Status Burden Research Articles

The Combination of Radiation Therapy and Immunotherapy Is Effective and Well-Tolerated for Unresectable Biliary Tract Cancer

For unresectable biliary tract cancer (BTC), chemotherapy (CT) alone is associated with poor survival and severe toxicity. Immunotherapy (IO) is potentially effective for BTC, and radiation therapy (RT) may synergize with IO. We investigated CT versus combined RT and anti-programmed cell death-1 (PD-1) IO for unresectable BTC. We prospectively observed 117 participants with unresectable BTC either at initial diagnosis or at first recurrence at a single center who chose 1 of 2 treatment options between August 2018 and October 2020. The options were (1) external beam RT combined with anti-PD-1 IO (RT/IO) or (2) CT alone. In the RT/IO group, camrelizumab (200 mg intravenously every 3 weeks) was initiated within 7 days after the completion of RT and continued until progression or intolerable side effects were noted. The median dose per fraction was 55 Gy/25 fractions (range, 50-60 Gy/20-25 fractions). In the CT group, cisplatin and gemcitabine were delivered intravenously every 3 weeks for 8 cycles. We analyzed the adverse events (AEs), overall survival (OS), and disease-free survival (DFS), and performed subgroup analysis according to tumor mutational burden (TMB) and microsatellite status in the combination group. Thirty-nine and 78 participants received RT/IO and CT, respectively. The crude rate of severe AEs (grade ≥3 AEs) was higher in the CT group (79.4% vs 7.7%, P < .001). The OS and DFS after RT/IO were longer than that after CT (median OS: 17.0 vs 11.5 months, P=.01; median DFS: 12.5 vs 7.9 months, P=.008). Participants with low TMB or microsatellite stability had a shorter median OS (13.6 vs 25.7 months, P=.03) and median DFS (9.8 vs 19.3 months, P=.012) than participants with high TMB or microsatellite instability. RT combined with anti-PD-1 IO may be well tolerated and associated with an improved response rate, DFS, and OS compared with CT alone in patients with unresectable BTC.

Establish of an Initial Platinum-Resistance Predictor in High-Grade Serous Ovarian Cancer Patients Regardless of Homologous Recombination Deficiency Status.

BackgroundsOvarian cancer (OC) is still the leading aggressive and lethal disease of gynecological cancers, and platinum-based regimes are the standard treatments. However, nearly 20%–30% of patients with OC are initial platinum resistant (IPR), and there is a lack of valid tools to predict whether they will be primary platinum resistant or not prior to chemotherapy.MethodsTranscriptome data from The Cancer Genome Atlas (TCGA) was downloaded as the training data, and transcriptome data of GSE15622, GSE102073, GSE19829, and GSE26712 were retrieved from Gene Expression Omnibus (GEO) as the validation cohorts. Differentially expressed genes (DEGs) were selected between platinum-sensitive and platinum-resistant patients from the training cohort, and multiple machine-learning algorithms [including random forest, XGboost, and least absolute shrinkage and selection operator (LASSO) regression] were utilized to determine the candidate genes from DEGs. Then, we applied logistic regression to establish the IPR signature based on the expression. Finally, comprehensive clinical, genomic, and survival feature were analyzed to understand the application value of the established IPR signature.ResultsA total of 532 DEGs were identified between platinum-resistant and platinum-sensitive samples, and 11 of them were shared by these three-machine learning algorithms and utilized to construct an IPR prediction signature. The area under receiver operating characteristic curve (AUC) was 0.841 and 0.796 in the training and validation cohorts, respectively. Notably, the prediction capacity of this signature was stable and robust regardless of the patients’ homologous recombination deficiency (HRD) and mutation burden status. Meanwhile, the genomic feature was concordant between samples with high- or low-IPR signature, except a significantly higher prevalence of gain at Chr19q.12 (regions including CCNE1) in the high-IPR signature samples. The efficacy of prediction of platinum resistance of IPR signature successfully transferred to the precise survival prediction, with the AUC of 0.71, 0.72, and 0.66 to predict 1-, 3-, and 5-year survival, respectively. At last, we found a significantly different tumor-infiltrated lymphocytes feature, including lower abundance of CD4+ naive T cells in the samples with high-IPR signature. A relatively lower tumor immune dysfunction and exclusion (TIDE) value and more sensitivity to multiple therapies including Gefitinib may suggest the potency to transfer from platinum-based therapy to immunotherapy or target therapies in patients with high-IPR signature.ConclusionOur study established an IPR signature based on the expression of 11 genes that could stably and robustly distinguish OC patients with IPR and/or poor outcomes, which may guide therapeutic regimes tailoring.

