Long-Term Second Malignancies in Prostate Cancer Patients Treated With Low-Dose-Rate Brachytherapy and Radical Prostatectomy.

PURPOSE: Second malignancy is a rare but potentially lethal event after prostate brachytherapy, but data remain scarce on its long-term risk. The objective of this study is to estimate the number of pelvic second malignancies following brachytherapy compared to radical prostatectomy (RP). MATERIALS AND METHODS: We retrospectively reviewed patients treated with low-dose 125I brachytherapy and RP in British Columbia from 1999 to 2010. Kaplan-Meier estimates for pelvic (bladder and rectum), invasive pelvic, any second malignancy, and death from any second malignancy were assessed. Cox multivariable analyses were performed adjusting for initial treatment type, age, post-RP adjuvant/salvage external beam radiation therapy status, and smoking history. RESULTS: Two thousand three hundred seventy-eight brachytherapy and 9089 RP patients were included. Median age was 66 years (interquartile range [IQR] 61-71) and 63 years (IQR 58-67), respectively. Median follow-up time to event or censured was 14 years (IQR 11.5-17.3). The Kaplan-Meier estimates for pelvic second malignancy at 15 and 20 years were 6.4% and 9.8%, respectively, after brachytherapy, and 3.2% and 4.2% after RP. Time to any second malignancy and time to death from any second malignancy were not significantly different (P > .05). On Cox multivariable analysis, brachytherapy, compared to surgery, was an independent factor for pelvic (hazard ratio [HR] 1.81 [95% CI 1.45-2.26], P < .001) and invasive pelvic second malignancy (HR 2.13 [95% CI 1.61-2.83], P < .001). Increased age and smoking were also associated with higher estimates of events (P < .001). CONCLUSIONS: After adjustment for age, post-RP adjuvant/salvage external beam radiation therapy status, and smoking status, numerically higher long-term HRs of pelvic and invasive pelvic second malignancy in patients treated with brachytherapy compared to RP were noted.

Prognostic impact of neurocognitive disorders in older patients with cancer: the ELCAPA prospective cohort study.

OBJECTIVE: To assess the prognostic value of neurocognitive disorder (NCD) for 12 month-overall mortality in patients aged 70 or more with a solid cancer. DESIGN: prospective, observational, multicenter cohort. SETTING AND PARTICIPANTS: We analyzed data from the ELCAPA longitudinal multicenter observational cohort of patients aged 70 or over, referred for a geriatric assessment (GA) before a new cancer treatment modality between January 31st, 2007, and December 29th, 2017. We defined the baseline NCD in four classes: no NCD, mild NCD, moderate NCD, and major NCD, based on the Mini-Mental State Examination (MMSE) score, memory complaint, and the Instrumental Activities of Daily Living (IADL) score. STATISTICAL METHODS: We compared the baseline characteristics of patients according to NCD classes, globally and by pairs (with Bonferroni' correction). Prognosis value of NCD classes were analysed by using univariable and then multivariable 12 month survival analysis with age as time-variable and with and without adjustement for the treatment strategy (curative, palliative or exclusive supportive care). RESULTS: 2784 patients with solid-cancer were included, with a median [interquartile range] age of 82 [78;86]. 36% of the patients were free of NCD, 34% had a mild NCD, 17% had a moderate NCD, and 13% had a major NCD. We identified the following independent prognostic factors for 12 month-overall mortality: NCD (adjusted hazard ratio (aHR) [95% confidence interval (CI)] for a major NCD = 1.54 [1.19-1.98] (p < 0.001), type of cancer, metastatic status, inpatient consultation, poor general health (assessed as the level of fatigue and Eastern Cooperative Oncology Group performance status [ECOG-PS]), greater weight loss, palliative treatment, and exclusive supportive care. Additional adjustment for the treatment strategy did not greatly change the strength of the association of a major NCD with 12 month-overall mortality (HR [95%CI] = 1.78 [1.39-2.29] (p < 0.001). CONCLUSION: Our results suggest that the presence of a major NCD has direct prognostic value (independently of other geriatric factors, the type of cancer and the treatment strategy) in older patients with a solid cancer.

