Real-world study: Impact of multidisciplinary management of apalutamide-associated adverse events in prostate cancer.

OBJECTIVE: To analyse the adverse events (AEs) associated with apalutamide and the impact of a multidisciplinary team (MDT) protocol on its management at a tertiary care hospital in a real-world setting. METHODS: This was an observational, prospective, cohort study based on real-world evidence at the Hospital Clínic de Barcelona. Includes patients diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC) or high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) and who started treatment with apalutamide between May 2019 and March 2023 in a real-world clinical setting. RESULTS: Of the 121 patients treated with apalutamide, 52.1% experienced an AE, 19.8% experienced temporarily interruption or a reduction in the dose of apalutamide, and 13.2% discontinued treatment due to AEs. Without MDT protocol (49 patients), 24.5% of patients had to temporarily interrupt or reduce the dose of apalutamide due to AEs, with a median time from the start of treatment of 10.1 months, and 24.5% discontinued apalutamide due to AEs, with a median time from the start of treatment of 3.1 months. Meanwhile, whit MDT protocol (72 patients), 16.7% of patients had to temporarily interrupt or reduce the dose of apalutamide due to AEs, with a median time from the start of treatment of 1.6 months, and 5.6% discontinued apalutamide due to AEs, with a median time from the start of treatment of 4 months. The risk reduction associated with treatment discontinuation was statistically significant (p-value = 0.003). CONCLUSIONS: This study highlights the importance of MDT management of AEs associated with apalutamide to reduce treatment discontinuation.

Prognostic Value of Liquid-Biopsy-Based Biomarkers in Upper Tract Urothelial Carcinoma.

Currently, there are no reliable prognostic factors to determine which upper tract urothelial carcinoma (UTUC) patients will progress after radical nephroureterectomy (RNU). We aim to evaluate whether liquid-biopsy-based biomarkers (circulating tumor cells (CTCs), cell-free DNA (cfDNA), and circulating tumor DNA (ctDNA)) were able to predict clinical outcomes in localized UTUC patients undergoing RNU. Twenty patients were prospectively enrolled between 2021 and 2023. Two blood samples were collected before RNU and three months later. CTCs and cfDNA were isolated and evaluated using the IsoFlux system and Quant-iT PicoGreen dsDNA kit, respectively. Droplet digital PCR was performed to determine ctDNA status. Cox regression analysis was performed on CTCs, cfDNA, and ctDNA at two different follow-up time points to examine their influence on tumor progression and cancer-specific survival (CSS). During a median follow-up of 18 months, seven (35%) patients progressed and three (15%) died. Multivariate analysis demonstrated that cfDNA levels three months after RNU are a significant predictor of tumor progression (HR = 1.085; p = 0.006) and CSS (HR = 1.168; p = 0.029). No associations were found between CTC enumeration and ctDNA status with any of the clinical outcomes evaluated. The evaluation of cfDNA levels in clinical practice could improve the disease management of UTUC patients.

Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold.

TRP channels are important pharmacological targets in physiopathology. TRPV2 plays distinct roles in cardiac and neuromuscular function, immunity, and metabolism, and is associated with pathologies like muscular dystrophy and cancer. However, TRPV2 pharmacology is unspecific and scarce at best. Using in silico similarity-based chemoinformatics we obtained a set of 270 potential hits for TRPV2 categorized into families based on chemical nature and similarity. Docking the compounds on available rat TRPV2 structures allowed the clustering of drug families in specific ligand binding sites. Starting from a probenecid docking pose in the piperlongumine binding site and using a Gaussian accelerated molecular dynamics approach we have assigned a putative probenecid binding site. In parallel, we measured the EC50 of 7 probenecid derivatives on TRPV2 expressed in Pichia pastoris using a novel medium-throughput Ca2+ influx assay in yeast membranes together with an unbiased and unsupervised data analysis method. We found that 4-(piperidine-1-sulfonyl)-benzoic acid had a better EC50 than probenecid, which is one of the most specific TRPV2 agonists to date. Exploring the TRPV2-dependent anti-hypertensive potential in vivo, we found that 4-(piperidine-1-sulfonyl)-benzoic acid shows a sex-biased vasodilator effect producing larger vascular relaxations in female mice. Overall, this study expands the pharmacological toolbox for TRPV2, a widely expressed membrane protein and orphan drug target.

