Older patients referred for geriatric consultation in the emergency department: characteristics and healthcare utilization.

BACKGROUND: Comprehensive geriatric assessment (CGA) is difficult to perform in the emergency department (ED) environment and performance of screening tools in identifying vulnerable older ED patients who are best candidates for a geriatric consultation remain questionable. AIM: To determine the characteristics of older patients referred for a geriatric consultation by ED staff and to investigate these patients' subsequent healthcare utilization. METHODS: Secondary analysis of data previously collected for a prospective observational study of patients aged 75 + years visiting the ED of an academic hospital in Switzerland over four months (Michalski-Monnerat et al., J Am Geriatr Soc 68(12):2914-20, 2020). Socio-demographic, health, functional (basic activities of daily living; BADL), cognitive, and affective status data were collected at admission by a research nurse using a standardized brief geriatric assessment. Information on geriatric consultations, hospitalization, discharge destination, and 30-day readmission were retrieved from hospital database. Bivariable and multivariable analyses were performed using this data set collected previously. RESULTS: Thirty-two (15.8%) of the 202 enrolled patients were referred for a geriatric consultation. Compared to the others, they were older (84.9 ± 5.4 vs 82.9 ± 5.4 years, p = .03), more impaired in BADL (4.8 ± 1.6 vs 5.5 ± 1.0, p = .01), with more comorbid conditions (5.3 ± 1.5 vs 4.5 ± 1.9, p = .03), more frequently admitted after a fall (43.7% vs 19.4%, p = .01), and hospitalized over the previous 6-month period (53.1% vs 30.6%, p = .02). Multivariable analyses that adjusted for variables significantly associated with outcomes in bivariable analysis found that being admitted after a fall (AdjOR 4.0, 95%CI 1.7-9.4, p < .01) and previously hospitalized (AdjOR 2.7, 95% CI 1.2-6.2, p = .02) remained associated with increased odds of consultation, whereas the inverse association with BADL performance remained (AdjOR 0.7, 95%CI 0.5-0.9, p = .01). Patients referred for geriatric consultation had higher odds of hospitalization (84.4% vs 49.4%; AdjOR 5.9, 95%CI 2.1-16.8, p < .01), but similar odds of home discharge when admitted, and of 30-day readmission. CONCLUSION: About one in six older ED patients were referred for a geriatric consultation who appeared to be those most vulnerable, as suggested by their increased hospitalization rate. Alternative strategies are needed to enhance access to geriatric consultation in the ED.

Fibroblast-derived IL-33 is dispensable for lymph node homeostasis but critical for CD8 T-cell responses to acute and chronic viral infection.

Upon viral infection, stressed or damaged cells can release alarmins like IL-33 that act as endogenous danger signals alerting innate and adaptive immune cells. IL-33 coming from nonhematopoietic cells has been identified as important factor triggering the expansion of antiviral CD8+ T cells. In LN the critical cellular source of IL-33 is unknown, as is its potential cell-intrinsic function as a chromatin-associated factor. Using IL-33-GFP reporter mice, we identify fibroblastic reticular cells (FRC) and lymphatic endothelial cells (LEC) as the main IL-33 source. In homeostasis, IL-33 is dispensable as a transcriptional regulator in FRC, indicating it functions mainly as released cytokine. Early during infection with lymphocytic choriomeningitis virus (LCMV) clone 13, both FRC and LEC lose IL-33 protein expression suggesting cytokine release, correlating timewise with IL-33 receptor expression by reactive CD8+ T cells and their greatly augmented expansion in WT versus ll33-/- mice. Using mice lacking IL-33 selectively in FRC versus LEC, we identify FRC as key IL-33 source driving acute and chronic antiviral T-cell responses. Collectively, these findings show that LN T-zone FRC not only regulate the homeostasis of naïve T cells but also their expansion and differentiation several days into an antiviral response.

[Treatment of congestive heart failure in older persons and SGLT2 inhibitors - Having your patient's best interests at heart]. / Traitement de l'insuffisance cardiaque chez la personne âgée et inhibiteurs du SGLT2 - En avoir le cœur net.

