Novel Delivery Systems and Pharmacotherapeutic Approaches for the Treatment of Non-muscle-invasive Bladder Cancer.

BACKGROUND AND OBJECTIVE: Therapeutic options for patients with non-muscle-invasive bladder cancer (NMIBC) have traditionally been limited to intravesical immunotherapy or chemotherapy. A considerable number of new options have been investigated in recent years. Our aim was to review the efficacy and toxicity of novel therapeutic options (results already reported or currently under investigation) for patients with NMIBC. METHODS: We assessed the efficacy of various novel therapeutic options by examining key endpoints in diverse settings, including recurrence, progression, overall survival, disease-specific survival, and complete response. We identified the principal advantages and limitations for each option. Safety was predominantly evaluated as the incidence of grade ≥3 adverse events. Our investigation focused on evidence from scientific articles and congress abstracts published in English within the past 5 yr. KEY FINDINGS AND LIMITATIONS: To date, pembrolizumab, nadofaragene firadenovec, and the combination of BCG with N-803 have received US Food and Drug administration approval for the treatment of BCG-unresponsive carcinoma in situ of the bladder (with or without papillary tumours). Five phase 3 trials are recruiting BCG-naïve patients with high-risk NMIBC. There is increasing interest in an ablative rather than an adjuvant approach for patients with intermediate-risk NMIBC. CONCLUSIONS AND CLINICAL IMPLICATIONS: Novel drugs and device-assisted drug delivery systems are on the verge of changing the treatment of NMIBC. Novel intravesical options seem to have the same efficacy with fewer adverse events in comparison to systemic therapies. PATIENT SUMMARY: We reviewed new therapy options for non-muscle-invasive bladder cancer. Two agents (pembrolizumab and nadofaragene firadenovec) have been approved to date. Ongoing trials are assessing direct delivery of drugs in solution into the bladder. This route seems to have similar efficacy and fewer side effects than intravenous immunotherapy.

Voided urine cytology is a useful tool predicting non-muscle-invasive bladder cancer risk before surgery.

OBJECTIVE: To determine the accuracy of voided urinary cytology (VUC) in predicting of non-muscle-invasive bladder cancer (NMIBC) risk stratification before surgery. METHODS: We prospectively collected data from all patients diagnosed with bladder cancer in our institution over 2 years. We have analyzed VUC accuracy of positive and suspicious VUC in the detection of high-risk tumors and negative and atypical VUC in the detection of low-risk tumors. To test this accuracy, we assessed sensitivity, specificity, positive (PPV) and negative predictive values (NPV), diagnostic odds ratio (DOR), and generated ROC curves (receiver operating characteristic curve). RESULTS: With 224 patients included, the positive VUC subcategory showed a specificity of 92.4% (95%CI: 83.2%-97.5%) and a PPV of 91.4 (95%CI: 81%-97.1%). DOR in this subgroup was 6.81. In the suspicious VUC, specificity was 90.9% (95%CI: 81.3%-96.6%), PPV was 88% (95%CI: 75.7%-95.5%) and DOR was 4.23. Combined analysis of positive and suspicious cytologies for detecting high-risk NMIBC showed a sensitivity of 65% (95%CI: 57.3%-73.2%) and a DOR of 9.51. Negative VUC showed high specificity in detecting low-risk (93.2% [95%CI: 87.9%-96.7%]) and a DOR of 6.90 (95%CI: 3.07-15.46). Atypical VUC was the least accurate and had rather low specificity and predictive values. CONCLUSIONS: VUC appears to be a good, inexpensive and easily available method to determine risk stratification before surgery. This can be useful in daily practice to determine which patients should receive a single instillation of MMC and to prioritize patients more likely to have a high- risk tumor.

Unlocking the Potential of Adequate Bacillus Calmette-Guérin Immunotherapy in Very-high-risk Non-muscle-invasive Bladder Carcinoma: A Multicenter Analysis of Oncological Outcomes and Risk Dynamics.