Lipidomic Analysis Reveals Alterations in Hepatic FA Profile Associated With MASLD Stage in Patients With Obesity.

CONTEXT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the intracellular lipid accumulation in hepatocytes. Excess caloric intake and high-fat diets are considered to significantly contribute to MASLD development. OBJECTIVE: To evaluate the hepatic and serum fatty acid (FA) composition in patients with different stages of MASLD, and their relationship with FA dietary intake and MASLD-related risk factors. METHODS: This was a case-control study in patients with obesity undergoing bariatric surgery at a university hospital between January 2020 and December 2021. Participants were distributed in 3 groups: no MASLD (n = 26), steatotic liver disease (n = 33), and metabolic dysfunction-associated steatohepatitis (n = 32). Hepatic and serum FA levels were determined by gas chromatography-mass spectrometry. Nutritional status was evaluated using validated food frequency questionnaires. The hepatic expression of genes involved in FA metabolism was analyzed by reverse transcription quantitative polymerase chain reaction. RESULTS: The hepatic, but not serum, FA profiles were significantly altered in patients with MASLD compared with those without MASLD. No differences were observed in FA intake between the groups. Levels of C16:0, C18:1, and the C18:1/C18:0 ratio were higher, while C18:0 levels and C18:0/C16:0 ratio were lower in patients with MASLD, being significantly different between the 3 groups. Hepatic FA levels and ratios correlated with histopathological diagnosis and other MASLD-related parameters. The expression of genes involved in the FA metabolism was upregulated in patients with MASLD. CONCLUSION: Alterations in hepatic FA levels in MASLD patients were due to enhancement of de novo lipogenesis in the liver.

Development and validation of equilibrium dialysis UHPLC-MS/MS measurement procedures for total and unbound concentrations of bictegravir, dolutegravir, darunavir and doravirine in human plasma. Application to patients with HIV.

BACKGROUND: Fixed-dose combinations of antiretroviral drugs are commonly used to treat HIV infection and therapeutic monitoring is not part of routine clinical practice. However, drug concentrations monitoring might have role in different clinical scenarios as well as for research purposes. This study aimed to develop and validate UHPLC-MS/MS procedures for measuring total and unbound concentrations of bictegravir, dolutegravir, darunavir and doravirine in human plasma. MATERIAL AND METHODS: Equilibrium dialysis preceded sample preparation (based on protein precipitation) for measuring unbound antiretroviral concentrations. Chromatographic separations were achieved on an Acquity®-UPLC® HSS™-T3 column (50 mm × 2.1 mm; 1.8 µm) using a non-linear water/acetonitrile gradient containing 0.1 % formic acid at a 0.5 mL/min flow rate. Antiretrovirals were detected by tandem mass spectrometry in positive electrospray ionisation and multiple reaction monitoring modes. RESULTS: No significant interferences or carry-over were observed. Imprecisions, absolute relative biases, normalised matrix effects and recoveries were ≤15.0 %, ≤11.1 %, (94.7-104.1)% and (96.7-105.5)%, respectively. Non-linear measuring intervals were observed between (25-10,000) µg/L for total/plasma dialysate concentrations and linearity schemes (1.00-100) µg/L for buffer dialysate concentrations. CONCLUSIONS: The UHPLC-MS/MS procedures developed could be used for research purposes and therapeutic drug monitoring of antiretrovirals in routine clinical practice.

Tumor-Agnostic Circulating Tumor DNA Testing for Monitoring Muscle-Invasive Bladder Cancer.