The treatment and management of heart failure (HF) are constantly evolving. The latest guidelines recommend the use of SGLT2 inhibitors (SGLT2i) as an integral part to treating HF with reduced ejection fraction (< 40%). However, given that the patients included in these trials do not reflect the heterogeneity of the health of many elderly patients, we recommend basing the therapeutic decision on the patient's state of frailty. If a SGLT2i treatment at a standard dose (10 mg 1x/day) is recommended for robust patients, we suggest initiating treatment at 5 mg 1x/day for vulnerable patients, and then after 1 month increasing the dose to 10 mg 1x/day. Finally, for dependent patients, we recommend therapeutic abstention in the absence of sufficient scientific evidence.

La prise en charge de l'insuffisance cardiaque (IC) est en constante évolution. Les dernières recommandations préconisent l'utilisation des inhibiteurs du SGLT2 (iSGLT2) pour le traitement de l'IC à fraction d'éjection réduite (< 40%). Cependant, les populations des études ne reflètent pas l'hétérogénéité de la population âgée en termes de santé et nous proposons de baser la décision thérapeutique selon la Clinical Frailty Scale : si, pour les patients robustes, un traitement par iSGLT2 à dose standard (10 mg 1 x/jour) est préconisé, nous proposons, pour les patients vulnérables, d'initier le traitement à 5 mg 1 x/jour, puis d'augmenter à 10 mg 1 x/jour après 1 mois. Finalement, pour les patients dépendants, nous recommandons une abstention thérapeutique en l'absence d'évidences scientifiques suffisantes.

[Geriatrics]. / Gériatrie.

Sleeping enough is associated with a reduced risk of mortality and dementia. New evidence support regular physical exercise, including at home, as a corner stone intervention to prevent falls and fractures. In contrast, supplementation with high doses of vitamin D is ineffective and even deleterious in this indication and a routine screening in asymptomatic adults is not recommended. Several studies illustrate our difficulties in prescribing and deprescribing in frail older patients and a study suggests that statins in cardiovascular primary prevention should considered only when a patient's life expectancy exceeds 2.5 years. Finally, several studies have fueled the debate about screening for hearing impairment.

Dormir ni trop ni trop peu est associé à une réduction du risque de mortalité et de déclin cognitif. De nouvelles études confirment que l'exercice physique régulier, y compris à domicile, constitue la clé de voûte de la prévention des chutes et des fractures. Par contre, la supplémentation par de hautes doses de vitamine D n'est pas efficace, voire délétère, dans cette indication et le dépistage systématique d'un déficit n'est pas recommandé chez les patients adultes asymptomatiques. Plusieurs études illustrent nos difficultés à prescrire et déprescrire, chez les patients âgés fragiles, et une étude suggère qu'un traitement de statines en prévention cardiovasculaire primaire ne se justifie que si l'espérance de vie du patient dépasse 2,5 ans. Finalement, plusieurs études sont venues nourrir le débat sur le dépistage de la presbyacousie.

[To D or not to D ? Why and how to treat vitamin D deficiency in older patients]. / « To D or not to D ¼ : pourquoi et comment traiter l'hypovitaminose D chez les personnes âgées.

Vitamin D deficiency is so frequent in older patients (aged 65 years and older) that the international consensus does not recommend routine vitamin D measurement. Assessment of overall health status is a cornerstone before considering vitamin D supplementation, as the effect of vitamin D supplementation has only been demonstrated in vulnerable or dependent but not for robust older patients. The effect of the different modalities of oral vitamin D supplementation are equivalent : 800-1'200 IU/day, 10'000 IU/week or 30'000-50'000 IU/month. Monitoring of vitamin D blood level monitoring is not necessary because of a large therapeutic margin. In the presence of osteoporosis, a dietary or supplementation intake of 1'200 mg per day of calcium should be added.

L'hypovitaminose D est très fréquente chez les personnes âgées (65 ans et plus), à tel point que le consensus international est de ne pas doser la vitamine D en routine. L'évaluation de l'état de santé global est primordiale avant d'envisager une supplémentation en vitamine D, son effet ayant été démontré seulement chez les personnes âgées vulnérables ou dépendantes, mais pas chez les robustes. L'efficacité des modalités de supplémentation en vitamine D per os sont équivalentes : 800-1200 UI/jour, 10 000 UI/semaine ou 30 000-50 000 UI/mois. Un monitoring du taux sanguin de vitamine D n'est pas nécessaire en raison d'une large marge thérapeutique. En présence d'une ostéoporose, cette supplémentation devrait être complétée par un apport alimentaire ou une supplémentation de 1200 mg de calcium par jour.