BACKGROUND: The European Association of Urology (EAU) recommends discussing upfront radical cystectomy for all patients with very high risk (VHR) non-muscle-invasive bladder carcinoma (NMIBC), but the role of bacillus Calmette-Guérin (BCG) treatment remains controversial. OBJECTIVE: To analyze oncological outcomes in VHR NMIBC patients (EAU risk groups) treated with adequate BCG. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional retrospective study involving patients with VHR NMIBC who received adequate BCG therapy from 2007 to 2020 was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A survival analysis estimated recurrence-free survival (RFS), progression-free survival (PFS), and the cumulative incidence of cancer-specific mortality (CSM) after accounting for other causes of mortality as competing risk events and of the overall mortality (OM). Conditional survival probabilities for 0-4 yr without events were computed. Cox regression assessed the predictors of oncological outcomes. RESULTS AND LIMITATION: A total of 640 patients, with a median 47 (32-67) mo follow-up for event-free individuals, were analyzed. High-grade RFS and PFS at 5 yr were 53% (49-57%) and 78% (74-82%), respectively. The cumulative incidence of CSM and OM at 5 yr was 13% (10-16%) and 16% (13-19%), respectively. Conditional RFS, PFS, overall survival, and cancer-specific survival at 4 yr were 91%, 96%, 87%, and 94%, respectively. Cox regression identified tumor grade (hazard ratio [HR]: 1.54; 1.1-2) and size (HR: 1.3; 1.1-1.7) as RFS predictors. Tumor multiplicity predicted RFS (HR: 1.6; 1.3-2), PFS (HR: 2; 1.2-3.3), and CSM (HR: 2; 1.2-3.2), while age predicted OM (HR: 1.48; 1.1-2). CONCLUSIONS: Patients with VHR NMIBC who receive adequate BCG therapy have a more favorable prognosis than predicted by EAU risk groups, especially among those with a sustained response, in whom continuing maintenance therapy emerges as a viable alternative to radical cystectomy. PATIENT SUMMARY: Our research shows that a sustained response to bacillus Calmette-Guérin in patients can lead to favorable outcomes, serving as a viable alternative to cystectomy for select cases.

Immune Predictors of Response after Bacillus Calmette-Guérin Treatment in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) has been the standard of care for the treatment of high-risk, non-muscle-invasive bladder cancer (NMIBC) for decades, but 49.6% of high-risk and very-high-risk patients will experience progression to muscle-invasive disease in five years. Furthermore, cytology and cystoscopy entail a high burden for both patients and health care systems due to the need for very long periods of follow-up. Subsequent adjuvant treatment using intravesical immunotherapy with BCG has been shown to be effective in reducing tumor recurrence and progression, but it is not free of severe adverse effects that ultimately diminish patients' quality of life. Because not all patients benefit from BCG treatment, it is of paramount importance to be able to identify responders and non-responders to BCG as soon as possible in order to offer the best available treatment and prevent unnecessary adverse events. The tumor microenvironment (TME), local immune response, and systemic immune response (both adaptive and innate) seem to play an important role in defining responders, although the way they interact remains unclear. A shift towards a proinflammatory immune response in TME is thought to be related to BCG effectiveness. The aim of this review is to collect the most relevant data available regarding BCG's mechanism of action, its role in modulating innate and adaptive immune responses and the secretion of certain cytokines, and their potential use as immunological markers of response; the aim is also to identify promising lines of investigation.

Optimizing outcomes for high-risk, non-muscle-invasive bladder cancer: The evolving role of PD-(L)1 inhibition.