Circulating tumor DNA (ctDNA) has recently emerged as a real-time prognostic and predictive biomarker for monitoring cancer patients. Here, we aimed to ascertain whether tumor-agnostic ctDNA testing would be a feasible strategy to monitor disease progression and therapeutic response in muscle-invasive bladder cancer (MIBC) patients after radical cystectomy (RC). Forty-two MIBC patients who underwent RC were prospectively included. Blood samples from these patients were collected at different follow-up time points. Two specific mutations (TERT c.1-124C>T and ATM c.1236-2A>T) were analyzed in the patients' plasma samples by droplet digital PCR to determine their ctDNA status. During a median follow-up of 21 months, 24% of patients progressed in a median of six months. ctDNA status was identified as a prognostic biomarker of tumor progression before RC and 4 and 12 months later (HR 6.774, HR 3.673, and HR 30.865, respectively; p < 0.05). Lastly, dynamic changes in ctDNA status between baseline and four months later were significantly associated with patient outcomes (p = 0.045). In conclusion, longitudinal ctDNA analysis using a tumor-agnostic approach is a potential tool for monitoring MIBC patients after RC. The implementation of this testing in a clinical setting could improve disease management and patients' outcomes.

Clinical Outcomes of Enzalutamide in Metastatic Hormone-sensitive Prostate Cancer in Patients Aged <75 and ≥75 Years: ARCHES Post Hoc Analysis.

BACKGROUND: In ARCHES, treatment intensification of androgen deprivation therapy (ADT) with enzalutamide versus placebo improved clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC). Understanding the benefits and tolerability of enzalutamide for men aged ≥75 yr may inform disease management. OBJECTIVE: To determine whether age is associated with clinical outcomes in mHSPC. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of the multinational, double-blind, randomized, placebo-controlled, phase 3 ARCHES trial in 1150 men with mHSPC (median follow-up [mo]: <75 yr, 44.6; ≥75 yr, 44.3) was performed. INTERVENTION: Randomization 1:1 to enzalutamide (160 mg/d) plus ADT or placebo plus ADT; stratification by disease volume and prior docetaxel use. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS), radiographic progression-free survival (rPFS), safety, and other secondary endpoints were compared between age groups (<75 and ≥75 yr) and treatment arms (Cox proportional hazard models). RESULTS AND LIMITATIONS: Men aged <75 versus ≥75 yr had longer OS (enzalutamide plus ADT: hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.47-0.91; p = 0.02; placebo plus ADT: HR 0.81; 95% CI 0.60-1.09; p = 0.13) and rPFS (enzalutamide plus ADT: HR 0.78; 95% CI 0.58-1.04; p = 0.12; placebo plus ADT: HR 0.98; 95% CI 0.74-1.30; p = 0.007). Enzalutamide improved OS (<75 yr: HR 0.61; 95% CI 0.47-0.79; ≥75 yr: HR 0.76; 95% CI 0.54-1.09) and secondary efficacy endpoints without evidence of statistical heterogeneity, and was generally well tolerated in both age groups, with minimal quality-of-life impact. Older versus younger patients experienced more frequent dose interruptions (20.2% vs 10.9%) and treatment-emergent adverse events (95.2% vs 89.1%). Post hoc examination and small sample size preclude definitive conclusions. CONCLUSIONS: Enzalutamide plus ADT improved efficacy outcomes and was generally well tolerated despite shorter treatment exposure in older patients, indicating enzalutamide's utility in patients with mHSPC aged <75 and ≥75 yr. PATIENT SUMMARY: Enzalutamide is a drug approved to treat men with prostate cancer. In this report, we compared patients aged <75 and ≥75 yr treated with enzalutamide plus androgen deprivation therapy to determine whether age affected how long they lived without the cancer spreading to other parts of their body. We found that, although younger patients had more favorable survival outcomes, enzalutamide was associated with longer survival and reduced disease spread in both age groups.

Assessment of aggressive bladder cancer mutations in plasma cell-free DNA.

Background and aims: The spatial and temporal genetic heterogeneity of bladder cancer (BC) makes challenging to find specific drivers of metastatic disease, thus preventing to determine those BC patients at high risk of tumor progression. Our aim was to identify DNA mutations providing aggressive behavior to bladder tumors and analyze them in patients' cell-free DNA (cfDNA) during their follow-up after radical cystectomy (RC) in order to monitor tumor evolution. Methods: Six BC patients who underwent RC and presented disease progression during their follow-up were included. Next-generation sequencing was used to determine somatic mutations in several primary tumor and metastatic specimens from each patient. Shared DNA mutations between primary bladder tumor and metastatic sites were identified in cfDNA samples through droplet digital PCR. Results: Besides BC genetic heterogeneity, specific mutations in at least one of these genes -TERT, ATM, RB1, and FGFR3- were found in primary tumors and their metastases in all patients. These mutations were also identified in the patients' cfDNA at different follow-up time points. Additionally, the dynamic changes of these mutations in cfDNA allowed us to determine tumor evolution in response to treatment. Conclusion: The analysis of BC mutations associated with poor prognosis in plasma cfDNA could be a valuable tool to monitor tumor evolution, thus improving the clinical management of BC patients.