[Geriatric medicine: update 2020]. / Gériatrie.

Several studies published in 2020 showed new data supporting the prescription of statins in some old and very old patients. Despite the enthusiasm about SGLT-2 inhibitors, caution must remain in frail and dependent older diabetic patients who are not well represented in most studies. Antihypertensive treatment appears more beneficial when taken at night rather than in the morning but beware of the prescribing cascade of a diuretic when a new prescription of a calcium channel blocker. Biomarkers, including plasmatic biomarkers, are becoming increasingly important in the diagnostic strategy of neurocognitive disorders. Finally, fall prevention studies showed heterogeneous results but multimodal interventions remain mainstream.

Plusieurs études publiées en 2020 ont relancé le débat concernant la prescription de statines chez certaines personnes âgées et très âgées. Malgré l'enthousiasme concernant les inhibiteurs du SGLT2, la prudence reste de mise chez les patients diabétiques âgés vulnérables et, surtout dépendants, peu ou pas représentés dans les études. La prise nocturne d'un traitement antihypertenseur semble plus efficace que diurne, mais attention à la prescription en cascade d'un diurétique de l'anse lorsqu'un traitement anticalcique est initié. La place des biomarqueurs, y compris plasmatiques, dans la stratégie diagnostique se renforce. Si les études de prévention des chutes ont montré des résultats variables, l'approche interventionnelle multimodale reste la référence.

[To screen or not to screen after age 75 ?] / Dépistages : que faire au-delà de 75 ans ?

The older population is heterogenous: at the same age, elderly patients can be robust, frail or dependent. Screening decisions must be individualized, taking into account the remaining life expectancy, the Time to Benefit (TTB: delay until preventive care gives a benefit), and patient preferences. Thus, robust patients, who have a longer life expectancy, can still benefit from some screening tests over age 75 that are inappropriate in vulnerable or dependent patients whose life expectancy is shorter than the TTB. Discussing life expectancy issues remains difficult outside of crises but medical encounters are unique opportunities to inquire about individual preferences and expectations, in order to define care objectives and discuss advanced care planning.

La population âgée est hétérogène : à âge identique, les patients peuvent être robustes, vulnérables ou dépendants. Le dépistage doit être individualisé en mettant en relation l'espérance de vie résiduelle estimée (EVR), le Time To Benefit (TTB : délai jusqu'à l'apparition de bénéfices après intervention) et les préférences du patient. Ainsi, les patients robustes, dont l'EVR est supérieure au TTB, peuvent encore bénéficier de certains examens de dépistage après 75 ans alors qu'ils seront inappropriés chez ceux dont l'EVR est inférieure au TTB (vulnérables, dépendants). Bien que discuter de l'EVR puisse être ardu, chaque consultation est une opportunité pour l'aborder, s'enquérir des préférences et attentes du patient quant à sa santé afin de définir ensemble les modalités de sa prise en charge et de son projet de soins anticipés.

[COVID-19 infection in the elderly in French-speaking Switzerland: an inventory of beliefs, convictions and certainties]. / Infection COVID-19 chez les personnes âgées en Suisse Romande - Un état des lieux entre croyances, convictions et certitudes.

Most patients hospitalized for COVID-19 are aged over 70 years old, and half of those who die are over 83 years old. Older patients do not always present with typical symptoms (fever, cough and dyspnoea) but sometimes are and remain asymptomatic (contact screening), or have aspecific presentations (altered general condition, falls, delirium, unusual fatigue). Rectal swab, which minimizes exposition risk, appears useful in long-term care patients with diarrhea. Older age is associated with worse prognosis, but the analysis should be refined by means of prognostic indexes that account for the heterogeneous health, functional, and cognitive status of the elderly population. Gathering elderly patients' wishes and assessing their remaining life expectancy allows to anticipate care decisions according to the level of tension in the health system.