Transurethral resection of bladder tumor followed by intravesical Bacillus Calmette-Guérin (BCG) is the standard of care in high-risk, non-muscle-invasive bladder cancer (NMIBC). Although many patients respond, recurrence and progression are common. In addition, patients may be unable to receive induction + maintenance due to intolerance or supply issues. Therefore, alternative treatment options are urgently required. Programmed cell death (ligand) 1 (PD-[L]1) inhibitors show clinical benefit in phase 1/2 trials in BCG-unresponsive NMIBC patients. This review presents the status of PD-(L)1 inhibition in high-risk NMIBC and discusses future directions. PubMed and Google scholar were searched for articles relating to NMIBC immunotherapy and ClinicalTrials.gov for planned and ongoing clinical trials. Preclinical and early clinical studies show that BCG upregulates PD-L1 expression in bladder cancer cells and, when combined with a PD-(L)1 inhibitor, a potent antitumor response is activated. Based on this mechanism, several PD-(L)1 inhibitors are in phase 3 trials in BCG-naïve, high-risk NMIBC in combination with BCG. Whereas PD-(L)1 inhibitors are well characterized in patients with advanced malignancies, the impact of immune-related adverse events (irAE) on the benefit/risk ratio in NMIBC should be determined. Alternative routes to intravenous administration, like subcutaneous and intravesical administration, may facilitate adherence and access. The outcomes of combination of PD-(L)1 inhibitors and BCG in NMIBC are highly anticipated. There will be a need to address treatment resources, optimal management of irAEs and education and training related to use of this therapy in clinical practice.

Organ-Sparing Surgery for Testicular Germ Cell Tumors: A Current Perspective.

Background and Objectives: We aimed to evaluate the oncological and functional outcomes of organ-sparing surgery for testicular germ cell tumors, a procedure that seeks to strike a balance between effective cancer control and organ preservation, in the treatment of testicular tumors. We aimed to discuss the surgical technique and complications, and determine the appropriate candidate selection for this approach. Material and Methods: A comprehensive literature search was conducted to identify relevant studies on organ-sparing surgery for testicular tumors. Various databases, including PubMed, Embase, and Cochrane Library, were used. Studies reporting on surgical techniques, complications, and oncologic and functional outcomes were included for analysis. Results: Current evidence suggests that organ-sparing surgery for testicular germ cell tumors can be considered a safe and efficacious alternative to radical orchiectomy. The procedure is associated with adequate oncological control, as indicated by low recurrence rates and low complication rates. Endocrine testicular function can be preserved in around 80-90% of patients and paternity can be achieved in approximately half of the patients. Candidate selection for this surgery is typically based on the following criteria: pre-surgery normal levels of testosterone and luteinizing hormone, synchronous or metachronous bilateral tumors, tumor in a solitary testis, and tumor size less than 50% of the testis. Conclusions: Organ-sparing surgery for testicular germ cell tumors offers a promising approach that balances oncological control and preservation of testicular function. Further research, including large-scale prospective studies and long-term follow-ups, is warranted to validate the effectiveness and durability of organ-sparing surgery and to identify optimal patient selection criteria.

Extrauterine Retroperitoneal Leiomyomas: 3 Case Reports and Review of the Literature.

Leiomyomas are benign mesenchymal tumors which originate from smooth muscle cells. Extrauterine leiomyomas are rare and they may arise where smooth muscle cells are found. Their diagnosis is challenging due to their heterogeneous ways of presentation. Histological analysis may reveal areas of sarcomatous differentiation; therefore, complete resection of the entire tumor is the only curative treatment. There is no adjuvant therapy proved to increase overall survival. It is essential to develop a standardized protocol, detailing how to follow up these patients since it is not reported in the literature to date; however, it is advisable to follow them because the local recurrence rate is high if small implants remain. In this review, we present 3 cases of extrauterine leiomyomas diagnosed and treated in our hospital. The management was different in each case, highlighting the heterogeneity of this condition. According to the literature, there are no solid guidelines on their management. We compare our experience with the data available to date in order to support the existing knowledge and provide our expertise for future studies.

Safety, Tolerability, and Preliminary Efficacy of TAR-200 in Patients With Muscle-invasive Bladder Cancer Who Refused or Were Unfit for Curative-intent Therapy: A Phase 1 Study.

