Age-matched Non-cancer Controls Research Articles

Cardiorespiratory Fitness in Childhood Cancer Survivors: A Systematic Review and Meta-Analysis.

Cardiovascular disease (CVD) is a leading cause of mortality in childhood cancer survivors (CCS) that may be related to the cardiotoxic effects of radiation or chemotherapy and concomitant reductions in cardiorespiratory fitness. Therefore, we sought to compare cardiorespiratory fitness (peak oxygen uptake, V̇O2peak) between CCS and age-matched non-cancer controls (CON). Secondary outcomes included hemodynamics and resting cardiac function. Embase, Scopus, MEDLINE, CINAHL and SPORTDiscus databases were searched from inception to June 2023 for eligible studies. Cross-sectional studies with V̇O2peak measured in CCS and CON were included. Differences in outcomes and pooled estimates for each outcome were estimated from a fixed effects meta-analysis and between group differences were reported as a weighted mean difference (WMD). Of 2026 studies identified, 18 reported V̇O2peak (CCS: n=786, 44% female, mean age: 16-years, time post-therapy: 5.8 years; CON: n=1379, 50% female, mean age: 16-years). V̇O2peak was lower in CCS (WMD: -7.08mL/kg/min, 95% CI: -7.75 to -6.42, I2: 79%, n=2,165) with no difference for peak exercise heart rate (WMD: -1.4bpm, 95% CI: -3.0 to 0.2, I2: 63%, n=741). Resting left-ventricular ejection fraction (WMD: -1.61%, 95% CI: -2.60 to -0.62, I2.: 49%, n=222) and systolic blood pressure were lower (WMD: -3.8mmHg, 95% CI: -5.7 to -1.9, I2: 25%, n=184) while resting heart rate was higher in CCS (WMD: 4.9bpm; 95% CI: 1.8 to 7.9, I2: 55%, n=262). CCS have a marked reduction in cardiorespiratory fitness (7.1ml/kg/min lower than CON) that may have important prognostic implications for their future risk of CVD and mortality.

A prospective study to evaluate the prevelance of chemobrain (CB) in patients (pts) receiving adjuvant treatment.

e23174 Background: Although adjuvant chemotherapy (CT) significantly improves the clinical outcome of pts with early-stage (ES) cancer, it is also known to cause side-effects. CT-induced cognitive impairment or CB refers to a clinical condition characterized by lack of mental sharpness, memory and concentration impairment and difficulty in processing information and executing simple tasks. Prospective data regarding the emergence of CB are limited. We aimed to explore the prevalence and predictors for CB among pts receiving adjuvant CT and to evaluate its impact on their quality of life (QoL). Methods: This was a prospective cohort study conducted at the University Hospital of Larissa. Pts who were recently diagnosed with ES breast (BC) or colorectal (CRC) cancer and were about to receive adjuvant CT containing doxorubicin (D) or oxaliplatin (O), respectively, were eligible for this study (C1). The first control group (C2) consisted of ES cancer pts that were not eligible for adjuvant CT and the second group (C3) was recruited from a pool of healthy controls (HCs). All participants (pcs) met the following inclusion criteria: age > 50 years old, ability to speak and write in Greek. Pts with pre-existing dementia/anxiety disorder and severe anemia were excluded from the study. Pts in C1 were assessed before receiving CT and 3 months after CT initiation. All subjects in C2 and C3 were assessed in 3 months intervals as well. After completion of the informed consent process, all pts and age-matched noncancer controls completed the Greek Version of Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) to specifically assess CB. QoL was measured using the EORTC QLQ-C30. Results: Overall, 82 pts (53 with BC and 29 with CRC) were included in C1, 36 pts (24 with BC and 12 with CRC) in C2 and 15 pcs in C3. At baseline, pts in C1 and C2 had significantly lower FACT-Cog scores than healthy controls in C3 (p: 0.028 and p:0.038, respectively), indicating a higher prevalence of self-reported cognitive impairment among pts with cancer after a curative surgery compared to age-matched HCs. However, after 3 months of CT the majority of pts in C1 (59/82, 72%) demonstrated a decline in their cognitive performance (35/53, 66% in BC pts receiving D and 24/29, 82% in CRC pts receiving O). Pts with CRC receiving O experienced more severe cognitive deficits. On the contrary, 55% of the pts in C2 (20/36, 16 with BC and 4 with CRC) demonstrated an improvement. The presence of CB (decline in cognitive functioning in the absence of severe anemia) was associated with decreased QoL (p = 0.004). Pts were mostly frustrated by the difficulty in executing simple tasks. Conclusions: As demonstrated in one of the largest cohorts of pts with ES cancer, CB is a common problem among pts receiving adjuvant CT and is associated with detrimental impact on daily life. Creating awareness is crucial to offer cancer survivors the best care directed at improving QoL.

