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A number of immunotherapies have been developed and adopted for the treatment of urothelial cancer (encompassing cancers arising from the bladder, urethra, or renal pelvis). For these immunotherapies to positively impact patient outcomes, optimal selection of agents and treatment scheduling, especially in conjunction with existing treatment paradigms, is paramount. Immunotherapies also warrant specific and unique considerations regarding patient management, emphasizing both the prompt identification and treatment of potential toxicities. In order to address these issues, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in the field of immunotherapy for urothelial cancer. The expert panel developed this clinical practice guideline (CPG) to inform healthcare professionals on important aspects of immunotherapeutic treatment for urothelial cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with urothelial cancer.

Immuno-oncology (IO) and targeted therapies, such as small molecule inhibitors, have changed the landscape of cancer treatment and prognosis; however, durable responses have been difficult to achieve due to tumor heterogeneity, development of drug resistance, and adverse effects that limit dosing and prolonged drug use. To improve upon the current medicinal armamentarium, there is an urgent need for new ways to understand, reverse, and treat carcinogenesis. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) 9 is a powerful and efficient tool for genome editing that has shown significant promise for developing new therapeutics. While CRISPR/Cas9 has been successfully used for pre-clinical cancer research, its use in the clinical setting is still in an early stage of development. The purpose of this review is to describe the CRISPR technology and to provide an overview of its current applications and future potential as cancer therapies.

Immune checkpoint inhibitors can produce distinct toxic effects that require prompt recognition and timely management. To develop a technology-enabled, dynamically adaptive protocol that can provide the accurate information needed to inform specific remedies for immune toxic effects in patients treated with immune checkpoint inhibitors. An open-label cohort study was conducted at a single tertiary referral center from September 6, 2019, to September 3, 2020. The median follow-up duration was 63 (interquartile range, 35.5-122) days. Fifty patients with genitourinary cancers treated with immune checkpoint inhibitors were enrolled. A fit-for-purpose electronic platform was developed to enable active patient and care team participation. A smartphone application downloaded onto patients' personal mobile devices prompted them to report their symptoms at least 3 times per week. The set of symptoms and associated queries were paired with alert thresholds for symptoms requiring clinical action. The primary end point of this interim analysis was feasibility, as measured by patient and care team adherence, and lack of increase in care team staffing. Operating characteristics were estimated for each symptom alert and used to dynamically adapt the alert thresholds to ensure sensitivity while reducing unnecessary alerts. Of the 50 patients enrolled, 47 had at least 1 follow-up visit and were included in the analysis. Median age was 65 years (range, 37-86), 39 patients (83%) were men, and 39 patients (83%) had metastatic cancer, with the most common being urothelial cell carcinoma and renal cell carcinoma (22 [47%] patients each). After initial onboarding, no further care team training or additional care team staffing was required. Patients had a median study adherence rate of 74% (interquartile range, 60%-86%) and 73% of automated alerts were reviewed within 3 days by the clinic team. Symptoms with the highest positive predictive value for adverse events requiring acute intervention included dizziness (21%), nausea/vomiting (26%), and shortness of breath (14%). The symptoms most likely to result in unnecessary alerts were arthralgia and myalgia, fatigue, and cough. The findings of this cohort study suggest an acceptable and fiscally sound method can be developed to create a dynamic learning system to detect and manage immune-related toxic effects.

Rosa canina L. powders are rich in bioactive compounds; however, thermal processing and carrier addition can markedly alter their composition, affecting nutritional quality, safety and potential health effects. This study assessed the impact of juice pasteurization, followed by freeze-drying and spray drying with maltodextrin, inulin, trehalose, or palatinose, on amino acids, sugars, phenolic compounds, and Maillard reaction products. In carrier-added samples, total amino acid content ranged from 364.6 to 430.4 mg/100 g dry matter (DM). Tryptophan and γ-aminobutyric acid (GABA) were proposed as indicator compounds, with their distinct stability patterns under pasteurization and drying providing a reliable measure of processing effects while representing both essential (tryptophan) and non-essential (GABA) amino acids of nutritional relevance. Carriers reduced total sugar content ≈ 2.5-fold (from 16.7 to 6.7 g/100 g powder DM) but modified sugar profiles. Powders obtained from pasteurized juice with inulin showed the highest level of free amino groups (0.49 g N-α-acetyl-L-lysine/100 g powder DM), the lowest fructosamine content (44.8 mmol DMF/100 g powder DM), and total phenolics of 10.4 g GAE/100 g powder DM. Fructosamine, an early Maillard reaction marker, proved valuable for predicting powder quality, with lower levels linked to pasteurization and carriers with low glycation potential. Acrylamide was absent in all samples (LC–MS/MS), confirming chemical safety. Processing parameters and carrier type were key determinants of nutritional composition and safety, with inulin-based powders from pasteurized juice offering a balanced profile of free amino acids and phenolics, while minimizing fructosamine formation. The combined use of amino acid profiling, phenolic quantification, and early Maillard reaction markers provides a powerful approach for quality evaluation of fruit-based powders within glycoscience.