PURPOSE: Half of patients with muscle-invasive bladder cancer worldwide may not receive curative-intent therapy. Elderly or frail patients are most affected by this unmet need. TAR-200 is a novel, intravesical drug delivery system that provides sustained, local release of gemcitabine into the bladder over a 21-day dosing cycle. The phase 1 TAR-200-103 study evaluated the safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who either refused or were unfit for curative-intent therapy. MATERIALS AND METHODS: Eligible patients had cT2-cT3bN0M0 urothelial carcinoma of the bladder. TAR-200 was inserted for 4 consecutive 21-day cycles over 84 days. The primary end points were safety and tolerability at 84 days. Secondary end points included rates of clinical complete response and partial response as determined by cystoscopy, biopsy, and imaging; duration of response; and overall survival. RESULTS: Median age of the 35 enrolled patients was 84 years, and most were male (24/35, 68.6%). Treatment-emergent adverse events related to TAR-200 occurred in 15 patients. Two patients experienced treatment-emergent adverse events leading to removal of TAR-200. At 3 months, complete response and partial response rates were 31.4% (11/35) and 8.6% (3/35), respectively, yielding an overall response rate of 40.0% (14/35; 95% CI 23.9-57.9). Median overall survival and duration of response were 27.3 months (95% CI 10.1-not estimable) and 14 months (95% CI 10.6-22.7), respectively. Progression-free rate at 12 months was 70.5%. CONCLUSIONS: TAR-200 was generally safe, well tolerated, and had beneficial preliminary efficacy in this elderly and frail cohort with limited treatment options.

Epidemiology, Diagnosis and Management of Penile Cancer: Results from the Spanish National Registry of Penile Cancer.

INTRODUCTION: Penile cancer (PC) is a rare malignancy with an overall incidence in Europe of 1/100,000 males/year. In Europe, few studies report the epidemiology, risk factors, clinical presentation, and treatment of PC. The aim of this study is to present an updated outlook on the aforementioned factors of PC in Spain. MATERIALS AND METHODS: A multicentric, retrospective, observational epidemiological study was designed, and patients with a new diagnosis of PC in 2015 were included. Patients were anonymously identified from the Register of Specialized Care Activity of the Ministry of Health of Spain. All Spanish hospitals recruiting patients in 2015 were invited to participate in the present study. We have followed a descriptive narration of the observed data. Continuous and categorical data were reported by median (p25th-p75th range) and absolute and relative frequencies, respectively. The incidence map shows differences between Spanish regions. RESULTS: The incidence of PC in Spain in 2015 was 2.55/100,000 males per year. A total of 586 patients were identified, and 228 patients from 61 hospitals were included in the analysis. A total of 54/61 (88.5%) centers reported ≤ 5 new cases. The patients accessed the urologist for visually-assessed penile lesions (60.5%), mainly localized in the glans (63.6%). Local hygiene, smoking habits, sexual habits, HPV exposure, and history of penile lesions were reported in 48.2%, 59.6%, 25%, 13.2%, and 69.7%. HPV-positive lesions were 18.1% (28.6% HPV-16). The majority of PC was squamous carcinoma (95.2%). PC was ≥cT2 in 45.2% (103/228) cases. At final pathology, PC was ≥pT2 in 51% of patients and ≥pN1 in 17% of cases. The most common local treatment was partial penectomy (46.9% cases). A total of 47/55 (85.5%) inguinal lymphadenectomies were open. Patients with ≥pN1 disease were treated with chemotherapy in 12/39 (40.8%) of cases. CONCLUSIONS: PC incidence is relatively high in Spain compared to other European countries. The risk factors for PC are usually misreported. The diagnosis and management of PC are suboptimal, encouraging the identification of referral centers for PC management.

Metastatic testicular cancer presenting with hematuria and flank pain.

Testicular cancer (TC) represents 1% of male neoplasms and 5% of urological tumors. Most of seminoma patients and about 55% of patients with nonseminoma TC have stage I disease at diagnosis. TC usually presents with a palpable testicular mass incidentally found by the patient himself or its partner by palpation. It shows excellent cure rates based on their chemosensitivity, especially to cisplatin-based chemotherapy, but careful staging at diagnosis, adequate early treatment based on a multidisciplinary approach and strict follow-up are necessary. We present a case of a 25-year-old male patient who was diagnosed of metastatic TC with an atypical presentation: hematuria, hydronephrosis, and direct infiltration of the ureter by the retroperitoneal mass, mimicking a renal colic. After orchiectomy and placement of a double-J stent, the evolution was favorable, with a good response after the first cycle of chemotherapy with quick resolution of hematuria. After the treatment, a retroperitoneal lymph node dissection was performed. The patient remains disease-free after 3 years of follow-up.