Brain-derived neurotrophic factor as a biomarker in cancer-related cognitive impairment among adolescent and young adult cancer patients

Brain-derived neurotrophic factor (BDNF) improves cognitive function by stimulating neurogenesis and neuroplasticity. We hypothesize that higher plasma BDNF levels are protective against cognitive toxicity among adolescent and young adult cancer patients (15–39 years old). In a prospective, longitudinal study, we recruited 74 newly diagnosed cancer and 118 age-matched non-cancer controls who completed the Cambridge Neuropsychological Test Automated Battery (CANTAB), Functional Assessment of Cancer Therapy-Cognitive Function questionnaire (FACT-Cog) and blood draws. Plasma BDNF was quantified using an enzyme-linked immunosorbent assay. Genomic DNA from buffy coat was genotyped for BDNF Val66Met. Most cancer participants were diagnosed with breast (24%) and head/neck (22%) cancers. After adjusting for sociodemographic variables (age, gender, race, marital status, education years), cancer participants had lower BDNF levels (ng/mL) at baseline (median: 10.7 vs 21.6, p < 0.001) and 6-months post-baseline (median: 8.2 vs 15.3, p = 0.001) compared to non-cancer controls. Through linear mixed modelling adjusted for sociodemographic variables, baseline cognition, fatigue, psychological distress, and time, we observed that among cancer participants, lower baseline BDNF levels were associated with worse attention (p = 0.029), memory (p = 0.018) and self-perceived cognitive abilities (p = 0.020) during cancer treatment. Met/Met was associated with enhanced executive function compared to Val/Val (p = 0.012). Plasma BDNF may serve as a predictive biomarker of cancer-related cognitive impairment.

DNA methylation patterns between tissue and blood samples in ovarian cancer.

5558 Background: Altered DNA methylation pattern, with functional consequences in the activity of key carcinogenic pathways, has been shown to be involved in the carcinogenesis of ovarian cancer. Tumor DNA is released into the blood via apoptosis or necrosis. Therefore, cell-free DNA (cfDNA) methylation alteration can also be detected in blood, which has shown promising performance in ovarian cancer early detection and prognostication. However, the difference of DNA methylation patterns between the tissue and blood samples of ovarian cancer is still unclear. Methods: PERCEIVE-I study (NCT04903665) is a prospective study aimed at the early detection of gynecological malignancies. Blood and paired tissue samples from this study were collected at the Fudan University Shanghai Cancer Center. Blood samples from age-matched non-cancer controls were also collected. All the blood and paired tissue samples were sequenced by a target methylation panel covering ~490,000 CpG sites. Finally, The ovarian cancer methylation patterns were analyzed based on 11 paired cancer-adjacent tissue samples and 170 blood samples (cancer, n=48; non-cancer control, n=122). Results: In total, 7,225 differentially methylated blocks (DMBs) were identified by comparing cancer and adjacent tissues, with 5,093 hypomethylated and 2,132 hypermethylated. By contrast, there were 5,853 hypomethylated and 8,685 hypermethylated DMBs in cancer blood samples compared with non-cancer controls. Among the 7,225 DMBs in tissues, 3,962 (54.8%) blocks were also observed to be altered in blood samples, including 2,354 hypomethylated blocks and 1,114 hypermethylated blocks. GO analysis revealed that these hypomethylated blocks were mainly associated with functions such as regulation of synaptic membrane and DNA-binding transcription activator activity, while the hypermethylated blocks were mainly enriched in the pattern specification process, transcription factor complex, and the DNA-binding transcription activator activity. The alteration of the above 3,962 DMBs in tissue were highly correlated with the alteration in blood (correlation coefficient of 0.71, 0.50, 0.73 and 0.73 for stage I-IV, respectively). Furthermore, in patients carrying germline BRCA1/2 mutations (n=11), most of the above DMBs were not significantly different from those without germline BRCA1/2 mutations (n=37). Conclusions: In this study, we demonstrated that blood DNA methylation alteration was highly consistent with tissue DNA methylation alteration in ovarian cancer, indicating the sustained release of DNA methylation signals from the primary cancer sites. These results suggest that cfDNA methylation can be used as reliable biomarkers for the early detection of ovarian cancer. Clinical trial information: NCT04903665 .

Abstract 1001: Urinary metabolite diagnostic and prognostic liquid biopsy biomarkers of lung cancer - never smokers versus tobacco smokers