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence. Chaib et al. find that therapy-induced senescent cells have high programmed cell death 1 ligand 2 (PD-L2), contributing to recurrence. They show that PD-L2 blocking combined with chemotherapy is therapeutically beneficial because it reduces senescent cells and immunosuppressive cell recruitment.

BackgroundPseudomyxoma peritonei (PMP) is a rare malignancy, classified according to the Peritoneal Surface Oncology Group International (PSOGI) classification, whose response to treatment remains highly heterogeneous within the high-grade (HG) category. Molecular profiling of PMP cases might help to better categorize patients and predict treatment responses.MethodsWe studied the Ki-67 proliferation rate and P53 overexpression in tissue samples from our historical cohort of HG-PMP patients. We established as cut-off levels the third quartile of each marker to perform univariate and multivariate Cox regression survival analyses. According to these results, the HG-PMP category was divided into subcategories and a new survival analysis was performed.ResultsA total of 90/117 patients with PMP undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) were selected for secondary analysis. The survival analysis of the HG-PMP category for preoperative variables showed that a proliferation index defined by Ki-67 >15% is a bad prognostic factor, with a hazard ratio (HR) of 3.20 (95% confidence interval [CI] 1.24–8.25). Accordingly, the HG-PMP group was divided using the Ki-67 15% cut-off. The new PSOGI/Ki-67 variable was an independent prognostic factor for overall survival (OS), with an HR of 3.74 (95% CI 1.88–7.47), and disease-free survival (DFS), with an HR of 4.184 (95% CI 1.79–9.75). The estimated 5-year OS rate was 100%, 70% and 24% for the LG-PMP, HG-PMP ≤15% and HG-PMP >15% groups, respectively (p = 0.0001), while the 5-year DFS rate was 90%, 44% and 0%, respectively (p = 0.0001).ConclusionDivision of the HG-PMP category of the PSOGI classification, according to the Ki-67 proliferation index, provides two well-defined subcategories, with significant differences in terms of OS and DFS, and hence high prognostic value.

Purpose Cardiovascular disease remains the global leading cause of death. We evaluated at baseline the association between the adherence to eight a priori high-quality dietary scores and the prevalence of individual and clustered cardiovascular risk factors (CVRF) in the PREDIMED-Plus cohort. Methods All PREDIMED-Plus participants (6874 men and women aged 55–75 years, with overweight/obesity and metabolic syndrome) were assessed. The prevalence of 4 CVRF (hypertension, obesity, diabetes, and dyslipidaemia), using standard diagnoses criteria, were considered as outcomes. The adherence to eight a priori-defined dietary indexes was calculated. Multivariable models were fitted to estimate differences in mean values of factors and prevalence ratios for individual and clustered CVRF. Results Highest conformity to any dietary pattern did not show inverse associations with hypertension. The modified Mediterranean Diet Score (PR = 0.95; 95% CI 0.90–0.99), Mediterranean Diet Adherence Score (MEDAS) (PR = 0.94; 95% CI 0.89–0.98), the pro-vegetarian dietary pattern (PR = 0.95; 95% CI 0.90–0.99) and the Alternate Healthy Eating Index 2010 (PR = 0.92; 95% CI 0.87–0.96) were inversely associated with prevalence of obesity. We identified significant inverse trend among participants who better adhered to the MEDAS and the Prime Diet Quality Score (PDQS) in the mean number of CVRF across categories of adherence. Better adherence to several high-quality dietary indexes was associated with better blood lipid profiles and anthropometric measures. Conclusions Highest adherence to dietary quality indexes, especially Mediterranean-style and PDQS scores, showed marginal associations with lower prevalence of individual and clustered CVRF among elderly adults with metabolic syndrome at high risk of cardiovascular disease