Comparison of the prognostic value of eight nutrition-related tools in older patients with cancer: A prospective study.

OBJECTIVES: The primary objective of the present study was to evaluate and compare the ability of eight nutrition-related tools to predict 1-year mortality in older patients with cancer. DESIGN, SETTING AND PARTICIPANTS: We studied older patients with cancer from the ELCAPA cohort and who had been referred for a geriatric assessment at one of 14 participating geriatric oncology clinics in the greater Paris area of France between 2007 and 2018. MEASUREMENTS: The studied nutrition-related tools/markers were the body mass index (BMI), weight loss (WL) in the previous 6 months, the Mini Nutritional Assessment, the Geriatric Nutritional Risk Index (GNRI), the Prognostic Nutritional Index, the Glasgow Prognostic Score (GPS), the modified GPS, and the C-reactive protein/albumin ratio. RESULTS: A total of 1361 patients (median age: 81; males: 51%; metastatic cancer: 49%) were included in the analysis. Most of the tools showed a progressively increase in the mortality risk as the nutrition-related risk category worsened (overall p-values <0.02 for all) after adjustment for age, outpatient status, functional status, severe comorbidities, cognition, mood, cancer treatment strategy, tumour site, and tumour metastasis. All the models were discriminant, with a C-index ranging from 0.748 (for the BMI) to 0.762 (for the GPS). The concordance probability estimate ranged from 0.764 (WL) to 0.773 (GNRI and GPS)). CONCLUSION: After adjustment for relevant prognostic factors, all eight nutrition-related tools/markers were independently associated with 1-year mortality in older patients with cancer. Depending on the time or context of the GA, physicians do not always have the time or means to perform and assess all the tools/markers compared here. However, even when some information is missing, each nutritional tool/marker has prognostic value and can be used in the evaluation.

Geriatric assessment and quality of life for 2 years in older patients with head and neck cancer.

Due to the location and toxicity of treatments, head and neck cancer (HNC) has a major impact on quality of life (QoL). Objective: to assess the effects of geriatric-assessment (GA)-driven interventions on QoL over 2 years in older adults with HNC.EGeSOR was a randomized study of HNC patients aged ≥65, receiving a pretreatment GA, a geriatric intervention and follow-up (intervention) or standard of care (control). The primary endpoint was QoL score using the European Organisation for Research and Treatment of Cancer's (EORTC QLQ-C30) and HNC (QLQ-HN35) QoL questionnaires over 24 months.In total, 475 patients were included (median age: 75.3; women: 31%; oral cancer: 44%). QoL scores improved over 24 months with various trajectories, without significant differences between the groups. A total of 74% of patients (interventional group) did not receive the complete intervention. Cancer characteristics, functional status, and risk of frailty were associated with change in the Global Health Status QoL score.There is a need to develop an alternative model of implementation such as patient-centered health-care pathways. TRIAL REGISTRATION: NCT02025062.

Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptoms.