Optimal Threshold of Neutrophil-Lymphocyte Ratio and its Association with Survival Outcome Among Patients with Head and Neck Cancer in the United States

<h3>Purpose/Objective(s)</h3> Given the role of inflammation in cancer progression, neutrophil-lymphocyte ratio (NLR) from peripheral blood has been suggested as a read-out of systemic inflammation and a prognostic marker in several solid malignancies. However, optimal threshold for NLR in North American head and neck cancer patients remains unclear. We performed an observational cohort study to determine the optimal NLR threshold as a prognostic biomarker for survival outcomes. <h3>Materials/Methods</h3> A single-institution, retrospective database was queried for patients with non-metastatic head and neck cancer who underwent radiation therapy from January 2005 to April 2021. A threshold for NLR was determined by Cox proportional hazard model for OS using restricted cubic splines (RCS), and patients were then stratified into two cohorts by above versus below the model-derived threshold for their NLR. Cox multivariable analysis (MVA) and Kaplan-Meier method were used to analyze overall survival (OS) and disease-specific survival (DSS) outcomes. Logistic MVA was performed to identify variables associated with elevated NLR. To reduce selection bias, propensity score matching was used based on nearest neighbor method in a 1:1 ratio without replacements. <h3>Results</h3> A total of 753 patients were included for analysis. Median follow up was 29.7 months (interquartile range 17.8-57.8). Cox MVA using RCS showed a threshold of NLR at 4.82, with worsening OS in a continuous fashion without plateau as NLR increases. High NLR above 4.82 was associated with worse OS (adjusted hazards ratio [aHR] 1.73, 95% confidence interval [CI] 1.26-2.37, p<0.001) and DSS (aHR 1.77, 95% CI 1.22-2.56, p=0.003). Similar findings were noted in 103 matched pairs (OS: aHR 1.85, 95% CI 1.19-2.90, p=0.007; DSS: aHR 1.91, 95% CI 1.11-3.28, p=0.02). On logistic MVA, patients were more likely to have high NLR if they had a higher T staging (adjusted odds ratio [aOR] 1.75, 95% CI 1.14-2.73, p=0.01), but less likely if they had a good performance status (aOR 0.45, 95% CI 0.29-0.69, p<0.001). Among 466 patients with available HPV data, high NLR was not associated with OS (aHR 1.38, 0.89-2.15, p=0.15) and DSS (aHR 1.15, 95% CI 0.67-1.97, p=0.62). <h3>Conclusion</h3> High NLR based on a model-derived threshold was associated with worse survival. Patients with significant primary disease burden and poor performance status were more likely to have high NLR. Further studies would be warranted to investigate the role of such prognostic marker to identify patients at risk to tailor interventions.

Tumor mutational burden and somatic mutation status to predict disease recurrence in advanced melanoma.

Tumor mutational burden (TMB) has recently been identified as a biomarker of response to immune checkpoint inhibitors in many cancers, including melanoma. Co-assessment of TMB with inflammatory markers and genetic mutations may better predict disease outcomes. The goal of this study was to evaluate the potential for TMB and somatic mutations in combination to predict the recurrence of disease in advanced melanoma. A retrospective review of 85 patients with stage III or IV melanoma whose tumors were analyzed by next-generation sequencing was conducted. Fisher's exact test was used to assess differences in TMB category by somatic mutation status as well as recurrence locations. Kaplan-Meier estimates and Cox-proportional regression model were used for survival analyses. The most frequently detected mutations were TERT (32.9%), CDKN2A (28.2%), KMT2 (25.9%), BRAF V600E (24.7%), and NRAS (24.7%). Patients with TMB-L + BRAFWT status were more likely to have a recurrence [hazard ratio (HR), 3.43; confidence interval (CI), 1.29-9.15; P = 0.01] compared to TMB-H + BRAF WT. Patients with TMB-L + NRASmut were more likely to have a recurrence (HR, 5.29; 95% CI, 1.44-19.45; P = 0.01) compared to TMB-H + NRAS WT. TMB-L tumors were associated with local (P = 0.029) and in-transit (P = 0.004) recurrences. Analysis of TMB alone may be insufficient in understanding the relationship between melanoma's molecular profile and the body's immune system. Classification into BRAFmut, NRASmut, and tumor mutational load groups may aid in identifying patients who are more likely to have disease recurrence in advanced melanoma.