Estrategia pedagógica para la corrección del retraso del lenguaje en niños preescolares

RESUMEN Fundamento El retraso del lenguaje es un trastorno que repercute negativamente en el desarrollo del niño, por lo que su corrección desde edades tempranas constituye un imperativo, para garantizar un desarrollo integral. Para su atención logopédica es importante la integralidad de las acciones que se desarrollan, las cuales deben involucrar también a las familias. Objetivo exponer los resultados de una estrategia pedagógica para la corrección del retraso del lenguaje en niños preescolares. Métodos estudio de intervención, con diseño de antes y después, que involucró a cuatro niños y sus familias, así como a logopedas de la Escuela especial para niños con trastornos del lenguaje y la comunicación, Pepín Salvat Ladrón de Guevara, del municipio Santiago de Cuba. Además de la observación, se emplearon entrevistas, técnicas de exploración logopédica y las pruebas de diagnóstico del lenguaje: Inventario de Primeras Palabras, Peabody Picture Vocabulary Test y la Prueba de evaluación del lenguaje espontáneo. Resultados se evidenciaron avances en el desarrollo del lenguaje de los niños, tanto desde el punto de vista cualitativo como cuantitativo. Asimismo, se apreció una mayor comprensión y compromiso de las familias en el cumplimiento de las orientaciones recibidas para la atención logopédica a sus niños. Conclusión la estrategia diseñada para la atención integral al desarrollo del lenguaje de los niños preescolares resultó efectiva. Su enfoque integral, con la participación de las familias y los especialistas, garantizó el éxito de las acciones diseñadas.

ABSTRACT Background Language disability is a disorder that has a negative impact on child development, so its correction from an early age is imperative to ensure comprehensive development. For the logopedic care, the integrality of the actions that are developed is important, which must also involve the families. Objective to expose the results of a pedagogical strategy for the correction of language disability in preschool children. Methods intervention study, with a before and after design, which involved four children and their families, as well as speech therapists from the Pepín Salvat Ladrón de Guevara Special School for Children with Language and Communication Disorders, in the Santiago de Cuba municipality. In addition to observation, interviews, speech therapy exploration techniques and language diagnostic tests were used: First Word Inventory, Peabody Picture Vocabulary Test and the Spontaneous Language Assessment Test. Results advances in children's language development were evidenced, both from a qualitative and quantitative point of view. Likewise, a greater understanding and commitment of the families in complying with the guidelines received for the speech therapy care of their children was appreciated. Conclusion the strategy designed for comprehensive attention to the language development of preschool children was effective. Its comprehensive approach, with the participation of families and specialists, guaranteed the success of the designed actions.

Mitomycin C allergy after passive and device-assisted hyperthermia for non-muscle invasive bladder cancer treatment: A retrospective cohort from a high-volume center.