Análisis de Datos Antropométricos y Madurativos para la Selección de Talentos en Voleibol / Analysis of Anthropometric and Maturational Data for Talents Selection in Volleyball

El proceso madurativo tiene una gran influencia sobre los factores antropométricos y las capacidades físicas del atleta, y por tanto, sobre el proceso de selección de talentos deportivos. El objetivo de este trabajo fue analizar el estado madurativo y las características antropométricas junto con la comparación de estos datos por sexo en una muestra de 39 jugadores jóvenes de voleibol dentro de un proceso de selección de talentos (19 damas de 14,88±1,05 años y 13 varones de 15,1 años). Se obtuvieron datos de edad cronológica, altura, peso, altura sentado, altura de la madre y padre, la edad pico de crecimiento, el "timing" o periodo de tiempo por encima o por debajo de la edad pico, altura al final del proceso madurativo, el porcentaje actual de altura máxima, los centímetros restantes y el estado madurativo (pre-púber, púber o pos-púber). Los jugadores mostraron una mayor altura en el momento de las mediciones (179,92±6,87 vs 171,05±4,80; p<0,001), así como una mayor altura final calculada (189,46±3,73 vs 178,52±5,17; p<0,001), en comparación a las jugadoras. El pico en la velocidad de crecimiento también fue superior en los jugadores (14,56±0,44 vs 12,60±0,57; p<0,001), aunque su timing era inferior al de las jugadoras (0,531±1,19 vs 2,27±0,64; p<0,001). Esto se debió a un mayor porcentaje de jugadores masculinos en estados puberales, incluyendo un jugador en estadio pre-puberal, mientras que fue abundante la presencia de jugadoras en estado pospuberal. Estos datos reflejan la gran cantidad de jugadores que tienden a estar en periodos avanzados de maduración en procesos de selección de talentos. Por tanto, entrenadores y seleccionadores deben contemplar estas variables para evitar sesgos en el proceso de identificación del talento deportivo.

SUMMARY: The maturation process has a great influence on the anthropometric factors and physical capabilities of the athlete, and therefore, on the selection process of sporting talents. The objective of this work was to analyze the maturational state and anthropometric characteristics together with the comparison of these data by sex in a sample of 39 young volleyball players within a talent selection process (19 ladies of 14.88±1. 05 years old and 13 males aged 15.1 years). Data were obtained on chronological age, height, weight, sitting height, height of the mother and father, peak age of growth, timing or period of time above or below the peak age, height at the end of the process. maturation, the current percentage of maximum height, the remaining centimeters and the maturation status (pre-pubertal, pubertal or post-pubertal). The players showed a greater height at the time of the measurements (179.92±6.87 vs. 171.05±4.80; p<0.001), as well as a greater final calculated height (189.46±3.73 vs. 178.52±5.17; p<0.001), compared to the female players. The peak in growth speed was also higher in male players (14.56±0.44 vs 12.60±0.57; p<0.001), although their timing was lower than that of female players (0.531±1.19 vs 2.27±0.64; p<0.001). This was due to a higher percentage of male players in pubertal states, including one player in a pre-pubertal stage, while the presence of female players in a post-pubertal stage was abundant. These data reflect the large number of players who tend to be in advanced periods of maturation in talent selection processes. Therefore, coaches and selectors must consider these variables to avoid biases in the process of identifying sporting talent.

The Complex Proteolipidic Behavior of the SARS-CoV-2 Envelope Protein Channel: Weak Selectivity and Heterogeneous Oligomerization.