Abstract P4-10-22: Patient reported symptoms and functional status in breast cancer

Abstract Background: To improve symptom management in cancer patients, the province of Ontario (Canada) implemented the collection of the Edmonton Symptom Assessment System (ESAS) and Patient-Reported Functional Status (PRFS) tool at cancer centre outpatient visits. ESAS measures 9 symptoms on a scale from 0 (no symptoms) to 10 (worst possible symptom); scores &amp;gt; 4 (moderate to severe) require intervention. The PRFS tool is a version of the Eastern Cooperative Oncology Group performance status tool designed to be completed by the patient; scores range from 0 (“normal with no limitation”) to 4 (“pretty much bedridden, rarely out of bed”). Our main objective was to describe the symptom burden and functional status of breast cancer (BC) patients.Methods: This cross-sectional study included women with stage I-IV BC who completed the ESAS and the PRFS tool during outpatient clinic visits at 2 Toronto academic centres. ESAS and PRFS scores were described for 3 participant groups: women diagnosed with early-stage BC (ESBC= stages I-III) in the year prior to enrolment; women with ESBC diagnosed &amp;gt; 1 year prior to enrolment; and women with metastatic BC. Multivariable logistic regression models were used to identify factors associated with ESAS scores &amp;gt; 4 for each ESAS symptom. Covariates included age, comorbidity, BC subtype, disease group, previous surgery, and current systemic therapy. Results: Of 381 women, 107 (28%) were diagnosed with ESBC ≤ 1 year prior to enrolment; 171 (45%) were diagnosed with ESBC &amp;gt; 1 year prior to enrolment; 103 (27%) had metastatic BC. Mean age was 57 (SD17) years. For ESBC, tiredness had the highest incidence of moderate to severe scores, followed by impaired well-being and anxiety (Table 1). For metastatic BC, impaired well-being had the highest incidence of moderate to severe symptoms, followed by tiredness and anxiety. More than 20% of metastatic BC patients had scores &amp;gt; 4 for pain, drowsiness, shortness of breath and depression. Most reported PRFS scores of 0 (“Normal with no limitations”) or 1 (“Not my normal self, but able to be up and about with fairly normal activities”), but 17% of metastatic BC patients reported a PRFS of 2 (“Not feeling up to most things, but in bed or chair less than half the day”). A comorbidity score ≥1 was associated with moderate to severe depression (OR 2.0; 95%CI 1.1-3.7), lack of appetite (OR 3.1; 95%CI 1.4-6.6), shortness of breath (OR 2.6; 95%CI 1.3-5.2), tiredness (OR 2.0; 95%CI 1.2-3.3) and impaired well-being (OR 2.0; 95%CI 1.2-3.4). Metastatic BC was associated with moderate to severe scores for anxiety (OR 2.3; 95%CI 1.2-4.5), pain (OR 3.0; 95%CI 1.4-6.4) and impaired well-being (OR 2.1; 95%CI 1.1-4.0). Conclusion: A high prevalence of symptom scores &amp;gt; 4 was found both in ESBC and metastatic BC, highlighting the need of symptom screening for all BC patients. Particular attention should be paid to patients with comorbidity scores ≥ 1, who have increased odds of presenting higher symptom scores. Table 1.- Prevalence of ESAS scores ≥ 4 and PRFS scores for each disease group.ESAS SymptomsPercent with ESAS scores ≥ 4 (moderate to severe)Early-Stage Breast Cancer – 1st year (N=107)Early-Stage Breast Cancer – &amp;gt; 1st year (N=171)Metastatic Breast Cancer (N=103)Total (N=381)Pain12.1%14.7%30.1%18.2%Tiredness25.2%30.1%39.8%31.3%Drowsiness1.8%12.9%25.2%16.6%Nausea9.4%3.5%7.8%4.2%Lack of Appetite10.3%7.1%13.6%9.5%Shortness of Breath14%7.6%22.3%12.4%Depression17.7%14.6%22.6%16.5%Anxiety24.3%17.2%35.3%21.3%Well-being1.8%25.7%44.1%30.3%PRFS scoresPercent with PRFS ScoreNormal with no limitations (0)30.8%49.7%28.2%38.6%Not my normal self, but able to be up and about with fairly normal activities (1)52.3%42.1%50.5%47.2%Not feeling up to most things, but in bed or chair less than half the day (2)12.2%4.7%16.5%10%Able to do little activity and spend most of the day in bed or chair (3)3.7%2.3%4.9%3.4%Pretty much bedridden, rarely out of bed (4)---- Citation Format: Sofia Torres, Ahmed Bayoumi, Geoffrey Liu, Ana Beatriz Kinupe Abrahao, Nicholas Mitsakakis, Murray Krahn, Maureen Trudeau. Patient reported symptoms and functional status in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-22.

