617000534381.

Knowledge of contemporary patterns of cancer-of-unknown-primary-origin (CUP) diagnostic work-up, treatment, and outcomes in routine healthcare is limited. Thus, we examined data from elderly patients diagnosed with CUP in real-world US clinical practice. From the Surveillance, Epidemiology, and End Results–Medicare-linked database, we included patients ≥ 66 years old with CUP diagnosed between 1 January 2013 and 31 December 2015. We analyzed baseline demographics, clinical characteristics, methods of diagnostic work-up (biopsy, immunohistochemistry, imaging), treatment-related factors, and survival. CUP diagnosis was histologically confirmed in 2813/4562 patients (61.7%). Overall, 621/4562 (13.6%) patients received anticancer pharmacotherapy; among these, 97.3% had a histologically confirmed tumor and 83.1% received all three procedures. Among those with a histologically confirmed tumor, increasing age, increasing comorbidity score, not receiving all three diagnostic measures, and having a not-further specified histologic finding of only ‘malignant neoplasm’ were all negatively associated with receipt of anticancer pharmacotherapy. Median overall survival was 1.2 months for all patients. Median time between CUP diagnosis and treatment initiation was 41 days. Limited diagnostic work-up was common and most patients did not receive anticancer pharmacotherapy. The poor outcomes highlight a substantial unmet need for further research into improving diagnostic work-up and treatment effectiveness in CUP.

Objectives To report clinician-perceived changes to cancer service delivery in response to COVID-19.Design Multidisciplinary Australasian cancer clinician survey in collaboration with the European Society of Medical Oncology.Setting Between May and June 2020 clinicians from 70 countries were surveyed; majority from Europe (n=196; 39%) with 1846 COVID-19 cases per million people, Australia (AUS)/New Zealand (NZ) (n=188; 38%) with 267/236 per million and Asia (n=75; 15%) with 121 per million at time of survey distribution.Participants Medical oncologists (n=372; 74%), radiation oncologists (n=91; 18%) and surgical oncologists (n=38; 8%).Results Eighty-nine per cent of clinicians reported altering clinical practices; more commonly among those with versus without patients diagnosed with COVID-19 (n=142; 93% vs n=225; 86%, p=0.03) but regardless of community transmission levels (p=0.26). More European clinicians (n=111; 66.1%) had treated patients diagnosed with COVID-19 compared with Asia (n=20; 27.8%) and AUS/NZ (n=8; 4.8%), p

Cervical cancer is the fourth most common cancer in women with 85% of the mortality burden occurring in less-developed regions of the world. The Cervix Cancer Research Network (CCRN) was founded by the Gynecologic Cancer InterGroup (GCIG) with a mission to improve outcomes in cervix cancer by increasing access to high-quality clinical trials worldwide, with particular attention to less-developed, underrepresented sites. The CCRN held its second international educational symposium in Mexico City with ninety participants from fifteen Latin America countries in January 2017. The purpose of this symposium was to advance knowledge in cervix cancer therapy, promote recruitment to CCRN clinical trials, and to identify relevant future CCRN clinical trial concepts that could improve global care standards for women with cervical cancer. Keywords: Cervix cancer, Cervical cancer, Radiotherapy, CCRN, Hypofractionation

Abstract Background Patient-reported outcome (PRO) data is central to the delivery of quality health care. Establishing sustainable, reliable and cost-efficient methods for routine collection and integration of PRO data into health information systems is challenging. This protocol paper describes the design and structure of a study to develop and pilot test a PRO framework to systematically and longitudinally collect PRO data from a cohort of lung cancer patients at a comprehensive cancer centre in Australia. Methods Best-practice guidelines for developing registries aimed at collecting PROs informed the development of this PRO framework. Framework components included: achieving consensus on determining the purpose of the framework, the PRO measures to be included, the data collection time points and collection methods (electronic and paper), establishing processes to safeguard the quality of the data collected and to link the PRO framework to an existing hospital-based lung cancer clinical registry. Lung cancer patients will be invited to give feedback on the PRO measures (PROMs) chosen and the data collection time points and methods. Implementation of the framework will be piloted for 12 months. Then a mixed-methods approach used to explore patient and multidisciplinary perspectives on the feasibility of implementing the framework and linking it to the lung cancer clinical registry, its clinical utility, perceptions of data collection burden, and preliminary assessment of resource costs to integrate, implement and sustain the PRO framework. The PRO data set will include: a quality of life questionnaire (EORTC-QLQ-C30) and the EORTC lung cancer specific module (QLQC-LC-13). These will be collected pre-treatment (baseline), 2, 6 and 12 months post-baseline. Also, four social isolation questions (PROMIS) will be collected at baseline. Discussion Identifying and deciding on the overall purpose, clinical utility of data and which PROs to collect from patients requires careful consideration. Our study will explore how PRO data collection processes that link to a clinical data set can be developed and integrated; how PRO systems that are easy for patients to complete and professionals to use in practice can be achieved, and will provide indicative costs of developing and integrating a longitudinal PRO framework into routine hospital data collection systems. Trial registration This study is not a clinical trial and is therefore not registered in any trial registry. However, it has received human research ethics approval (LNR/16/PMCC/45).