BACKGROUND: The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depressed patients. No clinical studies have investigated the crosstalk between the eCB system and the Trp/5-HT/Kyn pathways. Here, we hypothesized that the eCB system is associated with an enhanced Kyn production in relation to the severity of depressive symptoms. METHODS: Eighty-two subjects (51 patients with a diagnosis of depressive disorder (DSM-5) and 31 healthy volunteers), were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Scale, and Global Clinical Impression. Serum concentrations of eCBs (N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)); structurally related fatty acyl compounds 2-oleoylglycerol (2-OG), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA); Trp, Kyn, Kyn/Trp ratio (an index of Trp degradation into Kyn) and 5-HT were also determined. RESULTS: Following a principal component analysis including the severity of depression, Kyn and the Kyn/Trp ratio appear to be directly associated with 2-AG, AEA, and PEA. Interestingly, these biomarkers also permitted to distinguish the population into two main clusters: one of individuals having mild/severe depressive symptoms and the other with an absence of depressive symptoms. Using parametric analysis, higher serum levels of 2-AG, Kyn, and the ratio Kyn/Trp and lower levels of Trp and 5-HT were found in individuals with mild/severe depressive symptoms than in those without depressive symptoms. While in asymptomatic people, PEA was directly associated to Trp, and OEA indirectly linked to 5-HT, in individuals with depressive symptoms, these correlations were lost, and instead, positive correlations between AEA and 2-AG, PEA and AEA, and PEA vs 2-AG and OEA concentrations were found. CONCLUSIONS: Parametric and non-parametric analyses suggest a possible association between eCBs, tryptophan/kynurenine biomarkers, and severity of depression, confirming a likely interplay among inflammation, stress, and depression. The enhanced relationships among the biomarkers of the 2-AG and AEA pathways and related lipids seen in individuals with depressive symptoms, but not in asymptomatics, suggest an altered metabolism of the eCB system in depression.

Cancer mortality and competing causes of death in older adults with cancer: A prospective, multicentre cohort study (ELCAPA-19).

BACKGROUND: In older patients with cancer, comorbidities compete with cancer for cause of death. The objectives were to evaluate cancer mortality and factors associated, according to metastatic status. METHODS: Between 2007 and 2014, patients with cancer aged ≥70 referred for pre-therapeutic geriatric assessment (GA) were included through the ELCAPA prospective cohort study. The underlying cause of death was defined according to the International Classification of Diseases, 10th Revision. The World Health Organisation definition was used to categorise the cause of death as cancer versus another disease (e.g. cardiovascular disease, infectious disease, etc.) Competing risk models were used. RESULTS: Mean (SD) age of the 1445 included patients was 80.2 (5.8) and 48% were women. Most common tumour sites were colorectal (19%), breast (17%) and urinary (15%); 773 patients (49%) had metastases. After a 34-month median follow-up, 706 cancer deaths were observed among 843 deaths. The 6-month and 3-year cancer mortality rates (95% CI) were 12% (9-15) and 34% (29-38) for non-metastatic patients and 43% (39-47) and 79% (75-82) for metastatic patients, respectively. Dependency in activities of daily living and comorbidities were associated with 6-month and 3-year cancer mortality in non-metastatic (adjusted subhazard ratio [aSHR] = 1.68 [0.99-2.85] and 1.69 [1.16-2.45]; and 1.98 [1.08-3.63] and 3.38 [1.47-7.76], respectively) and metastatic patients (aSHR = 2.81 [2.01-3.93] and 2.95 [2.14-4.07]; and 1.63 [1.18-2.25] and 2.06 [1.39-3.05], respectively). Impaired Timed-Get-Up-and-Go test was associated with 6-month and 3-year cancer mortality in metastatic patients (aSHR = 1.5 [1.06-2.12] and 1.38 [1.06-1.81], respectively). Obesity was negatively associated with 3-year cancer death in non-metastatic (aSHR = 0.53 [0.29-0.97]) and metastatic patients (aSHR = 0.71 [0.51-1.00]). CONCLUSIONS: The majority of older adults with cancer referred for pre-therapeutic GA die from cancer. Geriatric parameters are independently associated with cancer mortality and should be considered for prognosis assessment, decision-making and care.

Brain decoding of the Human Connectome Project tasks in a dense individual fMRI dataset.