The envelope (E) protein is a small polypeptide that can form ion channels in coronaviruses. In SARS coronavirus 2 (SARS-CoV-2), the agent that caused the recent COVID-19 pandemic, and its predecessor SARS-CoV-1, E protein is found in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), where virion budding takes place. Several reports claim that E protein promotes the formation of "cation-selective channels". However, whether this term represents specificity to certain ions (e.g., potassium or calcium) or the partial or total exclusion of anions is debatable. Herein, we discuss this claim based on the available data for SARS-CoV-1 and -2 E and on new experiments performed using the untagged full-length E protein from SARS-CoV-2 in planar lipid membranes of different types, including those that closely mimic the ERGIC membrane composition. We provide evidence that the selectivity of the E-induced channels is very mild and depends strongly on lipid environment. Thus, despite past and recent claims, we found no indication that the E protein forms cation-selective channels that prevent anion transport, and even less that E protein forms bona fide specific calcium channels. In fact, the E channel maintains its multi-ionic non-specific neutral character even in concentrated solutions of Ca2+ ions. Also, in contrast to previous studies, we found no evidence that SARS-CoV-2 E channel activation requires a particular voltage, high calcium concentrations or low pH, in agreement with available data from SARS-CoV-1 E. In addition, sedimentation velocity experiments suggest that the E channel population is mostly pentameric, but very dynamic and probably heterogeneous, consistent with the broad distribution of conductance values typically found in electrophysiological experiments. The latter has been explained by the presence of proteolipidic channel structures.

Probing electrophysiological activity of amphiphilic Dynorphin A in planar neutral membranes reveals both ion channel-like activity and neuropeptide translocation.

Dynorphin A (DynA) is an endogenous neuropeptide that besides acting as a ligand of the κ-opioid receptor, presents some non-opioid pathophysiological properties associated to its ability to induce cell permeability similarly to cell-penetrating peptides (CPPs). Here, we use electrophysiology experiments to show that amphiphilic DynA generates aqueous pores in neutral membranes similar to those reported previously in charged membranes, but we also find other events thermodynamically incompatible with voltage-driven ion channel activity (i.e. non-zero currents with no applied voltage in symmetric salt conditions, reversal potentials that exceed the theoretical limit for a given salt concentration gradient). By comparison with current traces generated by other amphiphilic molecule known to spontaneously cross membranes, we hypothesize that DynA could directly translocate across neutral bilayers, a feature never observed in charged membranes following the same electrophysiological protocol. Our findings suggest that DynA interaction with the cellular membrane is modulated by the lipid charge distribution, enabling either passive ionic transport via membrane remodeling and pore formation or by peptide direct internalization independent of cellular transduction pathways.

Impact of robotic-assisted kidney transplantation on post-transplant infections: a case-control study.

BACKGROUND: The aim of this study was to determine the differences in the incidence, epidemiology, clinical characteristics and risk factors of infections in living donor kidney transplant recipients using robotic-assisted kidney transplantation (RAKT) and open approach. METHODS: We conducted a retrospective observational study from January 2016 to December 2019. For the risk factor analysis, a matched case-control study (1:1 ratio) was performed (robotic vs open). Control subjects were matched for living donor and time of transplantation. The data included de novo immunosuppressive regimen, delayed graft function, urological complications, acute allograft rejection and incidence, clinical features, microbiological findings and outcomes of infections. RESULTS: Ninety-four RAKT and 84 controls were included. There were no differences between groups in terms of age, gender, BMI, median days of hospitalization, immunosuppressive regimen, need for surgical urologic procedures post-transplantation, presence of urinary leak or acute allograft rejection. Thirty-five percent of all recipients analyzed presented an infection, mostly asymptomatic bacteriuria (49%), symptomatic urinary tract infection (31%) and surgical site infection (10%). Pseudomonas aeruginosa was the most frequent isolated microorganism in 67%, followed by E. coli (20%), Enterococcus faecalis (17%) and Klebsiella pneumoniae (10%). Eight percent of the microorganisms were multidrug resistant. The open kidney transplantation group presented more infections compared to RAKT (43 vs 27%, p = 0.04). After multivariate analysis, need for surgical urologic procedure post-transplantation (OR 6.2, 95% CI 1.1-35), BMI ≥ 30 (OR 3.6, 95% CI 1.5-9) and acute allograft rejection (OR 3.2, 95% CI 1.2-8.5) were associated with infection, whereas RAKT (OR 0.5, 95% CI 0.2-0.9) and the use of JJ catheter (OR 0.36, 95% CI 0.17-0.72) were protective factors. CONCLUSIONS: Infection is a frequent event in patients receiving a living donor kidney transplant. Acute allograft rejection, need for surgical urologic procedure post-transplantation and BMI were associated with infection, whereas robotic surgery was a protective factor in living donor kidney transplantation.