La majorité des patients COVID-19 hospitalisés ont plus de 70 ans et 50 % de ceux qui en décèdent ont plus de 83 ans. La clinique typique n'est pas toujours présente chez les personnes très âgées qui peuvent être et rester totalement asymptomatiques (dépistage contact) ou avoir des manifestations aspécifiques (baisse de l'état général, chutes, delirium, fatigue). Le frottis anal, qui minimise le risque d'exposition, peut s'avérer très utile en EMS lors de diarrhées. L'âge avancé est un marqueur de mauvais pronostic, mais devrait être pondéré à l'aide d'index pronostiques pour tenir compte de l'hétérogénéité de l'état de santé, fonctionnel et cognitif à l'âge avancé. Recueillir les souhaits de la personne et évaluer son espérance de vie restante permet d'anticiper les décisions de soins selon le niveau de tension du système de santé.

[Geriatric medicine†: Update 2019]. / Gériatrie.

Up-dated recommendations published in 2019 about inappropriate medications in older persons and management for type 2 diabetes mellitus are discussed. New evidence has also been published regarding the benefits of physical activity in secondary prevention for falls as well as in the prevention of cognitive decline and dementia, independent of genetic and vascular risk profile. SPRINT MIND study reports a significant 19 % decreased risk of minor neurocognitive impairment with intensive BP treatment. A meta-analysis about prevention of delirium with antipsychotics report benefits only in cardiac and orthopedic post-operative settings, whereas another meta-analysis about delirium treatment did not find any benefits from antipsychotics.

Les mises à jour 2019 des critères de Beers (médicaments à éviter chez les personnes âgées) et des recommandations pour le traitement du diabète de type 2 sont résumées. De nouvelles études renforcent les évidences concernant les bénéfices de l'activité physique en prévention secondaire des chutes, mais aussi pour ralentir le déclin cognitif et réduire le risque de démence, indépendamment du risque génétique ou vasculaire. L'étude SPRINT MIND rapporte une réduction de 19 % de l'incidence des troubles neurocognitifs mineurs sous traitement HTA intensif. Finalement, une méta-analyse concernant la prévention pharmacologique de l'état confusionnel aigu (ECA) suggère une efficacité des neuroleptiques limitée aux situations post-chirurgie cardiaque et orthopédique, alors qu'une autre concernant le traitement de l'ECA nous laisse sur notre faim.

[Management of peripheral neuropathy in the elderly]. / Prise en charge des polyneuropathies sensitives chez la personne âgée.

Polyneuropathies occur frequently (> 30 %) among elderly people and can result in increased morbidity and impaired quality of life. Diabetes, chronic kidney disease, water-soluble vitamins deficiencies, drugs and alcohol side effects are the major etiologies after a systematic assessment. Neurologist referral is indicated when the diagnosis remains unclear and therapeutic options exist. Treatment strategies focus on reversal of underlying conditions, prevention, stabilization and alleviation of symptoms, especially neuropathic pain and maintain the best autonomy.

Les polyneuropathies sensitives sont observées chez environ 30 % des personnes âgées et sont potentiellement grevées d'une importante morbidité. Une approche systématique permet souvent un diagnostic étiologique : diabète, insuffisance rénale chronique, carences vitaminiques hydrosolubles, effets secondaires médicamenteux et consommation d'alcool en tête. L'avis neurologique est indiqué après un premier bilan négatif, en présence d'options thérapeutiques. Le traitement vise à corriger les étiologies lorsque cela est possible, à prévenir, stabiliser et soulager les symptômes, en particulier la douleur neuropathique, ainsi qu'à préserver la meilleure autonomie possible.

[Year in review : geriatrics]. / Gériatrie.

In 2018, new recommendations about the prevention of falls and fractures emphasized the benefits from exercise and from multimodal prevention programs but did not endorse any more vitamin D supplementation for falls prevention. Results were contrasted for several studies testing exercise (negative) and cognitive training (mixed results) in the management of older patients suffering from neurocognitive disorders. The new direct oral anticoagulants are increasingly prescribed in older patients despite the paucity of data. New information has been released in 2018 from « real-world ¼ data that seem reassuring about their risk/benefit ratio in old-old patients, provided a careful prescription. Finally, the Mediterranean diet is still gaining credit with a new study showing its benefits in preventing frailty in community-dwelling older persons.