Abstract Introduction: Never smokers account for 10-13% of all lung cancer cases in the United States. The etiology is attributed to multiple causes including exposure to passive smoking, parental smoking, asbestos and radon. However, these lung cancer cases do not fit the current United States Government-funded criterion of low-dose computed tomography that identifies early stages of lung cancer with higher survival following surgical removal. Methods: The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA), were analyzed and quantified by liquid chromatography-mass spectrometry to determine if never smokers with non-small cell lung cancer (NSCLC) can also be identified alongside tobacco smoker NSCLC cases as compared with gender and age-matched non-cancer population controls. Results: These cancer biomarkers were significantly higher and comparable in never-smokers and tobacco smokers cases compared to population controls. Receiver Operating Characteristics (ROC) analysis in never smokers was equivalent for CR and NANA levels area under the curve (AUC) 0.91. In contrast, combined CR and NANA levels resulted in better predictive performance (AUC 0.94). Kaplan-Meier survival curves showed that high levels of CR and NANA were associated (p&amp;lt;0.05) with increased cancer-specific death in never-smokers and tobacco smokers. Therefore these metabolites are independent of Tobacco smoking. NANA metabolite category factor, histology and stage were independent predictors of survival (p&amp;lt;0.05) in multivariate analyses for never smokers as shown in Table 1. Conclusions: These results indicate that measuring CR and NANA in liquid biopsy urine could identify never-smoking lung cancer candidates for LDCT screening and warrant prospective studies of these biomarkers in high-risk environments. Table 1. Univariate and multivariate regression analysis for factors associated with survival in the never smokers population Univariate Analysis Multivariate analysis Factors Levels N HR 95%CI P-value HR 95%CI P-value Stage Early Stage (I &amp; II); Late Stage (III &amp; IV) 145 3.52 2.3, 5.3 &amp;lt;0.001 3.94 2.2, 6.8 &amp;lt;0.001 Histology Adenocarcinoma; Squamous cell carcinoma 114 1.62 0.7, 3.5 0.26 3.42 1.4, 7.9 0.01 CR Category Low; High 166 1.34 0.8-2.1 0.19 1.67 0.9, 3.0 0.08 NANA Category Low; High 166 2.11 1.1-3.9 0.009 2.31 1.0, 5.0 0.02 Age N=166 166 1.00 0.9, 1.0 0.50 0.99 0.9, 1.0 0.4 Sex Male; Female 166 0.87 0.5, 1.2 0.49 0.90 0.5, 1.5 0.7 Race African American; European American 166 0.82 0.2, 2.5 0.75 0.40 0.1, 1.3 0.2 Citation Format: Bhavik Dalal, Takeshi Tada, Daxesh P. Patel, Mohammed Khan, Takahiro Oike, Yasuyuki Kanke, Amelia Parker, Majda Haznadar, Leila Toulabi, Kristopher Krausz, Ana Robles, Elise Bowman, Frank Gonzalez, Curtis Harris. Urinary metabolite diagnostic and prognostic liquid biopsy biomarkers of lung cancer - never smokers versus tobacco smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1001.

Novel computerized neurocognitive test battery is sensitive to cancer-related cognitive deficits in survivors.

There is increasing interest in developing new methods to improve sensitivity in detecting subtle cognitive deficits associated with cancer and its treatments. The current study aimed to evaluate the ability of a novel computerized battery of cognitive neuroscience-based tests to discriminate between cognitive performance in breast cancer survivors and controls. Breast cancer survivors (N = 174) and age-matched non-cancer controls (N = 183) completed the Enformia Cogsuite Battery of cognitive assessments, comprised of 7 computerized tests of multiple cognitive domains. Primary outcome measures included accuracy, reaction times (RT), and coefficients of variation (CV) for each task, as well as global scores of accuracy, RT, and CV aggregated across tests. Linear regressions adjusting for age, education, and remote vs. in-office administration showed that compared to non-cancer controls, survivors had significantly lower performance on measures of attention, executive function, working memory, verbal ability, visuospatial ability, and motor function. Survivors had significantly greater CV on measures of attention, working memory, and processing speed, and significantly slower RT on measures of verbal fluency. The Cogsuite battery demonstrates sensitivity to cancer-related cognitive dysfunction across multiple domains, and is capable of identifying specific cognitive processes that may be affected in survivors. The sensitivity of these tasks to subtle cognitive deficits has advantages for initial diagnosis of cancer-related cognitive dysfunction, as well as detecting changes in survivors' cognitive function over time. The remote delivery of the battery may help overcome barriers associated with in-office administration and increase access to neurocognitive evaluation.

Abstract 5927: A comparison of the gut microbiome in the context of body mass index in patients with and without breast cancer