Genomic landscape in small intestine cancer from real-world data (RWD) of clinical genomic testing.

642 Background: Panel-based comprehensive genomic profiling (CGP) is used in clinical practice worldwide, however, large aggregated RWD of patients with advanced small intestine cancer have not been characterized. In particular, there has been limited data regarding examining CGP in pediatric/ Adolescent and Young Adult (AYA) small intestine cancer. For patient subgroups, it is unclear what clinically relevant alterations co-occur. Here, we investigated the genomic landscape of small intestine cancer patients, stratified by sub-group to help refine and discover new targets for improved cancer therapies in advanced small intestine cancer. Methods: This is a collaborative biomarker study using RWD paired with CGP testing (Foundation Medicine, Inc.). Hybrid capture was carried out on up to 395 cancer-related genes and select introns from up to 31 genes frequently rearranged in cancer. One thousand three hundred sixty-four patients were available for analyses and were stratified by age (≥40/ &lt; 40), MSI status, tumor mutational burden (TMB) status (High ≥10/Low &lt; 10Muts/Mb), and select gene alterations. Using a chi-square test with Yate’s correction, frequencies of alterations were analyzed according to clinical or genomic background. Results: Genes with frequent alterations including mutation, amplification, and rearrangement/fusion were TP53 (59.8%), KRAS (54.8%), APC (27.7%), CDKN2A (22.4%), and SMAD4 (20.2%). Genomic profiling according to age, MSI, and TMB status is shown in the following table. In pediatric/AYA patients, frequency of APC alterations was significantly low ( P&lt; 0.001). In KRAS mutated tumors, codon 12 most abundant mutations were G12D (31.1%) followed by G12V (22.3%), G12C (6.2%), and G12R (5.1%), while G13D (13.8%) was the predominant mutation in codon 13. In TMB-High tumors, which were detected in 12% of patients, the mutation rate of KRAS was modestly lower compared to TMB-Low tumors (42.3% vs. 53.3%). Frequent genes with amplification were MYC (6.7%), MDM2 (5.9%), GATA6 (5.5%), CCND1 (3.4%), FGF19 (3.3%), and ERBB2 (2.3%). The number of any gene amplification was lower in MSI-High compared to TMB-High population. Conclusions: RWD from clinical panel testing revealed the genomic landscape in small intestine cancer and differences in CGP according to clinical or genomic background. These findings would provide insight on the direction of the future development of the treatment in advanced small intestine cancer.[Table: see text]

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Preliminary Clinical Validation of a Filtration-Based CTC Assay for Tumor Burden and HER2 Status Monitoring in Metastatic Breast Cancer

Background: Bearing multidimensional tumor-relevant information ranging from genomic alterations to proteomic makeup, circulating tumor cells (CTCs) constitute a promising material for liquid biopsy. The clinical validity of CTCs has been most extensively studied in metastatic breast cancer (MBC). The Cellsearch assay is currently the most widely used, while alternative strategies are pursued. A filtration-based microfluidic device has been described for CTC enrichment, but its clinical relevance remains unknown. Methods: In this preliminary study, we prospectively enrolled 47 MBC patients and evaluated the performance of the abovementioned CTC assay for tumor burden monitoring and human epidermal growth factor receptor 2 (HER2) status determination. Results: At baseline, 51.1% patients (24/47) were CTC positive. CTC count and positivity were also significantly higher in samples that accompanied poorer radiographic response evaluations. Serial blood draws suggested that CTC count enabled more accurate monitoring of tumor burden than serum markers carcinoembryonic antigen and cancer antigen 15-3. Also, in contrast to previous reports, CTC-HER2 status was moderately consistent with tumor-HER2 status. CTC-HER2 status assessment was further supported by HER2 copy number measurements in select samples. Conclusion: The preliminary results from this study suggest promise for the interrogated CDC assay in several aspects, including sensitive CTC detection, accurate disease status reflection, and HER2 status determination. More studies are warranted to validate these findings and further characterize the value of CTC assay.