Living donor-gifted allograft lithiasis: surgical experience after bench surgery stone removal and follow-up.

This study presents the surgical experience and long-term outcomes of living donor kidney transplantations involving asymptomatic kidney stones, using ex vivo flexible ureterorenoscopy (f-URS) during bench surgery for stone removal. Out of 1743 living kidney donors assessed between January 2012 and October 2022, 18 (1%) were diagnosed with urolithiasis. Among them, 12 donors were rejected, and 6 were accepted for kidney donation. Stone removal was successfully performed using f-URS during bench surgery, with no immediate complications or acute rejections observed. The study analyzed six living kidney transplants, of which 4 (67%) donors and three recipients were female, and 4 (67%) donors were blood-related to the recipient. The median age for donors and recipients was 57.5 and 51.5 years, respectively. The stones, primarily located in the lower calyx, had a median size of 6 mm. The median cold ischemia time during surgery was 41.6 min, and ex vivo f-URS ensured complete stone removal in all cases. After a median follow-up of 120 months, the remaining grafts were functioning well, and no urinary stone recurrence was observed in either the recipients or living donors. The findings suggest that bench f-URS is a safe approach for managing urinary stones in kidney grafts, providing good functional outcomes without stone recurrence in selected cases.

The Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Oligometastatic Hormone-sensitive Prostate Cancer: A Post Hoc Analysis of ARCHES.

BACKGROUND: Few phase 3 studies have evaluated optimal systemic treatment strategies for patients with oligometastatic hormone-sensitive prostate cancer (HSPC), who may be at risk of undertreatment. OBJECTIVE: To evaluate outcomes for patients with oligometastatic and polymetastatic HSPC treated with enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of data for 927 patients with nonvisceral metastatic HSPC in the ARCHES trial (NCT02677896). INTERVENTION: Patients were randomized 1:1 to enzalutamide (160 mg/d orally) plus ADT or placebo plus ADT with HSPC categorized as oligometastatic (1-5 metastases) or polymetastatic (≥6 metastases). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The treatment effect on radiographic progression-free survival (rPFS), overall survival (OS), and secondary efficacy endpoints was evaluated in terms of the number of metastases. Safety was assessed. Cox proportional hazards models were used to generate hazard ratios (HRs). The Brookmeyer and Crowley method was used to generate 95% confidence intervals (CIs) for Kaplan-Meier median values. RESULTS AND LIMITATIONS: Enzalutamide plus ADT improved rPFS (HR 0.27, 95% CI 0.16-0.46; p < 0.001), OS (HR 0.59, 95% CI 0.40-0.87; p < 0.005), and secondary endpoints in patients with oligometastatic or polymetastatic disease (rPFS: HR 0.33, 95% CI 0.23-0.46; p < 0.001; OS: HR 0.55, 95% CI 0.41-0.74; p < 0.001). Safety profiles were generally similar across subgroups. Limitations include the small numbers of patients with fewer than three metastases. CONCLUSIONS: This post hoc analysis demonstrated the utility of enzalutamide, irrespective of metastatic burden or type of oligometastatic disease, and suggests that earlier treatment intensification with systemic potent androgen receptor inhibition is advantageous. PATIENT SUMMARY: This study considered two treatment options for metastatic hormone-sensitive prostate cancer in patients with one to five metastases or six or more metastases. Treatment with enzalutamide plus ADT improved survival and other outcomes over ADT alone, whether patients had few or many metastases.

A Systematic Review of Oncological Outcomes Associated with Bladder-sparing Strategies in Patients Achieving Complete Clinical Response to Initial Systemic Treatment for Localized Muscle-invasive Bladder Cancer.