Abstract Background: Through diverse interactions with systemic immunosurveillance and metabolism, the gut microbiome is an important factor in the development and treatment of solid tumors including breast cancer (BC). The gut microbiome is also implicated in elevated body mass index (BMI), which is a well-established risk factor for the development of BC. This study determined associations between gut microbiome diversity and BC, adjusting for BMI. Methods: Stool samples were collected from 38 patients with newly-diagnosed BC and 43 age-matched non-cancer controls. Data obtained from 16S rRNA sequencing of fecal samples were clustered into amplicon sequence variants using DADA2. Diversity measures were calculated using vegan and phyloseq, and the statistical differences were compared using t-test or Wilcoxon rank-sum tests. Data were agglomerated at the family level for differential abundance analyses, which were performed with DESeq2. Results: The majority of BC cases observed were stage I (55.26%), hormone-receptor positive (70.97%), and detected during routine screening (68.42%). Mean BMI was greater among patients diagnosed with BC than controls (mean BMI cases: 27.9, controls: 25.23, p=0.04). Alpha diversity measured by the Shannon, Inverse Simpson and Pielou indices was lower in the BC cohort compared with the control cohort (p = 0.02, 0.01, and 0.05, respectively). Beta diversity by non-metric multidimensional scaling on Bray-Curtis distance did not differ between cases and controls (p = 0.74). Five versus seven families and orders were differentially abundant when the analysis was adjusted for BMI versus not, respectively (Table). Conclusion: Differential abundance analysis results differed with and without BMI adjustment, indicating that adjusting for this potentially confounding variable is relevant for BC microbiome studies. BMI should be considered an adjusting variable in studies of the gut microbiome in BC. Negative values for log 2 fold change indicate organisms with greater abundance in controls. Result of DESeq2 analysis without BMI adjustment Family Log 2 Fold Change P adjusted Hungateiclostridiaceae -1.115 0.0034 Enterobacteriaceae 2.925 &amp;lt;0.0001 Fusobacteriaceae 2.043 &amp;lt;0.0001 Lactobacillaceae -1.097 0.0063 Selenomonadaceae 0.985 0.0004 Order Gastranaerophilales -2.653 &amp;lt;0.0001 Flavobacteriales -1.462 0.0002 Result of DESeq2 analysis with BMI adjustment Family Log 2 Fold Change P adjusted Hungateiclostridiaceae -1.273 &amp;lt;0.0001 Enterobacteriaceae 2.379 &amp;lt;0.0001 Selenomonadaceae 1.015 &amp;lt;0.0001 Order Gastranaerophilales -1.838 &amp;lt;0.0001 Flavobacteriales -1.460 &amp;lt;0.0001 Citation Format: Brie Chun, Duygu Altinok Dindar, Keaton Stagaman, Amy Palma, Erin Dahl, Kristin Kasschau, Shaun M. Goodyear, Zahi I. Mitri, Thomas Sharpton, Lisa Karstens, Zhenzhen Zhang. A comparison of the gut microbiome in the context of body mass index in patients with and without breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5927.

Impact of carbonic anhydrase 9 gene polymorphism on the progression of colorectal cancer.

Colorectal cancer (CRC) is a commonly occurring tumor type worldwide, and its development is governed by a connection between genetic variations and acquired factors. Carbonic anhydrase 9 (CA9) is a cell-surface pH modulator that has been demonstrated to contribute to key steps of cancer progression. Here, we attempted to interrogate the effect of CA9 gene polymorphisms on the development of CRC in 470 cases and 470 gender- and age-matched non-cancer controls. We found that none of three CA9 single-nucleotide polymorphisms (SNPs) tested, including rs2071676, rs3829078, and rs1048638, was significantly associated with the occurrence of CRC. Yet, while evaluating the clinicopathological variables, cases carrying at least one reference allele (G allele) of rs2071676 tended to develop poorly differentiated tumors less frequently than those who are homozygous for the alternative allele (A allele) of rs2071676 (GA+GG vs AA; OR, 0.483; 95% CI, 0.242-0.963; p=0.036). Further stratification revealed that as compared to homozygous carriers of the alternative allele (AA), cases of colon cancer bearing at least one reference allele of rs2071676 (GA+GG) less frequently developed poorly differentiated tumors (OR, 0.449; 95% CI, 0.221-0.911; p=0.024) and lymphovascular invasion (OR, 0.570; 95% CI, 0.361-0.900; p=0.015). Such genetic effect was exclusively observed in colon cancer but not in rectal cancer. Our results indicate an anatomical site-specific impact of CA9 gene polymorphisms on modulating the progression of colorectal malignancies.

Initial encoding deficits with intact memory retention in older long-term breast cancer survivors.

Cancer survivors frequently report significant forgetfulness, but standard neuropsychological tests often fail to detect primary memory deficits. Past research has suggested survivors may misattribute forgetfulness to memory decay rather than impairments in initial encoding, but no studies have tested whether this pattern is evident in older survivors, who are more vulnerable to age-related memory difficulties. We examined whether long-term breast cancer survivors treated in older adulthood demonstrate deficits in initial encoding, as opposed to increased rates of memory decay, relative to non-cancer controls. Three hundred twenty-eight breast cancer survivors age 60 and above, 5-15years post-treatment, and 162 age-matched non-cancer controls completed list learning and narrative memory assessments at four time-points over 2years. Performance on learning trials and delayed recall was analyzed at each time-point to assess group differences in memory encoding, and memory decay was assessed by analyzing changes in performance across delays. Univariate ANCOVAs correcting for age and education showed that survivors had worse initial encoding performance across multiple time-points, which were compensated for with multiple learning trials to produce recall performance comparable to controls. There were no significant group differences in memory decay. Older long-term breast cancer survivors exhibit a consistent pattern of initial encoding deficits, but memory retention was comparable to controls. Future research should consider the role of encoding deficits and age-related factors when evaluating cognitive function in older survivors. Commonly reported memory problems may stem from encoding deficits in older long-term cancer survivors.

IgM and IgA augmented autoantibody signatures improve early-stage detection of colorectal cancer prior to nodal and distant spread.