This randomized controlled trial compared the effectiveness of high-intensity off- and on-bike resistance training (RT) in well-trained cyclists. Thirty-seven cyclists incorporated into their cycling routine a 10-week RT only differing in the exercise used: full squat (off-bike RT, n = 12) or high-intensity all-out pedaling efforts (on-bike RT, n = 12). RT variables like intensity (% maximal dynamic force, MDF), volume, sets, and rest were identical between groups. A third group of cyclists who continued their cycling routine but did not include additional RT stimuli was used as a control (n = 13). The cycling volume at each intensity zone was also matched between the three groups. No significant differences were found between off- and on-bike RT in any parameter. RT groups improved the maximal aerobic power (ES ≥ 0.37) and that attained at the respiratory compensation point (RCP, ES ≥ 0.20). The on-bike RT also significantly enhanced power attained at the ventilatory threshold (ES = 0.24). Off-bike MDF was meaningfully enhanced by both RT groups (ES ≥ 0.16), whereas the on-bike group also significantly increased pedaling MDF (ES = 0.67). Quadriceps size was significantly increased by the off-bike group (ES = 0.22), whereas the on-bike RT also tended to augment this parameter (ES = 0.15) and patellar tendon size (ES = 0.35). Improvements in both RT regimes for time-to-exhaustion capacity (ES ≥ 0.30) were considerable but not significant. The off-bike group tended to increase injury-related symptoms (ES ≥ 0.33). The control group significantly decreased off-and on-bike MDF (ES ≤ -0.40) and quadriceps size (ES = -0.26). These findings suggest that high-intensity on-bike RT is an effective alternative to off-bike RT to safely increase strength, muscle-tendon structure, and cycling performance.

Background Following acute and sub-acute rehabilitation from severe traumatic brain injury (TBI), minimal to no efficacious interventions to treat ongoing cognitive deficits are available. Aerobic exercise is a non-invasive behavioral intervention with promise to treat cognitive deficits in TBI populations. Methods Six individuals, aged 24–62 years, with chronic (> 8 months since injury) severe (Glasgow Coma Scale of 3–8) TBI were recruited from two outpatient rehabilitation centers. In an A-B-A study design, 20-weeks of supervised aerobic exercise interventions were delivered three times per week (phase B) in addition to participants typical rehabilitation schedules (phases A). The effect of phase B was tested on a trail making test part B (primary outcome measure of executive function) as well as objective daily physical activity (PA), using both group level (linear mixed effect models) and single subject statistics. Results Five of six participants increased trail-making test part B by more than 10% pre-to-post phase B, with three of six making a clinically meaningful improvement (+ 1SD in normative scores). A significant main effect of time was seen with significant improvement in trail-making test part B pre-to-post exercise (phase B). No significant effects in other planned comparisons were found. Statistically significant increases in daily moderate-to-vigorous PA were also seen during phase B compared to phase A with three of six individuals making a significant behaviour change. Conclusions The addition of supervised aerobic exercise to typical rehabilitation strategies in chronic survivors of severe TBI can improve executive set shifting abilities and increase voluntary daily PA levels. Trial registration Retrospective trial registration on July 11 2024 with trial number: ISRCTN17487462.

Physical activity (PA) has been hypothesized to be effective to maintaining cognitive function and delay cognitive decline in the elderly, but physical fitness (PF) could be a better predictor of cognitive function. We aimed to study the association between PA and PF with cognitive function and quality of life using cross-sectional data from 6874 participants of the PREDIMED-Plus trial (64.9 ± 4.9 years, 48.5% female). PF and PA were measured with a Chair Stand Test, the REGICOR and Rapid Assessment Physical Activity questionnaires. Cognitive function was measured with Mini-mental State Examination, Control Oral Word Association Test, Trail Making Test and Digit Span tests; whereas health-related quality of life was assessed with the SF36-HRQL test. Cognitive and quality of life scores were compared among PF quartiles and PA levels (low, moderate and high) with ANCOVA and with Chair Stand repetitions and energy expenditure from total PA with multivariable linear regression adjusted for confounding factors. PF associated with higher scores in phonemic and semantic verbal fluency tests and with lower TMT A time. However, PA was not associated with the neurocognitive parameters evaluated. Both PF and PA levels were strongly associated with a better quality of life. We concluded that PF, but not PA, is associated with a better cognitive function. This trial was retrospectively registered at the International Standard Randomized Controlled Trial (ISRCTN89898870, https://www.isrctn.com/ISRCTN89898870?q=ISRCTN89898870&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-search ) on 07/24/2014.