Brain decoding aims to infer cognitive states from patterns of brain activity. Substantial inter-individual variations in functional brain organization challenge accurate decoding performed at the group level. In this paper, we tested whether accurate brain decoding models can be trained entirely at the individual level. We trained several classifiers on a dense individual functional magnetic resonance imaging (fMRI) dataset for which six participants completed the entire Human Connectome Project (HCP) task battery >13 times over ten separate fMRI sessions. We evaluated nine decoding methods, from Support Vector Machines (SVM) and Multi-Layer Perceptron (MLP) to Graph Convolutional Neural Networks (GCN). All decoders were trained to classify single fMRI volumes into 21 experimental conditions simultaneously, using ∼7 h of fMRI data per participant. The best prediction accuracies were achieved with GCN and MLP models, whose performance (57-67 % accuracy) approached state-of-the-art accuracy (76 %) with models trained at the group level on >1 K hours of data from the original HCP sample. Our SVM model also performed very well (54-62 % accuracy). Feature importance maps derived from MLP -our best-performing model- revealed informative features in regions relevant to particular cognitive domains, notably in the motor cortex. We also observed that inter-subject classification achieved substantially lower accuracy than subject-specific models, indicating that our decoders learned individual-specific features. This work demonstrates that densely-sampled neuroimaging datasets can be used to train accurate brain decoding models at the individual level. We expect this work to become a useful benchmark for techniques that improve model generalization across multiple subjects and acquisition conditions.

Is Engineered Tissue the Future of Bladder Reconstruction: Con.

Tissue engineering, once promising, faces significant technical challenges. Current limitations impede progression of the field, as evidenced by clinical trial failures over the past decades. Existing established surgical techniques remain the only proven, successful, and durable methods for bladder reconstruction.

Spatial Transcriptomics Reveal Pitfalls and Opportunities for the Detection of Rare High-Plasticity Breast Cancer Subtypes.

Breast cancer is one of the most prominent types of cancers, in which therapeutic resistance is a major clinical concern. Specific subtypes, such as claudin-low and metaplastic breast carcinoma (MpBC), have been associated with high nongenetic plasticity, which can facilitate resistance. The similarities and differences between these orthogonal subtypes, identified by molecular and histopathological analyses, respectively, remain insufficiently characterized. Furthermore, adequate methods to identify high-plasticity tumors to better anticipate resistance are lacking. Here, we analyzed 11 triple-negative breast tumors, including 3 claudin-low and 4 MpBC, via high-resolution spatial transcriptomics. We combined pathological annotations and deconvolution approaches to precisely identify tumor spots, on which we performed signature enrichment, differential expression, and copy number analyses. We used The Cancer Genome Atlas and Cancer Cell Line Encyclopedia public databases for external validation of expression markers. By focusing our spatial transcriptomic analyses on tumor cells in MpBC samples, we bypassed the negative impact of stromal contamination and identified specific markers that are neither expressed in other breast cancer subtypes nor expressed in stromal cells. Three markers (BMPER, POPDC3, and SH3RF3) were validated in external expression databases encompassing bulk tumor material and stroma-free cell lines. We unveiled that existing bulk expression signatures of high-plasticity breast cancers are relevant in mesenchymal transdifferentiated compartments but can be hindered by abundant stromal cells in tumor samples, negatively impacting their clinical applicability. Spatial transcriptomic analyses constitute powerful tools to identify specific expression markers and could thus enhance diagnosis and clinical care of rare high-plasticity breast cancers.

Individual and contextual risk factors for mortality in nursing home residents during the first wave of COVID-19 in France: a multilevel analysis of a nationwide cohort study.