ObjectivesTumor‐associated autoantibodies (AAbs) in individuals with cancer can precede clinical diagnosis by several months to years. The objective of this study was to determine whether the primary immune response in form of IgM and gut mucosa‐associated IgA can aid IgG AAbs in the detection of early‐stage colorectal cancer (CRC).MethodsWe developed a novel protein array comprising 492 antigens seropositive in CRC. The array was used to profile IgG, IgM and IgA antibody signatures in 99 CRC patients and 99 sex‐ and age‐matched non‐cancer controls. A receiver operating curve (ROC), Kaplan–Meier survival analysis and univariate and multivariate Cox regression analyses were conducted.ResultsWe identified a panel of 16 multi‐isotype AAbs with a cumulative sensitivity of 91% and specificity of 74% (AUC 0.90, 95% CI: 0.850–0.940) across all CRC stages. IgM and IgG isotypes were conversely associated with disease stage with IgM contributing significantly to improved stage I and II sensitivity of 96% at 78% specificity (AUC 0.928, 95% CI: 0.884–0.973). A single identified IgA AAb reached an overall sensitivity of 5% at 99% specificity (AUC 0.520, 95% CI: 0.440–0.601) balanced across all CRC stages. Kaplan–Meier analysis revealed that se33‐1 (ZNF638) IgG AAbs were associated with reduced 5‐year overall survival (log‐rank test, P = 0.012), whereas cumulative IgM isotype signatures were associated with improved 5‐year overall survival (log‐rank test, P = 0.024).ConclusionIgM AAbs are associated with early‐stage colorectal cancer. Combining IgG, IgM and IgA AAbs is a novel strategy to improve early diagnosis of cancers.

Arterial Stiffness as a Cardiovascular Risk Factor in Prostate Cancer Survivors: A Case–Control Study

In New Zealand, prostate cancer (PCa) is the most commonly diagnosed cancer in men and the third most common cause of male cancer deaths. Among these patients, the most common non-cancer related cause of death is cardiovascular disease (CVD). Aortic arterial stiffness may be clinically viable solution for detecting and tracking CVD risk factor in PCa survivors. The aim of the study was to determine whether aortic arterial stiffness is increased in PCa survivors compared to age-matched controls. Participants recruited for this prospective comparative study were PCa survivors who had completed treatment (other than endocrine therapy) or were on active surveillance compared, or were age-matched non-cancer controls. During a single 1-h appointment, all participants had measures of aortic arterial stiffness, arterial wave reflection, central blood pressure and body composition taken. Ninety-eight men were recruited, 51 PCa survivors and 47 controls. There was no significant between group difference for aortic arterial stiffness [12.0 m/s (SD: 1.7) vs. 12.0 m/s (SD: 1.9), P = 0.953, d = 0.0]. Fat free mass [60.7 kg (SD: 4.9) vs. 65.1 kg (SD: 8.3), P = 0.007, d = 0.6] and skeletal muscle index [8.6 kg/m2 (SD: 0.6) vs. 9.0 kg/m2 (SD: 0.9), P = 0.050, d = 0.5] were lower in the PCa group. Aortic arterial stiffness is not increased (worse) in men with PCa who receive various treatments, compared to age-matched controls. These findings may indicate that factors other than increased aortic arterial stiffness contribute to heightened risk of cardiovascular events in this population.

Associations of inflammation with frailty in patients with breast cancer aged 50 and over receiving chemotherapy

PurposeChronic inflammation is a significant physiologic feature of frailty; however, its role and clinical utility in cancer-related frailty remains unknown. We sought to determine if pre-chemotherapy inflammation is predictive of frailty after chemotherapy in patients with breast cancer. MethodsFemale patients (N = 144; age ≥ 50) with stage I-III breast cancer scheduled to receive chemotherapy and age-matched non-cancer controls (N = 142) were included in this secondary analysis and assessed pre- and post-chemotherapy. Controls were assessed at equivalent time-points. Frailty was assessed using a modified Fried's score (0–4) using self-reported measures of weakness, exhaustion, walking speed, and physical activity. Serum levels of interleukin (IL) 6, and soluble tumor necrosis factor-alpha (sTNFR) I and II were measured. Associations between pre-chemotherapy cytokine and receptors level (median as cutoff) and post-chemotherapy frailty were evaluated using t-tests. ResultsPre-chemotherapy, patients with breast cancer were more frail than non-cancer controls (mean score: 1.17 vs 0.65; p < .01). Patients also became more frail post-chemotherapy (mean score: 1.17 vs 2.08; p < .01). Patients with pre-chemotherapy serum levels of IL-6, sTNFRI, and sTNFRII above the median were more frail after chemotherapy than those with levels below the median [IL-6 (2.31 vs. 1.86; p = .03), sTNFRI (2.30 vs. 1.88; p = .04), and sTNFRII (2.30 vs. 1.88; p = .04)]. No differences were observed in non-cancer controls within the same timeframe. ConclusionsBoth cancer and chemotherapy were associated with frailty. Higher pre-chemotherapy inflammatory cytokine levels were associated with post-chemotherapy frailty. This supports the utility of inflammatory cytokines to identify patients who develop worsening of frailty characteristics with chemotherapy.