INTRODUCTION: Mitomycin C (MMC) is one of the most frequently utilized intravesical chemotherapy drugs for the management of non-muscle-invasive bladder cancer (NMIBC). Allergic reactions (Type 4 delayed hypersensitivity) are seldomly reported in the literature but not so infrequent in daily practice, its incidence has been increasing with the use of device-assisted hyperthermia. This study aims to identify the incidence, risk factors, and clinical characteristics of patients with allergic reactions to MMC. PATIENTS AND METHODS: Single-center retrospective cohort from June 2014 to August 2018. Patients with intermediate or high-risk NMIBC were included. Patients received passive MMC (4 weekly and eleven monthly instillations of 40mg of MMC) or Chemohyperthermia (CHT) with MMC (6 weekly and 6-monthly instillations, heated at 43°C [+/- 0.5°C] using Combat BRS). RESULTS: We included 258 patients (MMC = 157, CHT = 101) and found 7 (4.4%) suspected and 4 confirmed (2.4%) allergies in the passive MMC group and 11 suspected (10.9%) and 7 confirmed (6.9%) in the CHT group. The mean number of instillations received before developing the allergy was 6 in the passive MMC and 5 in the CHT group. Seven out of 18 suspected allergy cases were pseudo-allergic reactions with negative allergy tests. Early postoperative MMC instillation was associated with an increased risk of allergy (OR 2.47 [CI 1.39-4.36], P = 0.001), while neither history of atopy nor history of other medications allergy was found to increase the risk. CONCLUSION: MMC allergy risk is increased with the use of device-assisted hyperthermia with an incidence of 2.4% for passive MMC and 6.9% for CHT. History of prior allergies does not seem to increase the risk of developing MMC allergy. In this series 38% of suspected cases were found to be pseudo-allergic reactions, highlighting the need to confirm the diagnosis before definitively stopping the treatment.

Toward Tumor Fight and Tumor Microenvironment Remodeling: PBA Induces Cell Cycle Arrest and Reduces Tumor Hybrid Cells' Pluripotency in Bladder Cancer.

Bladder cancer (BC) is the second most frequent cancer of the genitourinary system. The most successful therapy since the 1970s has consisted of intravesical instillations of Bacillus Calmette-Guérin (BCG) in which the tumor microenvironment (TME), including macrophages, plays an important role. However, some patients cannot be treated with this therapy due to comorbidities and severe inflammatory side effects. The overexpression of histone deacetylases (HDACs) in BC has been correlated with macrophage polarization together with higher tumor grades and poor prognosis. Herein we demonstrated that phenylbutyrate acid (PBA), a HDAC inhibitor, acts as an antitumoral compound and immunomodulator. In BC cell lines, PBA induced significant cell cycle arrest in G1, reduced stemness markers and increased PD-L1 expression with a corresponding reduction in histone 3 and 4 acetylation patterns. Concerning its role as an immunomodulator, we found that PBA reduced macrophage IL-6 and IL-10 production as well as CD14 downregulation and the upregulation of both PD-L1 and IL-1ß. Along this line, PBA showed a reduction in IL-4-induced M2 polarization in human macrophages. In co-cultures of BC cell lines with human macrophages, a double-positive myeloid-tumoral hybrid population (CD11b+EPCAM+) was detected after 48 h, which indicates BC cell-macrophage fusions known as tumor hybrid cells (THC). These THC were characterized by high PD-L1 and stemness markers (SOX2, NANOG, miR-302) as compared with non-fused (CD11b-EPCAM+) cancer cells. Eventually, PBA reduced stemness markers along with BMP4 and IL-10. Our data indicate that PBA could have beneficial properties for BC management, affecting not only tumor cells but also the TME.

Recirculating hyperthermic intravesical chemotherapy with mitomycin C (HIVEC) versus BCG in high-risk non-muscle-invasive bladder cancer: results of the HIVEC-HR randomized clinical trial.

PURPOSE: The purpose of the study was to compare the outcomes of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) patients treated with BCG vs recirculating hyperthermic intravesical chemotherapy (HIVEC) with mitomycin C (MMC). METHODS: A pilot phase II randomized clinical trial was conducted including HR-NMIBC patients, excluding carcinoma in situ. Patients were randomized 1:1 to receive intravesical BCG for 1 year (once weekly for 6 weeks plus subsequent maintenance) or HIVEC with 40 mg MMC, administered using the Combat BRS system (once weekly instillations were given for 6 weeks, followed by once monthly instillation for 6 months). Total recirculating dwell time for HIVEC was 60 min at a target temperature of 43° ± 0.5 °C. Primary endpoint was recurrence-free survival. Secondary endpoints were time to recurrence, progression-free survival, cancer-specific survival, and overall survival at 24 months. Adverse events were routinely assessed. RESULTS: Fifty patients were enrolled. Mean age was 73.5 years. Median follow-up was 33.7 months. Recurrence-free survival at 24 months was 86.5% for HIVEC and 71.8% for BCG (p = 0.184) in the intention-to-treat analysis and 95.0% for HIVEC and 75.1% for BCG (p = 0.064) in the per protocol analysis. Time to recurrence was 21.5 and 16.1 months for HIVEC and BCG, respectively. Progression-free survival for HIVEC vs BCG was 95.7% vs 71.8% (p = 0.043) in the intention-to-treat analysis and 100% vs 75.1% (p = 0.018) in the per protocol analysis, respectively. Cancer-specific survival at 24 months was 100% for both groups and overall survival was 91.5% for HIVEC vs 81.8% for BCG. CONCLUSION: HIVEC provides comparable safety and efficacy to BCG and is a reasonable alternative during BCG shortages. TRIAL REGISTRATION: EudraCT 2016-001186-85. Date of registration: 17 March 2016.