CONTEXT: Bladder-sparing strategies (BSSs) have been proposed for the treatment of muscle-invasive bladder cancer (MIBC) patients achieving clinical complete response (cCR) to initial systemic treatment to avoid toxicity related to radical cystectomy. OBJECTIVE: To systematically review the current literature evaluating oncological outcomes of BSSs in patients achieving cCR to initial systemic treatment for localized MIBC. EVIDENCE ACQUISITION: A computerized bibliographic search of the Medline, Embase, and Cochrane databases was performed for all studies reporting oncological outcomes of MIBC patients undergoing either surveillance or radiation therapy after achieving cCR to initial systemic treatment. Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we identified 23 noncomparative prospective or retrospective studies published between 1990 and 2021. The mean bladder and metastatic recurrence rates (range) as well as the mean bladder preservation rate (BPR; range) were calculated, and overall survival (OS) was extracted from included reports. EVIDENCE SYNTHESIS: Overall, 16 and seven studies evaluated surveillance (n = 610) and radiation therapy (n = 175) in MIBC patients achieving cCR to initial systemic treatment, respectively. With regard to surveillance, the median follow-up ranged from 10 to 120 mo, with a mean bladder recurrence rate of 43% (0-71%), including 65% of non-muscle-invasive bladder cancer (NMIBC) and 35% of MIBC recurrences. The mean BPR was 73% (49-100%). The mean metastatic recurrence rate was 9% (0-27%), while 5-yr OS rates ranged from 64% to 89%. With regard to radiation therapy, the median follow-up ranged from 12 to 60 mo, with a mean bladder recurrence rate of 15% (0-29%), including 24% of NMIBC, 43% of MIBC, and 33% of unspecified recurrences. The mean BPR was 74% (71-100%). The mean metastatic recurrence rate was 17% (0-22%), while the 4-yr OS rate was 79%. CONCLUSIONS: Our systematic review showed that only low-level evidence supports the effectiveness of BSSs in selected patients achieving cCR to initial systemic treatment for localized MIBC. These preliminary findings highlight the need for further prospective comparative research to demonstrate its efficacy. PATIENT SUMMARY: We reviewed studies evaluating bladder-sparing strategies in patients achieving complete clinical response to initial systemic treatment for localized muscle-invasive bladder cancer. Based on low-level evidence, we observed that selected patients could benefit from surveillance or radiation therapy in this setting, but prospective comparative research is requested to confirm their efficacy.

Plasma short-chain fatty acid changes after bariatric surgery in patients with severe obesity.

BACKGROUND: Obesity has reached epidemic dimensions in recent decades. Bariatric surgery (BS) is one of the most effective interventions for weight loss and metabolic improvement in patients with obesity. Short-chain fatty acids (SCFA) are gut microbiota-derived metabolites with a key role in body weight control and insulin sensitivity. Although BS is known to induce significant changes in the gut microbiota composition, its impact on the circulating levels of certain metabolites produced by the gut microbiota such as SCFA remains poorly understood. OBJECTIVE: To determine the impact of BS on the circulating SCFA levels in patients with severe obesity. SETTING: University hospital. METHODS: An observational, prospective study was performed on 51 patients undergoing Roux-en-Y gastric bypass. Plasma samples were collected at baseline (1 day before surgery) and at 6 and 12 months after BS. Plasma SCFA levels were determined by liquid chromatography-mass spectrometry. RESULTS: The results revealed significant changes in the circulating levels of SCFA after BS. A marked increase in propionate, butyrate, isobutyrate, and isovalerate levels and a decrease in acetate, valerate, hexanoate, and heptanoate levels were observed 12 months after BS. Furthermore, the changes in the levels of propionate, butyrate, and isobutyrate negatively correlated with changes in body mass index, while those of isobutyrate correlated negatively with changes in the homeostatic model assessment for insulin resistance index. CONCLUSION: These results suggest that propionate, butyrate, and isobutyrate levels could be related to weight loss and improved insulin sensitivity in patients with severe obesity after BS.

Optimizing the Preparation of Silk Fibroin Nanoparticles and Their Loading with Polyphenols: Towards a More Efficient Anti-Inflammatory Effect on Macrophages.