Depression predicts longitudinal declines in social support among women with newly diagnosed breast cancer.

Among breast cancer survivors, low social support is associated with adverse clinical and psychosocial outcomes. This study prospectively examined longitudinal trends in perceived social support in women with newly diagnosed breast cancer as a function of depression status prior to initiation of cancer treatment. One hundred ten patients with newly diagnosed breast cancer and 59 age-matched noncancer controls completed behavioral measures at four assessments: prior to treatment and at 1month, 1year, and 2years post-treatment. Participants reported their perceived tangible and emotional/informational support using the Medical Outcomes Study Social Support Survey and were categorized as "depressed" or "non-depressed" based on the Brief Symptom Inventory-18 (BSI-18). Analyses first compared longitudinal trends in support between patients and controls and then examined differences in longitudinal trends as a function of depression status in patients only, controlling for key covariates. Both tangible and emotional/informational support decreased among breast cancer patients but increased or remained unchanged among noncancer controls across the assessments. Among patients, depressed individuals experienced a significant decline in both tangible (P=0.004) and emotional/informational support (P=0.013) between 1month and 1year post-treatment, which remained unchanged between 1year and 2years post-treatment. In contrast, nondepressed individuals had stable levels across all assessments. Depressed patients also had lower levels of both support types compared with nondepressed patients across all assessments. Breast cancer patients with depressive symptomatology have an elevated risk for declines in perceived social support over time.

Profiling plasma extracellular vesicle by pluronic block-copolymer based enrichment method unveils features associated with breast cancer aggression, metastasis and invasion

ABSTRACTExtracellular vesicle (EV)-based liquid biopsies have been proposed to be a readily obtainable biological substrate recently for both profiling and diagnostics purposes. Development of a fast and reliable preparation protocol to enrich such small particles could accelerate the discovery of informative, disease-related biomarkers. Though multiple EV enrichment protocols are available, in terms of efficiency, reproducibility and simplicity, precipitation-based methods are most amenable to studies with large numbers of subjects. However, the selectivity of the precipitation becomes critical. Here, we present a simple plasma EV enrichment protocol based on pluronic block copolymer. The enriched plasma EV was able to be verified by multiple platforms. Our results showed that the particles enriched from plasma by the copolymer were EV size vesicles with membrane structure; proteomic profiling showed that EV-related proteins were significantly enriched, while high-abundant plasma proteins were significantly reduced in comparison to other precipitation-based enrichment methods. Next-generation sequencing confirmed the existence of various RNA species that have been observed in EVs from previous studies. Small RNA sequencing showed enriched species compared to the corresponding plasma. Moreover, plasma EVs enriched from 20 advanced breast cancer patients and 20 age-matched non-cancer controls were profiled by semi-quantitative mass spectrometry. Protein features were further screened by EV proteomic profiles generated from four breast cancer cell lines, and then selected in cross-validation models. A total of 60 protein features that highly contributed in model prediction were identified. Interestingly, a large portion of these features were associated with breast cancer aggression, metastasis as well as invasion, consistent with the advanced clinical stage of the patients. In summary, we have developed a plasma EV enrichment method with improved precipitation selectivity and it might be suitable for larger-scale discovery studies.

Pre-existing malignancy results in increased prevalence of distinct populations of CD4+ T cells during sepsis.

The presence of pre-existing malignancy in murine hosts results in increased immune dysregulation and risk of mortality following a septic insult. Based on the known systemic immunologic changes that occur in cancer hosts, we hypothesized that the presence of pre-existing malignancy would result in phenotypic and functional changes in CD4+ T cell responses following sepsis. In order to conduct a non-biased, unsupervised analysis of phenotypic differences between CD4+ T cell compartments, cohorts of mice were injected with LLC1 tumor cells and tumors were allowed to grow for 3 weeks. These cancer hosts and age-matched non-cancer controls were then subjected to CLP. Splenocytes were harvested at 24h post CLP and flow cytometry and SPADE (Spanning-tree Progression Analysis of Density-normalized Events) were used to analyze populations of CD4+ cells most different between the two groups. Results indicated that relative to non-cancer controls, cancer mice contained more resting memory CD4+ T cells, more activated CD4+ effectors, and fewer naïve CD4+ T cells during sepsis, suggesting that the CD4+ T cell compartment in cancer septic hosts is one of increased activation and differentiation. Moreover, cancer septic animals exhibited expansion of two distinct subsets of CD4+ T cells relative to previously healthy septic controls. Specifically, we identified increases in both a PD-1hi population and a distinct 2B4hi BTLAhi LAG-3hi population in cancer septic animals. By combining phenotypic analysis of exhaustion markers with functional analysis of cytokine production, we found that PD-1+ CD4+ cells in cancer hosts failed to make any cytokines following CLP, while the 2B4+ PD-1lo cells in cancer mice secreted increased TNF during sepsis. In sum, the immunophenotypic landscape of cancer septic animals is characterized by both increased CD4+ T cell activation and exhaustion, findings that may underlie the observed increased mortality in mice with pre-existing malignancy following sepsis.