Intravesical Chemohyperthermia vs. Bacillus Calmette-Guerin Instillation for Intermediate- and High-Risk Non-muscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis.

Background: The efficacy of intravesical chemotherapy maintenance for patients with non-muscle invasive bladder cancer (NMIBC) is inferior compared to intravesical bacillus Calmette-Guerin (BCG). How intravesical chemohyperthermia (CHT) compares with BCG is under investigation. Objective: To compare the oncological outcomes and safety profile between intravesical CHT and BCG treatment for intermediate- and high-risk NMIBC. Methods: We performed a systematic review and meta-analysis of clinical studies comparing CHT with BCG for intermediate- and high-risk NMIBC patients. A comprehensive literature search on OVID MEDLINE, EMBASE, and Cochrane Library was conducted. Risk of bias was assessed by the Cochrane RoB tool and ROBINS-I. Certainty of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Results: A total of 2,375 articles were identified and five studies were finally included. Among them, four randomised trials comprising 327 patients (CHT group: 156 patients; BCG group: 171 patients) were included in the meta-analysis. There were no significant differences in the 24-36 months recurrence rates (CHT: 29.5%, BCG: 37.4%; RR: 0.83, 95% CI 0.61-1.13; moderate certainty of evidence) and the 24-36 months progression rates (CHT: 4.4%, BCG: 7.6%, RR = 0.62, 95% CI 0.26-1.49; low certainty of evidence). There were also no significant differences in grade 1-2 adverse events (CHT group: 59.9%, BCG group 54.5%; RR = 1.10, 95% CI 0.93-1.30; moderate certainty of evidence) and grade 3 or above adverse events (CHT group: 23.2%, BCG group 22.5%; RR = 0.99, 95% CI 0.69-1.43; low certainty of evidence). Conclusions: Intravesical CHT had equivalent oncological outcomes and similar safety profile when compared to BCG maintenance therapy for patients with intermediate- and high-risk NMIBC. CHT is a possible alternative treatment in the times of BCG shortage.

Affective Episodic Memory System for Virtual Creatures: The First Step of Emotion-Oriented Memory.

Episodic memory and emotions are considered essential functions in human cognition. Both allow us to acquire new knowledge from the environment, ranging from the objects around us to how we feel towards them. These qualities make them crucial functions for systems trying to create human-like behaviour. In the field of cognitive architectures (CAs), there are multiple studies covering memory and emotions. However, most of them treat these subjects in an isolated manner, considering emotions only as a reward signal unrelated to a retrieved experience. To address this lack of direct interaction, we propose a computational model that covers the common processes that are related to memory and emotions. Specifically, this proposal focuses on affective evaluations of episodic memories. Neurosciences and psychology are the bases of this model. That is, the model's components and the processes that they carry out on the information they receive are designed based on evidence from these cognitive sciences. The proposed model is a part of Cuáyóllótl, a cognitive architecture for cybernetic entities such as virtual creatures and robots. Case studies validate our proposal. They show the relevance of the integration of emotions and memory in a virtual creature. The virtual creature endowed with our emotional episodic model improves its learning and modifies its behaviour according to planning and decision-making processes.