En 2018, l'intérêt de l'activité physique et des programmes de prévention multimodaux est confirmé pour la prévention des chutes, mais l'utilisation de la vitamine D dans cette indication est remise en question. Pour les pathologies neurocognitives, les résultats sont contrastés concernant l'activité physique, alors qu'une revue systématique confirme les bénéfices, certes modestes, de l'entraînement cognitif sur les performances cognitives et la qualité de vie des patients et de leurs proches. Les nouveaux anticoagulants sont de plus en plus largement utilisés chez les patients âgés malgré des données encore limitées, mais plusieurs études du « monde réel ¼ semblent confirmer leur bon rapport risques/bénéfices aussi chez ces patients. Le régime méditerranéen a le vent en poupe, une étude rapporte un bénéfice sur l'incidence de la fragilité.

[Staying at home : which dimensions to assess in older persons ?] / Maintien à domicile : quelles dimensions prendre en compte chez les personnes âgées ?

Defining the limits of home long term care is not an easy task. For the health care professionals, deciding whether to support older patients in their plan to stay at home requires a structured approach, based on objective information. It is critical to systematically collect information on a patient's needs resulting from medical problems and their management, from his or her functional, cognitive, affective and nutritional status, as well as on mobility, social, spiritual, and financial resources that can be mobilized by the patient, his or her relatives, and the health care professionals. This information allows to first determine the potential gap between the patient's needs and available resources, and then to define possible scenarios to discuss with the patient and his or her relatives to reach a sustainable decision.

Définir les limites du maintien à domicile d'une personne âgée est rarement simple. Lorsque la situation paraît précaire, la réflexion qui prépare la décision des professionnels de soutenir ou pas un patient dans son projet de rester à domicile doit se baser sur une approche structurée et la récolte d'informations si possible objectives. Il faut aborder systématiquement les besoins en soutien découlant des problèmes médicaux, de l'état fonctionnel, cognitif, affectif et nutritionnel, ainsi que la mobilité, les ressources sociales, spirituelles et financières mobilisables par le patient, son entourage et/ou les professionnels. Une fois l'étendue du décalage entre besoins et ressources déterminée, des scénarios peuvent être élaborés, priorisés, puis discutés avec le patient et, le cas échéant, son entourage afin d'aboutir à une décision.

[Anticoagulation in old fallers : a common challenge]. / Les chuteurs âgés traités par anticoagulants : un challenge quotidien.

Long term anticoagulation is required to reduce the risk of stroke or other thromboembolic events resulting from atrial fibrillation. Thus, anticoagulation is frequently considered in older persons who are at increased risk for hemorrhagic adverse events. This is even more so as about a third of older persons aged 65 years and over will fall over a year. Nevertheless, benefits from risk reduction in stroke incidence and its consequences (functional depen-dency, cognitive decline, altered quality of life, death) resulting from anticoagulant prescription remains superior to its related risk.

Les anticoagulants peuvent être prescrits au long cours, par exemple en prévention primaire pour diminuer le risque thromboembolique artériel, associé à une fibrillation atriale (FA). Ces médicaments sont souvent utilisés chez des personnes âgées chez qui le potentiel iatrogène hémorragique est redouté. Ce risque est d'autant plus marqué que les chutes affectent au moins un tiers de ces personnes au cours d'une année. Néanmoins, le bénéfice, pour réduire l'incidence et les conséquences d'un AVC (dépendance, surmortalité, qualité de vie altérée, atteinte cognitive) de ces médicaments, est supérieur à leur risque intrinsèque.

[Dementia: management and prevention]. / Prise en charge et prévention des pathologies démentielles.

Dementia represents a great challenge for health care providers. Detection of cognitive impairment is critical for early diagnosis of dementia. Early diagnosis allows to initiate individualized management that focuses on maintaining patient's autonomy and supporting their caregivers. Proposed multimodal interventions include physical activity, cognitive training, mediterranean diet, and management of cardiovascular risk factors. Before the initiation of pro-cognitive therapy, medication review is essential to evaluate current treament and determine specific therapeutic objectives, based on patient's overall health and preferences. Overall risk reduction for dementia revolves around similar measures that target physical activity, cognition, diet and management of cardiovascular risk factors.