ZCCHC17 Served as a Predictive Biomarker for Prognosis and Immunotherapy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the common malignant tumors. The prognosis and five-year survival rate of HCC are not promising due to tumor recurrence and metastasis. Exploring markers that contribute to the early diagnosis of HCC, markers for prognostic evaluation of HCC patients, and effective targets for treating HCC patients are in the spotlight of HCC therapy. Zinc Finger CCHC-Type Containing 17 (ZCCHC17) encodes the RNA binding protein ZCCHC17, but its role in HCC is still unclear. Here, 90 paraffin-embedded specimens combined with bioinformatics were used to comprehensively clarify the value of ZCCHC17 in the diagnosis and prognosis of HCC and its potential functions. Paraffin-embedded specimens were used to assess ZCCHC17 protein expression and its correlation with prognosis in 90 HCC patients. the public data sets of HCC patients from TCGA, ICG, and GEO databases were also used for further analysis. It was found that protein and mRNA levels of ZCCHC17 in HCC tissues were significantly higher than those in normal tissues. The abnormally high expression may be related to the abnormal DNA methylation of ZCCHC17 in tumor tissues. The high expression of ZCCHC17 is related to AFP, histologic grade, tumor status, vascular invasion, and pathological stage. Multi-data set analysis showed that patients with high ZCCHC17 expression had a worse prognosis, and multivariate cox regression analysis showed an independent prognostic significance of ZCCHC17. The results of functional analysis, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA), indicate that ZCCHC17 is mainly involved in immune regulation. Subsequently, further single-sample gene set enrichment analysis (ssGSEA) showed that the expression of ZCCHC17 was related to the infiltration of immune cells. Importantly, we also analyzed the relationship between ZCCHC17 and immune checkpoint genes, tumor mutation burden (TMB), microsatellite instability (MSI) and TP53 status in HCC patients and evaluated the role of ZCCHC17 in cancer immunotherapy. In summary, ZCCHC17 is a novel marker for the diagnosis and prognostic evaluation of HCC. Concurrently, it regulates immune cells in the tumor microenvironment (TME) of HCC patients, which has a specific reference value for the immunotherapy of HCC.

Monocyte or white blood cell counts and β2 microglobulin predict the durable efficacy of daratumumab with lenalidomide.

Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab. We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status. We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database. We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database. In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower β2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen. We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/μl; 1 point for <200/μl) or WBC counts (0 points for ⩾3500/μl; 1 point for <3500/μl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p < 0.001). To confirm this concept, our results will need to be validated in other cohorts.

Investigation of Care Burden and Depression Status of Mothers Who Have a Child with Cystic Fibrosis in Terms of Some Sociodemographic Variables

Investigation of Care Burden and Depression Status of Mothers Who Have a Child with Cystic Fibrosis in Terms of Some Sociodemographic Variables

Exploring tumor mutational burden status and clinical benefit of immune checkpoint inhibitors in endometrial cancer

Tumor mutations are key in the generation of anticancer immunity. Tumors with high mutational burden (TMB) are more likely to harbor high levels of neoantigens that make them targets of activated immune cells and thus may have superior and/or prolonged response to immune checkpoint inhibitors (ICI) when compared to TMB-low counterparts. A recently published biomarker analysis of KEYNOTE-158 reported that tumors with TMB-high status had a higher objective response to pembrolizumab monotherapy than non-TMB-high tumors leading to FDA approval of Pembrolizumab in TMB-high solid tumors. Importantly, among TMB-high responses, 57% had durable response >12 months. Reported objective response in endometrial cancer cohort was 46.6% in TMB-high (7/15) vs 4.9% (4/67) non-TMB high. In our study, we aimed to further investigate this identified association between TMB-high status and sensitivity to ICI in endometrial cancer by evaluating clinical benefit and duration of clinical benefit in TMB-high vs TMB-low patient groups.