Abstract Background Lung cancer is one of the most commonly diagnosed cancers, and is a leading cause of cancer mortality world-wide. Due to lack of early specific symptoms, the majority of patients present with advanced, inoperable disease and five-year relative survival across all stages of non-small cell lung cancer (NSCLC) is 14%. People with lung cancer also report higher levels of symptom distress than those with other forms of cancer. Several benefits for survival and patient reported outcomes are reported from physical activity and exercise in other tumour groups. We report the protocol for a study investigating the benefits of exercise, behaviour change and symptom self-management for patients with recently diagnosed, inoperable, NSCLC. Methods This multi-site, parallel-group, assessor-blinded randomised controlled trial, powered for superiority, aims to assess functional and patient-reported outcomes of a multi-disciplinary, home-based exercise and supportive care program for people commencing treatment. Ninety-two participants are being recruited from three tertiary-care hospitals in Melbourne, Australia. Following baseline testing, participants are randomised using concealed allocation, to receive either: a) 8 weeks of home-based exercise (comprising an individualised endurance and resistance exercise program and behaviour change coaching) and nurse-delivered symptom self-management intervention or b) usual care. The primary outcome is the between-group difference in the change in functional exercise capacity (six-minute walk distance) from baseline to post-program assessment. Secondary outcomes include: objective and self-reported physical activity levels, physical activity self-efficacy, behavioural regulation of motivation to exercise and resilience, muscle strength (quadriceps and grip), health-related quality of life, anxiety and depression and symptom interference. Discussion There is a lack of evidence regarding the benefit of exercise intervention for people with NSCLC, particularly in those with inoperable disease receiving treatment. This trial will contribute to evidence currently being generated in national and international trials by implementing and evaluating a home-based program including three components not yet combined in previous research, for people with inoperable NSCLC receiving active treatment and involving longer-term follow-up of outcomes. This trial is ongoing and currently recruiting. Trial registration This trial was prospectively registered on the Australian New Zealand Clinical Trials Registry ( ACTRN12614001268639 : (4/12/14).

Background/purpose: Chemoradiation (CRT) is standard therapy for locally advanced cervical cancer (LACC). However, there is a lack of biomarkers to identify patients at high relapse-risk. We examine metabolic (glucose transporter-1 [Glut-1]), hypoxic (hypoxia inducible factor [HIF-1α]; carbonic anhydrase [CA-9]) and proliferative (Ki-67) markers for prognostic utility in LACC. Materials/methods: 60 LACC patients treated with CRT had pre-treatment biopsies. Immunohistochemistry was performed for Glut-1, HIF-1a and CA-9, to generate a histoscore from intensity and percentage staining; and Ki-67 scored by percentage of positive cells. For each biomarker, treatment response and survival was compared between low and high-staining groups by logrank testing and multivariate analyses. Results: High Glut-1 expression was associated with inferior progression-free survival (PFS), (hazard ratio [HR] 2.8, p = 0.049) and overall survival (OS), (HR 5.0, p = 0.011) on multifactor analysis adjusting for stage, node positivity, tumour volume and uterine corpus invasion. High Glut-1 correlated with increased risk of distant failure (HR 14.6, p = 0.001) but not local failure. Low Glut-1 was associated with higher complete metabolic response rate on post-therapy positron emission tomography scan (odds ratio 3.4, p = 0.048). Ki-67 was significantly associated with PFS only (HR 1.19 per 10 units increase, p = 0.033). Biomarkers for hypoxia were not associated with outcome. Conclusions: High Glut-1 in LACC is associated with poor outcome post CRT. If prospectively validated, Glut-1 may help select patients for more intensive treatment regimens.

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.

Background and Objectives In vitro studies suggest that thalidomide has an immunoregulatory role and alters the marrow microenvironment. We assessed laboratory and clinical parameters in patients with myeloma treated with thalidomide as potential prognostic markers and looked for changes with therapy.Design and Methods Seventy-five patients with relapsed/refractory myeloma received thalidomide in a phase II trial. Serial samples of platelet-poor plasma and bone marrow were tested for angiogenic cytokines including vascular endothelial growth factor (VEGF), marrow microvessel-density (MVD), mast cells and CD57+ cell expression. The effects of these parameters on response rate (RR), progression-free survival (PFS) and overall survival (OS) were analyzed.Results Elevated baseline VEGF predicted for a superior RR (p=0.018) and PFS. Elevated CD57+ cells also predicted superior PFS (p=0.012). MVD did not predict for RR, PFS or OS, but MVD and VEGF fell significantly in responders. Multivariate analysis identified that inferior OS was associated with age >65 years (p=0.017), raised lactate dehydrogenase (p=0.001), raised hepatocyte growth factor levels (p=0.012) and low pre-treatment CD57+ cells (p