Subjective cognitive impairment and brain structural networks in Chinese gynaecological cancer survivors compared with age-matched controls: a cross-sectional study

BackgroundSubjective cognitive impairment can be a significant and prevalent problem for gynaecological cancer survivors. The aims of this study were to assess subjective cognitive functioning in gynaecological cancer survivors after primary cancer treatment, and to investigate the impact of cancer treatment on brain structural networks and its association with subjective cognitive impairment.MethodsThis was a cross-sectional survey using a self-reported questionnaire by the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) to assess subjective cognitive functioning, and applying DTI (diffusion tensor imaging) and graph theoretical analyses to investigate brain structural networks after primary cancer treatment.ResultsA total of 158 patients with gynaecological cancer (mean age, 45.86 years) and 130 age-matched non-cancer controls (mean age, 44.55 years) were assessed. Patients reported significantly greater subjective cognitive functioning on the FACT-Cog total score and two subscales of perceived cognitive impairment and perceived cognitive ability (all p values <0.001). Compared with patients who had received surgery only and non-cancer controls, patients treated with chemotherapy indicated the most altered global brain structural networks, especially in one of properties of small-worldness (p = 0.004). Reduced small-worldness was significantly associated with a lower FACT-Cog total score (r = 0.412, p = 0.024). Increased characteristic path length was also significantly associated with more subjective cognitive impairment (r = −0.388, p = 0.034).ConclusionWhen compared with non-cancer controls, a considerable proportion of gynaecological cancer survivors may exhibit subjective cognitive impairment. This study provides the first evidence of brain structural network alteration in gynaecological cancer patients at post-treatment, and offers novel insights regarding the possible neurobiological mechanism of cancer-related cognitive impairment (CRCI) in gynaecological cancer patients. As primary cancer treatment can result in a more random organisation of structural brain networks, this may reduce brain functional specificity and segregation, and have implications for cognitive impairment. Future prospective and longitudinal studies are needed to build upon the study findings in order to assess potentially relevant clinical and psychosocial variables and brain network measures, so as to more accurately understand the specific risk factors related to subjective cognitive impairment in the gynaecological cancer population. Such knowledge could inform the development of appropriate treatment and rehabilitation efforts to ameliorate cognitive impairment in gynaecological cancer survivors.

Longitudinal assessment of cancer-related cognitive impairment (CRCI) up to six-months post-chemotherapy with multiple cognitive testing methods in 943 breast cancer (BC) patients and controls.

10014 Background: Large nationwide studies are needed to assess CRCI. Methods: NCORPs recruited BC patients and age-matched non-cancer controls. Computerized ((CANTAB Delayed Match to Sample (DMS), Rapid Visual Processing (RVP), Verbal Recognition Memory (VRM)), paper-based ((Controlled Oral Word Association (COWA), and Trail Making Test (TMT)) , and phone-based (category fluency, word recall, backward counting and digits backward) cognitive assessments of memory, attention, and executive function at pre-chemotherapy, post-chemotherapy, and 6 months follow-up (or time-equivalent for controls) were completed. Longitudinal mixed model (LMM)s included group, time, time*group, and adjusted for age, education, reading, anxiety, and depression. Results: 580 BC patients (mean age = 54) and 363 controls (mean age = 53) were assessed. In all LMMs, there was a significant group*time interaction depicting lower scores in patients compared to controls (p &lt; 0.005) except for TMT (p = 0.09). For longitudinal change on the DMS memory test (primary aim), we observed no significant difference between groups from pre- to post-chemotherapy but did observe a significant difference from pre-chemotherapy to follow-up (p = 0.017) where patients significantly declined (p = 0.005) and controls did not change. We observed similar results for RVP. For VRM, there was a significant pre- to post-chemotherapy group difference (p = 0.003). For COWA, patients significantly declined and controls significantly improved reflecting a significant between group difference (p &lt; 0.001) from pre- to post-chemotherapy. For TMT, both groups significantly improved with patients improving less than controls reflected by a significant between group difference (p = 0.04) that remained a trend at follow-up (p = 0.06). On all phone tests, there was a significant between group effect from both pre- to post-chemotherapy and at follow-up with patients doing less well than controls (all p &lt; 0.001). Conclusions: This nationwide study shows CRCI in BC patients persists in multiple cognitive domains up to 6 months post-chemotherapy compared to controls. Clinical trial information: NCT01382082.