Long-Term Care Service Use and Caregiver Burden, Depression, and Health: A Systematic Review and Meta-Analysis

This study examined whether long-term care service use (LTCSU) is associated with informal caregivers’ burden, depression, and health status. Eligible articles collected data directly from caregivers, written in English, and allowed for extraction or computation of effect sizes. MEDLINE, PsycINFO and ProQuest Dissertations & Theses Global databases were searched between September 2017 and January 2018. The risk of bias of individual studies was assessed regarding confounding, study power, and other biases. This unfunded study was registered with PROSPERO: CRD42018108827. Of the 419, 209 and 346 articles identified, 24, 14 and 15 articles that involved 12,530, 6,687 and 7,331 informal caregivers respectively, were eligible for analyses regarding the above associations. With unadjusted effect sizes, omnibus tests found statistically non-significant overall effect estimates in the association of LTCSU with caregiver burden, depression, and health status. Subgroup analyses, however, revealed that the above associations differed by service type, caregiver sex, and country, respectively.

Mental Health Among Informal Caregivers of Older Adults in Asia

The purpose of this symposium is to highlight the mental health needs and factors associated with mental health among informal caregivers of older adults in Asia. The symposium consists of five papers. The first paper explores the perceived role, needs, and rewards of informal caregiving among caregivers of residents in independent long-term care facilities in South India. The second paper presents a systematic review and meta-analysis on the association between long-term care service use and informal caregiver burden, depression, and health status. The third paper examines the association between caregivers’ characteristics and quality of life among informal caregivers of older adults with cognitive impairment in China. The fourth paper examines the association between coping strategies and caregiver burden and depression among Chinese caregivers of older adults with cognitive impairment. The last paper examines the association between cohort, meaning making, and depression among adult caregivers during the COVID-19 pandemic in Hong Kong. Taken together, these five papers underscore of the mental health needs and protective and risk factors of mental well-being among caregivers in Asia. Findings of those papers inform the development and adaptation of culturally sensitive interventions to improve mental health outcomes among informal caregivers in Asia. The disccuant will comment on the strengths and limitations of these papers in terms of their contributions to the theory, research, and practice on mental health among informal caregivers in Asia.

Changing treatments paradigms and role of immunotherapy in recurrent endometrial cancer.

Over the past decade, the treatment of patients diagnosed with endometrial cancer (EC) shifted away from the use of chemotherapy to more novel targeted therapy and immunotherapy approaches. The Cancer Genome Atlas data demonstrated different subgroups within ECs, more specifically, it facilitated the identification of predictive biomarkers. In particular, immunotherapies (immuno-oncology (IO)) are active either as monotherapy or in combination with other agents, depending on the biomarker profile of the tumor. In May 2017, pembrolizumab was approved for patients with microsatellite instability high (MSI-H) EC. More recently, this approval was extended for patients harvesting tumors with a high tumor mutational burden status. Furthermore, in July 2021, the combination of pembrolizumab and lenvatinib was approved for patients who do not exhibit MSI-H disease. Given the wealth of targets in EC and different targetable mutations, the challenge will be to choose the proper treatment and the proper sequencing to derive the best outcome in the first-line setting and improve outcomes in subsequent settings. This review summarizes the current indications of immunotherapy for the treatment of advanced and recurrent EC. We outline the role of testing for uterine cancer and its implication in therapy management. Finally, we address new concepts for immunotherapy combinations with other therapies.

Association of tau pathology and vascular risk factor burden with longitudinal measures of plasma neurofilament light