BACKGROUND: Mortality amongst nursing home (NH) residents increased by 43% during the first wave of coronavirus disease 2019 (COVID-19). We estimated the 'contextual effect' on mortality, tried to explain it by NH characteristics and identified resident- and NH-level risk factors for mortality. METHODS: The contextual effect was measured for two cohorts of NH residents managed by the general scheme in metropolitan France (RESIDESMS data from 03/01/2020 to 05/31/2020 and 03/01/2019 to 05/31/2019) by the intraclass correlation coefficient (ICC) estimated from mixed-effects logistic regression. RESULTS: Amongst 385,300 residents (5,339 NHs) included in 2020 (median age 89 years, 25% men), 9.1% died, versus 6.7% of 379,926 residents (5,270 NHs) in 2019. In the empty model, the ICC was 9.3% in 2020 and 1.5% in 2019. Only the geographic location partially explained the heterogeneity observed in 2020 (ICC: 6.5% after adjustment). Associations with mortality were stronger in 2020 than in 2019 for male sex and diabetes and weaker for heart disease, chronic respiratory disease and residence <6 months. Mortality was higher in 2020 (15.1%) than 2019 (6.3%) in NHs with at least one death with a mention of COVID-19 and more heterogeneous (ICC: 8.0%) than in the others (mortality: 6.7% in both years; ICC: 1.1%). CONCLUSION: Our results suggest that the COVID-19 crisis had a heterogeneous impact on mortality in NH residents and that geographic location explain a part of the contextual effect, which appears to have had little influence on mortality in NHs not being affected by the virus.

The genitourinary impacts of electronic cigarette use: a systematic review of the literature.

PURPOSE: Electronic cigarette (e-cig) use is prevalent. The health implications of e-cig use on the genitourinary (GU) system are uncertain. This systematic review aims to evaluate how e-cig use impacts the GU system. METHODS: A systematic search was conducted in PubMed, Embase and Ovid alongside citation searching. Review articles, non-English papers, animal model/cell line studies or articles only on combustible cigarettes were excluded. Quality assessment was undertaken using the Joanna Briggs Institute checklists. The primary endpoint was the impact of e-cig use on bladder cancer incidence. Secondary outcomes included urinary carcinogens, chronic kidney disease (CKD), reproductive disorders, and other GU diseases. RESULTS: The search yielded 244 articles, 28 were ultimately included. One study assessed risk of bladder cancer and found the use of e-cig was associated with an increased odds ratio of 1.577 for its diagnosis. Twenty-one articles measured potential urinary carcinogens-including crotonaldehyde and benzene-associated with bladder cancer. Two articles evaluated the association of e-cig use with CKD and reported mixed outcomes. Three articles reported on reproductive disorders, specifically, stuttering priapism and changes to sperm quantity and quality. One study reported on other GU diseases, specifically burns to the GU system. After quality assessment, all articles were deemed to be of acceptable quality for inclusion. CONCLUSIONS: E-cig use was associated with an increased risk of bladder cancer, increased exposure to carcinogenic compounds, mixed evidence on CKD, increased risk of reproductive disorders and burns to the GU system. Further studies are needed to understand long-term GU effects.

Towards an optimization of functional localizers in non-human primate neuroimaging with (fMRI) frequency-tagging.

Non-human primate (NHP) neuroimaging can provide essential insights into the neural basis of human cognitive functions. While functional magnetic resonance imaging (fMRI) localizers can play an essential role in reaching this objective (Russ et al., 2021), they often differ substantially across species in terms of paradigms, measured signals, and data analysis, biasing the comparisons. Here we introduce a functional frequency-tagging face localizer for NHP imaging, successfully developed in humans and outperforming standard face localizers (Gao et al., 2018). FMRI recordings were performed in two awake macaques. Within a rapid 6 Hz stream of natural non-face objects images, human or monkey face stimuli were presented in bursts every 9 s. We also included control conditions with phase-scrambled versions of all images. As in humans, face-selective activity was objectively identified and quantified at the peak of the face-stimulation frequency (0.111 Hz) and its second harmonic (0.222 Hz) in the Fourier domain. Focal activations with a high signal-to-noise ratio were observed in regions previously described as face-selective, mainly in the STS (clusters PL, ML, MF; also, AL, AF), both for human and monkey faces. Robust face-selective activations were also found in the prefrontal cortex of one monkey (PVL and PO clusters). Face-selective neural activity was highly reliable and excluded all contributions from low-level visual cues contained in the amplitude spectrum of the stimuli. These observations indicate that fMRI frequency-tagging provides a highly valuable approach to objectively compare human and monkey visual recognition systems within the same framework.