Evaluation of adipocytokines and traditional cardiometabolic risk factors in young male cancer survivors: an age-matched control study

SummaryBackground Life expectancy of cancer survivors has doubled in the past four decades; however, death due to cardiovascular disease is more prevalent in survivors than the general population. Objective, design and methods We evaluated novel and traditional cardiometabolic risk factors in young male cancer survivors in a cross-sectional study of male cancer survivors aged 25–45 years compared with age-matched noncancer controls. Demographic and anthropometric data were recorded and biochemical and hormonal parameters assayed from fasting blood samples in 176 survivors and 213 controls (lipids were measured in all survivors and 97 controls). Results Compared with controls, survivors had significantly higher body mass index, adipocytokines, insulin resistance, total cholesterol and triglyceride levels and lower free androgen index (FAI). Handgrip strength, smoking, alcohol consumption, free oestrogen index, insulin-like growth factor 1 and high-density lipoprotein cholesterol levels did not differ between cancer survivors and controls. Risk factors were analysed simultaneously using stepwise multivariable logistic regression, and this showed that high leptin: adiponectin ratio (odds ratio = 2·63; 95% confidence interval: 1·34–5·15; P = 0·005), hypercholesterolaemia (odds ratio = 1·85; 95%CI: 1·08–3·17; P = 0·025) and low FAI (odds ratio = 2·01; 95% confidence interval: 1·07–3·79; P = 0·030) were independently more common in survivors. The odds ratio in survivors for having at least two of these three risk factors rose to 6·58 (95% confidence interval: 3·30–13·12; P < 0·001). Among survivors, risk factors were not different between cancer therapies but worse in survivors who had radiotherapy involving the testes (hyperleptinaemia and insulin resistance) or age at diagnosis above group median (hypertriglyceridaemia and hypercholesterolaemia). Conclusions A high leptin: adiponectin ratio, hypercholesterolaemia and low FAI are observed in young male cancer survivors, especially those who received radiotherapy involving the testes or were diagnosed at a later age. In view of their youth and known increased risk of cardiovascular death, treatment strategies are required to address this cardiovascular risk.

Evaluation of adipocytokines and traditional cardiometabolic risk factors in young male cancer survivors: an age-matched control study.

Life expectancy of cancer survivors has doubled in the past four decades; however, death due to cardiovascular disease is more prevalent in survivors than the general population. We evaluated novel and traditional cardiometabolic risk factors in young male cancer survivors in a cross-sectional study of male cancer survivors aged 25-45years compared with age-matched noncancer controls. Demographic and anthropometric data were recorded and biochemical and hormonal parameters assayed from fasting blood samples in 176 survivors and 213 controls (lipids were measured in all survivors and 97 controls). Compared with controls, survivors had significantly higher body mass index, adipocytokines, insulin resistance, total cholesterol and triglyceride levels and lower free androgen index (FAI). Handgrip strength, smoking, alcohol consumption, free oestrogen index, insulin-like growth factor 1 and high-density lipoprotein cholesterol levels did not differ between cancer survivors and controls. Risk factors were analysed simultaneously using stepwise multivariable logistic regression, and this showed that high leptin: adiponectin ratio (odds ratio=2·63; 95% confidence interval: 1·34-5·15; P=0·005), hypercholesterolaemia (odds ratio=1·85; 95%CI: 1·08-3·17; P=0·025) and low FAI (odds ratio=2·01; 95% confidence interval: 1·07-3·79; P=0·030) were independently more common in survivors. The odds ratio in survivors for having at least two of these three risk factors rose to 6·58 (95% confidence interval: 3·30-13·12; P<0·001). Among survivors, risk factors were not different between cancer therapies but worse in survivors who had radiotherapy involving the testes (hyperleptinaemia and insulin resistance) or age at diagnosis above group median (hypertriglyceridaemia and hypercholesterolaemia). A high leptin: adiponectin ratio, hypercholesterolaemia and low FAI are observed in young male cancer survivors, especially those who received radiotherapy involving the testes or were diagnosed at a later age. In view of their youth and known increased risk of cardiovascular death, treatment strategies are required to address this cardiovascular risk.

Quality of Life in Long-Term Breast Cancer Survivors

There is considerable interest in the quality of life (QOL) of long-term breast cancer (BC) survivors. We studied changes in QOL from time of BC diagnosis to long-term survivorship and compared QOL in long-term survivors to that of age-matched women with no history of BC. In all, 535 women with localized BC (T1-3N0-1M0) were recruited from 1989 to 1996 and followed prospectively, completing QOL questionnaires at diagnosis and 1 year postdiagnosis. Between 2005 and 2007, those alive without distant recurrence were recontacted to participate in a long-term follow-up (LTFU) study. A control group was recruited from women presenting for screening mammograms, and both groups completed LTFU QOL questionnaires. Longitudinal change in BC survivors and differences between BC survivors and controls were assessed in eight broad categories with clinically significant differences set at 5% and 10% of the breadth of each QOL scale. A total of 285 patients with BC were included in the study, on average 12.5 years postdiagnosis. Longitudinally, clinically significant improvements were observed in overall QOL by 1 year postdiagnosis with further improvements by LTFU. Some clinically significant improvements over time were seen in all categories. A total of 167 controls were recruited. Deficits were observed in self-reported cognitive functioning (5.3% difference) and financial impact (6.3% difference) in BC survivors at LTFU compared with controls. Long-term BC survivors show improvement in many domains of QOL over time, and they appear to have similar QOL in most respects to age-matched noncancer controls, although small deficits in cognition and finances were identified.