AbstractBackgroundIn the context of Alzheimer’s disease (AD), tau pathology is a major driver of the neurodegenerative cascade that ultimately leads to loss of neurons and synapses. In fact, studies have shown that neurodegeneration is more strongly associated with tau pathology than amyloid‐β (Aβ) accumulation. Although plasma neurofilament light (NfL) is a neuroaxonal damage biomarker that currently is in the research spotlight, the factors influencing the association between its longitudinal trajectory and tau pathology remains unclear. Since vascular risk factors (VRFs) present an important role in AD etiology and progression, here we aimed to determine whether tau pathology, in combination with or independently of VRF burden, is associated with longitudinal plasma NfL trajectory.MethodWe assessed 901 participants [276 CU, 455 MCI and 170 AD] from ADNI with baseline plasma p‐tau181 and [18F]AV45 Aβ‐PET, as well as longitudinal plasma NfL measurements (up to 4 years). Baseline VRF burden was calculated considering the history for cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, stroke or transient ischemic attack, smoking, atrial fibrillation and left ventricular hypertrophy. Individuals were dichotomized as following: elevated VRF burden if ≥2 VRFs (V+), tau positive if plasma p‐tau181 ≥ 17.7 pg/mL (T+) and amyloid positive if global Aβ‐PET SUVR ≥ 1.11 (A+). Subjects who were A‐T+ were excluded. Linear mixed‐effects models (LMMs) were performed to evaluate plasma NfL’s longitudinal trajectories.ResultThe LMMs demonstrated that tau positivity (T+) was significantly associated with a higher rate of longitudinal increase in plasma NfL levels in comparison to the tau‐negative group (Fig. 1). However, analysis dividing the groups both by tau and VRF burden status demonstrated that the rates of increase in plasma NfL were greater only in the presence of both VRF burden and tau positivity (T+V+; t‐value=2.54, p&lt;0.05), when compared to the reference group (T‐V‐; Fig. 2). Moreover, specific slope‐contrast analyses confirmed that only the T+V+ group presented a clearly separate trajectory.ConclusionOur findings suggest that an elevated VRF burden influences the relation between tau pathology and neurodegeneration in AD.Therefore, tau‐mediated neurodegeneration seems to be most relevant in combination with vascular‐mediated neuroaxonal injury. These findings reinforce the pivotal contribution of vascular pathology to AD development.

Longitudinal Smartphone-Based Post-hospitalisation Symptom Monitoring in SARS-CoV-2 Associated Respiratory Failure: A Multi-Centre Observational Study.

Background: We aimed to longitudinally monitor the recovery in breathlessness, symptom burden, health-related quality-of-life, and mental health status in individuals hospitalised due to SARS-CoV-2 associated respiratory failure.Methods: Individuals hospitalised due to SARS-CoV-2 associated respiratory failure were recruited at hospital discharge in three participating centres. During the 90 day follow-up, European Quality of Life−5 Dimensions−5 Levels Instrument (EQ-5D-5L), modified Medical Research Council (mMRC) Dyspnoea Scale, COPD Assessment Test (CAT), and weekly Hospital Anxiety and Depression Scale (HADS) questionnaires were assessed using a smartphone application. The results were presented using descriptive statistics and graphics. Linear mixed models with random intercept were fitted to analyse differences of intensive-care unit status on the recovery course in each outcome.Results: We included 58 participants, 40 completed the study. From hospital discharge until 90 days post-discharge, EQ-5D-5L index changed from 0.83 (0.66, 0.92) to 0.96 (0.82, 1.0), VAS rating on general health status changed from 62 (50, 75) % to 80 (74, 94) %, CAT changed from 13 (10, 21) to 7 (3, 11) points, mMRC changed from 1 (0, 2) to 0 (0, 1) points, HADS depression subscale changed from 6 (4, 9) to 5 (1, 6) points, HADS anxiety subscale changed from 7 (3, 9) to 2 (1, 8) points. Differences in the recovery courses were observed between intensive-care and ward participants. Participants that were admitted to an intensive-care unit during their hospitalisation (n = 16) showed increases in CAT, mMRC, HADS scores, and decreases in EQ-5D-5L 30 days after hospital discharge.Conclusion: Being admitted to an ICU led to statistically significant reductions in recovery in the EQ-5D-5L and the CAT. Furthermore, the flare-up in symptom burden and depression scores, accompanied by an attenuated recovery in HrQoL and general health status in the ICU-group suggests that a clinical follow-up 1 month after hospital discharge can be recommended, evaluating further treatments.Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT04365595].

Higher Coffee Consumption Is Associated With Slower Cognitive Decline and Less Cerebral Aβ-Amyloid Accumulation Over 126 Months: Data From the Australian Imaging, Biomarkers, and Lifestyle Study.