[Geriatry]. / Gériatrie.

n 2015, several studies about hypertension and TAVI emphasize the importance of individualizing treatment goals in very old or vulnerable patients. The anti-pneumococcal conjugate vaccine has demonstrated its effectiveness in community-acquired pneumonia and the arsenal against shingles is extended by a subunit vaccine. A clinical trial confirms the ineffectiveness of testosterone supplementation in arteriosclerotic disease but not its safety. Regarding dementia, a rigorous study shows that a multimodal approach can reduce the risk of cognitive decline. The value of imaging technologies using Tau protein radiotracers is confirmed for monitoring the evolution of Alzheimer's disease and the latest studies about anti-amyloid vaccines finally demonstrate encouraging results.

[Review in geriatric medicine 2014]. / Gériatrie.

Several studies contributed to improving the diagnostic and prognostic assessment of delirium in hospitalized older patients. Direct patient education proved efficient in benzodiazepines withdrawal. A position statement of the American Geriatrics Society does not recommend tube feeding when eating difficulties arise in older persons suffering from advanced dementia. Several studies emphasized once again the potential importance of preventative interventions (in particular physical activity) to prevent or delay dementia occurrence. Two randomized controlled trials of monoclonal antibodies that bind amyloid did not show benefit in patients with mild-to-moderate Alzheimer's dementia (AD). In contrast, vitamin E reduced functional decline in these patients, and citalopram reduced agitation among AD patients as well as their caregiver's stress.

Frequency of barodontalgia among military or civilian pilots and aircrew members.

BACKGROUND: Barodontalgia is dental pain triggered by a change in barometric pressure and can be severe enough to cause in-flight incapacitation. There is a large variation of in-flight barodontalgia incidence in the literature and most of the current epidemiological data on barodontalgia has been compiled from military aircrew. The aim of this study was to evaluate the frequency of barodontalgia in French military and civilian aircrew. METHODS: A cross-sectional study was conducted in 2010. The pilots and crewmembers attending 10 medical units of the French Air Force and Navy, and 5 dedicated to civilian pilots and aircrew were given a standardized and anonymous questionnaire to complete regarding demographic and professional characteristics as well as their barodontalgia. RESULTS: Out of the 1475 questionnaires distributed, 1184 responded (response rate of 80.3%), and 6.6% of these participants (N = 74) reported at least one event of barodontalgia during their career (95% CI: 5.1-8.1%); 43 (6.8%) from the air force and 31 (6.5%) from a civilian service. Median pain intensity during barodontalgia was evaluated at 5.5 out of 10. Pain appeared most commonly during descent (47.3%) and was more frequent below 8000 m. In 10 cases (13.5%), the pilots reported that barodontalgia could have compromised flight security. DISCUSSION: Despite the improvement of aeronautical equipment and the quality of dental care, barodontalgias were still present in 2010 in the French military and in civilian aircrews. We recommend prevention programs be established in order to minimize the frequency of barodontalgias and their potential repercussions on flight safety.

Hyponatremia and aging-related diseases: key player or innocent bystander? A systematic review.

BACKGROUND: Hyponatremia is frequent in older age; whether it is a key player, a surrogate marker, or an innocent bystander in age-related diseases is still unclear. OBJECTIVE: To understand the role of hyponatremia in falls, osteoporosis, fractures, and cognitive impairment in old patients. METHOD: Eligibility criteria for study inclusions were: written in English, peer-reviewed observational and intervention studies, clinical trial, prospective and retrospective controlled cohort studies, and case-controlled studies without limitations regarding the date of publication. INFORMATION SOURCES: Protocol available on the International Prospective Register of Systematic Reviews (PROSPERO, CRD42021218389). MEDLINE, Embase, and PsycINFO were searched. Final search done on August 8, 2021. Risk-of-bias assessment: Risk-of-Bias Assessment tool for Non-randomized Studies (RoBANS) and the Bradford Hill's criteria for causality. RESULTS: Includes studies: One-hundred thirty-five articles retained for the revision. Synthesis of results - Falls: Eleven studies were included. Strong association between hyponatremia and falls in all the studies was found. Osteoporosis and fractures: nineteen articles were included. The association between hyponatremia and osteoporosis is unclear. Cognitive impairment: Five articles were included. No association between hyponatremia and cognitive impairment was found. DISCUSSION: Interpretation: Falls, osteoporosis, and fractures are multifactorial. Hyponatremia is not temporally related with the outcomes; we suggest that hyponatremia may be regarded as a marker of unhealthy aging and a confounder instead of a causal factor or an innocent bystander for falls and fractures. Concerning cognitive impairment, there are no evidence supporting a real role of hyponatremia to be regarded as an innocent bystander in neurodegeneration.