Silk fibroin nanoparticles (SFN) have become a promising tool in drug delivery systems due to their physicochemical characteristics. SFN have shown their outstanding properties as an active vehicle for polyphenols, enhancing their antioxidant and anti-inflammatory effects on macrophages; therefore, it becomes necessary to have an easy, reproducible and scalable production method. In order to improve the production of nanoparticles, we performed direct precipitation of non-dialyzed silk fibroin solutions and evaluated the reproducibility of the method using dynamic light scattering. We also studied the loading efficiency of three different natural polyphenols using propylene glycol as a solvent. The loaded nanoparticles were fully characterized and used to treat human macrophage cells to assess the anti-inflammatory activity of these nanoparticles. The measured hydrodynamic characteristics of the SFN and the overall yield of the process showed that the new preparation method is highly reproducible and repeatable. Thus, we not only present a new scalable method to prepare silk nanoparticles but also how to improve the loading of natural polyphenolic compounds to the SFN, as well as the important anti-inflammatory effects of these loaded nanoparticles in a cell model of human macrophage cells.

Assessment of Predictive Genomic Biomarkers for Response to Cisplatin-based Neoadjuvant Chemotherapy in Bladder Cancer.

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer (MIBC). It has been shown that somatic deleterious mutations in ERCC2, gain-of-function mutations in ERBB2, and alterations in ATM, RB1, and FANCC are correlated with pathological response to NAC in MIBC. The objective of this study was to validate these genomic biomarkers in pretreatment transurethral resection material from an independent retrospective cohort of 165 patients with MIBC who subsequently underwent NAC and radical surgery. Patients with ypT0/Tis/Ta/T1N0 disease after surgery were defined as responders. Somatic deleterious mutations in ERCC2 were found in nine of 68 (13%) evaluable responders and two of 95 (2%) evaluable nonresponders (p = 0.009; FDR = 0.03). No correlation was observed between response and alterations in ERBB2 or in ATM, RB1, or FANCC alone or in combination. In an exploratory analysis, no additional genomic alterations discriminated between responders and nonresponders to NAC. No further associations were identified between the aforementioned biomarkers and pathological complete response (ypT0N0) after surgery. In conclusion, we observed a positive association between deleterious mutations in ERCC2 and pathological response to NAC, but not overall survival or recurrence-free survival. Other previously reported genomic biomarkers were not validated. PATIENT SUMMARY: It is currently unknown which patients will respond to chemotherapy before definitive surgery for bladder cancer. Previous studies described several gene mutations in bladder cancer that correlated with chemotherapy response. This study confirmed that patients with bladder cancer with a mutation in the ERCC2 gene often respond to chemotherapy.

Anti-inflammatory potential of digested Brassica sprout extracts in human macrophage-like HL-60 cells.

Cruciferous vegetables have been reported to be a great source of anti-inflammatory compounds. Specifically, sprouts from the Brassicaceae family stand out for their high content of glucosinolates (and their bioactive derivatives, isothiocyanates), phenolic acids, and anthocyanins. Despite the evident anti-inflammatory activity of certain Brassica phytochemicals such as sulforaphane or phenolic acids, the effect of digested Brassica vegetables on inflammation remains understudied. In this work, we aimed to evaluate the anti-inflammatory potential of the bioaccessible forms of cruciferous bioactives (from red cabbage sprouts (RCS) and red radish sprouts (RRS)) obtained upon in vitro gastrointestinal digestion in the HL-60 macrophage-like differentiated human cell line. The study was performed under basal conditions or stimulated with a low dose of LPS for 24 hours as a validated in vitro model of chronic inflammation. The cell viability was determined by MTT assay. The gene expression and production of pro-inflammatory cytokines TNF-α, IL-6 and IL-1ß were determined by RT-qPCR and ELISA respectively. Our results revealed no cytotoxicity with any of the treatments in LPS-stimulated macrophage-like HL60 cells. Regarding cytokine production, digestates significantly decreased the production of the three pro-inflammatory cytokines at concentrations of 50 and 100 µg mL-1 except for IL-1ß treated with RCS digestates. Furthermore, the RT-qPCR analysis showed a decrease in the relative expression of pro-inflammatory cytokines in LPS-stimulated cells treated with RRS digestates at 100 µg mL-1 but not with red cabbage digestates. In conclusion, RRS bioaccessible compounds in the extracts could be used as dietary coadjuvants given their potential anti-inflammatory effect on this in vitro model of chronic inflammation.