Background: Worldwide, coffee is one of the most popular beverages consumed. Several studies have suggested a protective role of coffee, including reduced risk of Alzheimer’s disease (AD). However, there is limited longitudinal data from cohorts of older adults reporting associations of coffee intake with cognitive decline, in distinct domains, and investigating the neuropathological mechanisms underpinning any such associations.Methods: The aim of the current study was to investigate the relationship between self-reported habitual coffee intake, and cognitive decline assessed using a comprehensive neuropsychological battery in 227 cognitively normal older adults from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, over 126 months. In a subset of individuals, we also investigated the relationship between habitual coffee intake and cerebral Aβ-amyloid accumulation (n = 60) and brain volumes (n = 51) over 126 months.Results: Higher baseline coffee consumption was associated with slower cognitive decline in executive function, attention, and the AIBL Preclinical AD Cognitive Composite (PACC; shown reliably to measure the first signs of cognitive decline in at-risk cognitively normal populations), and lower likelihood of transitioning to mild cognitive impairment or AD status, over 126 months. Higher baseline coffee consumption was also associated with slower Aβ-amyloid accumulation over 126 months, and lower risk of progressing to “moderate,” “high,” or “very high” Aβ-amyloid burden status over the same time-period. There were no associations between coffee intake and atrophy in total gray matter, white matter, or hippocampal volume.Discussion: Our results further support the hypothesis that coffee intake may be a protective factor against AD, with increased coffee consumption potentially reducing cognitive decline by slowing cerebral Aβ-amyloid accumulation, and thus attenuating the associated neurotoxicity from Aβ-amyloid-mediated oxidative stress and inflammatory processes. Further investigation is required to evaluate whether coffee intake could be incorporated as a modifiable lifestyle factor aimed at delaying AD onset.

Utility of a Patient-Reported Symptom and Functioning Assessment Tool for Geriatric Oncology Care in China

ObjectivesSymptom and functional assessment is challenging in geriatric oncology care. This multicenter cross-sectional study examined the use of a multiple-symptom assessment tool, the MD Anderson Symptom Inventory (MDASI), on Chinese patients with cancer aged 65 years and older. MethodsPatient-rated symptoms and functioning were assessed using MDASI and the European Organization for Research and Treatment of Cancer quality-of-life questionnaire. ResultsThe most severe symptoms were fatigue and poor appetite. The older group (75-84 years old, n = 224) reported a more severe difficulty remembering (effect size [ES] 0.32; P < .001), shortness of breath (ES 0.20; P = .020), and interference with general activity (ES 0.14; P = .027), with significantly worse physical functioning (ES −0.33; P < .001) and cognitive functioning on the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (ES 0.20; P < .001) than the younger group (65-74 years old, n = 555). For MDASI measures of the core symptoms and total interference with daily activity, Cronbach α coefficients were 0.90 and 0.93, respectively, for the younger group; and 0.93 and 0.94 for the older group, respectively. Moderate to severe (score ≥4) interference with general activity and walking on MDASI accurately indicated poor performance status (area under the curve 0.8089 and 0.7969, respectively) and lack of independence status of Activities of Daily Living (area under the curve 0.7993 and 0.8304, respectively). ConclusionsMDASI is psychometrically reliable, valid, and clinically sensitive for the measuring symptom burden and functional status of Chinese patients with cancer aged 65 years and older. MDASI could be adopted to measure multiple symptoms and physical functioning outcomes in geriatric oncology practice as well as for research on treatment benefits.

A new perspective on women’s care burden and employment in Turkey

AbstractWomen’s intra-household care burden is one of the main reasons behind women’s low employment rates in Turkey. Many empirical studies have tested this relationship by focusing on the existence of dependent household members, if any. They have largely overlooked the use of care services and the time spent on caring for dependent household members to evaluate women’s care burden.The purpose of this study is to examine the relationship between women’s care burden and employment prospects and status in Turkey from the perspective of access to care services and the time dimension of the care burden. This relationship is analyzed through the logit model by using latest available data from the 2014–2015 Time Use Survey. The article shows that the time spent by women caring for dependent household members, and access to care services, are the most important factors influencing women’s employment probability in Turkey. Benefiting from informal childcare services increases the employment probability of women approximately twenty-seven times, while benefiting from formal childcare services increases two times and informal adult-care services 2.6 times. Ensuring the accessibility of institutional care services improves women’s employment status by enabling women’s transition from part-time to full-time jobs, and from unskilled to professional jobs.