Phenotype and Reactivity of Lymphocytes Expanded from Benign Prostate Hyperplasic Tissues and Prostate Cancer.

Benign prostate hyperplasia (BPH) is a frequent condition in aging men, which affects life quality, causing principally lower urinary tract symptoms. Epidemiologic studies suggest that BPH may raise the risk of developing prostate cancer (PCa), most likely promoting a chronic inflammatory environment. Studies aiming at elucidating the link and risk factors that connect BPH and PCa are urgently needed to develop prevention strategies. The BPH microenvironment, similar to the PCa one, increases immune infiltration of the prostate, but, in contrast to PCa, immunosuppression may not be established yet. In this study, we found that prostate-infiltrating lymphocytes (PILs) expanded from hyperplastic prostate tissue recognized tumor-associated antigens (TAA) and autologous tissue, regardless of the presence of tumor cells. PILs expanded from BPH samples of patients with PCa, however, seem to respond more strongly to autologous tissue. Phenotypic characterization of the infiltrating PILs revealed a trend towards better expanding CD4+ T cells in infiltrates derived from PCa, but no significant differences were found. These findings suggest that T cell tolerance is compromised in BPH-affected prostates, likely due to qualitative or quantitative alterations of the antigenic landscape. Our data support the hypothesis that BPH increases the risk of PCa and may pave the way for new personalized preventive vaccine strategies for these patients.

Intravesical Ty21a treatment of non-muscle invasive bladder cancer induces immune responses that correlate with safety and may be associated to therapy potential.

BACKGROUND: Standard of care treatment of non-muscle invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette Guérin (BCG) is associated with side effects, disease recurrence/progression and supply shortages. We recently showed in a phase I trial (NCT03421236) that intravesical instillation in patients with NMIBC with the maximal tolerated dose of Ty21a/Vivotif, the oral vaccine against typhoid fever, might have a better safety profile. In the present report, we assessed the immunogenicity of intravesical Ty21a in patients of the clinical trial that had received the maximal tolerated dose and compared it with data obtained in patients that had received standard BCG. METHODS: Urinary cytokines and immune cells of patients with NMIBC treated with intravesical instillations of Ty21a (n=13, groups A and F in NCT03421236) or with standard BCG in a concomitant observational study (n=12, UROV1) were determined by Luminex and flow cytometry, respectively. Serum anti-lipopolysaccharide Typhi antibodies and circulating Ty21a-specific T-cell responses were also determined in the Ty21a patients. Multiple comparisons of different paired variables were performed with a mixed-effect analysis, followed by Sidak post-test. Single comparisons were performed with a paired or an unpaired Student's t-test. RESULTS: As compared with BCG, Ty21a induced lower levels of inflammatory urinary cytokines, which correlated to the milder adverse events (AEs) observed in Ty21a patients. However, both Ty21a and BCG induced a Th1 tumor environment. Peripheral Ty21a-specific T-cell responses and/or antibodies were observed in most Ty21a patients, pointing the bladder as an efficient local immune inductive site. Besides, Ty21a-mediated stimulation of unconventional Vδ2 T cells was also observed, which turned out more efficient than BCG. Finally, few Ty21a instillations were sufficient for increasing urinary infiltration of dendritic cells and T cells, which were previously associated with therapeutic efficacy in the orthotopic mouse model of NMIBC. CONCLUSIONS: Ty21a immunotherapy of patient with NMIBC is promising with fewer inflammatory cytokines and mild AE, but induction of immune responses with possible antitumor potentials. Future phase II clinical trials are necessary to explore possible efficacy of intravesical Ty21a.