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1.
Proc Natl Acad Sci U S A ; 120(35): e2306782120, 2023 08 29.
Artículo en Inglés | MEDLINE | ID: mdl-37607227

RESUMEN

CD40 is a central costimulatory receptor implicated in productive antitumor immune responses across multiple cancers, including bladder cancer. Despite strong preclinical rationale, systemic administration of therapeutic agonistic antibodies targeting the CD40 pathway has demonstrated dose-limiting toxicities with minimal clinical activity, emphasizing an important need for optimized CD40-targeted approaches, including rational combination therapy strategies. Here, we describe a role for the endogenous IL-15 pathway in contributing to the therapeutic activity of CD40 agonism in orthotopic bladder tumors, with upregulation of transpresented IL-15/IL-15Rα surface complexes, particularly by cross-presenting conventional type 1 DCs (Dendritic Cells), and associated enrichment of activated CD8 T cells. In bladder cancer patient samples, we identify DCs as the primary source of IL-15, although they lack high levels of IL-15Rα at baseline. Using humanized immunocompetent orthotopic bladder tumor models, we demonstrate the ability to therapeutically augment this interaction through combined treatment with anti-CD40 agonist antibodies and exogenous IL-15, including the fully-human Fc-optimized antibody 2141-V11 currently in clinical development for the treatment of bladder cancer. Collectively, these data reveal an important role for IL-15 in mediating antitumor CD40 agonist responses in bladder cancer and provide key proof-of-concept for combined use of Fc-optimized anti-CD40 agonist antibodies and agents targeting the IL-15 pathway. These data support expansion of ongoing clinical studies evaluating anti-CD40 agonist antibodies and IL-15-based approaches to develop combinations of these promising therapeutics for the treatment of patients with bladder cancer.


Asunto(s)
Interleucina-15 , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Terapia Combinada , Antígenos CD40 , Fragmentos Fc de Inmunoglobulinas
2.
World J Urol ; 42(1): 315, 2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38734774

RESUMEN

INTRODUCTION: The combination of sequential intravesical gemcitabine and docetaxel (Gem/Doce) chemotherapy has been considered a feasible option for BCG (Bacillus Calmette-Guérin) treatment in non-muscle invasive bladder cancer (NMIBC), gaining popularity during BCG shortage period. We seek to determine the efficacy of the treatment by comparing Gem/Doce induction alone vs induction with maintenance, and to evaluate the treatment outcomes of two different dosage protocols. METHODS: A bi-center retrospective analysis of consecutive patients treated with Gem/Doce for NMIBC between 2018 and 2023 was performed. Baseline characteristics, risk group stratification (AUA 2020 guidelines), pathological, and surveillance reports were collected. Kaplan-Meier survival analysis was performed to detect Recurrence-free survival (RFS). RESULTS: Overall, 83 patients (68 males, 15 females) with a median age of 73 (IQR 66-79), and a median follow-up time of 18 months (IQR 9-25), were included. Forty-one had an intermediate-risk disease (49%) and 42 had a high-risk disease (51%). Thirty-seven patients (45%) had a recurrence; 19 (23%) had a high-grade recurrence. RFS of Gem/Doce induction-only vs induction + maintenance was at 6 months 88% vs 100%, at 12 months 71% vs 97%, at 18 months 57% vs 91%, and at 24 months 31% vs 87%, respectively (log-rank, p < 0.0001). Patients who received 2 g Gemcitabine with Docetaxel had better RFS for all-grade recurrences (log-rank, p = 0.017). However, no difference was found for high-grade recurrences. CONCLUSION: Gem/Doce induction with maintenance resulted in significantly better RFS than induction-only. Combining 2 g gemcitabine with docetaxel resulted in better RFS for all-grade but not for high-grade recurrences. Further prospective trials are necessary to validate our results.


Asunto(s)
Desoxicitidina , Docetaxel , Gemcitabina , Invasividad Neoplásica , Neoplasias Vesicales sin Invasión Muscular , Anciano , Femenino , Humanos , Masculino , Administración Intravesical , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Docetaxel/administración & dosificación , Relación Dosis-Respuesta a Droga , Quimioterapia de Inducción/métodos , Quimioterapia de Mantención/métodos , Neoplasias Vesicales sin Invasión Muscular/tratamiento farmacológico , Estudios Retrospectivos , Medición de Riesgo , Resultado del Tratamiento
3.
Neurosurg Focus ; 52(2): E7, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35104796

RESUMEN

OBJECTIVE: Prior studies have demonstrated a relationship between underlying tumor genetics and lymphocyte infiltration in meningiomas. In this study, the authors aimed to further characterize the relationship between meningioma genomics, CD4+ and CD8+ T-cell infiltration, and oncological outcomes of meningiomas. Understanding specific characteristics of the inflammatory infiltration could have implications for treatment and prognostication. METHODS: Immunohistochemically stained meningioma slides were reviewed to assess the CD4+ and CD8+ cell infiltration burden. The relationship between immune cell infiltration and tumor genomics was then assessed using an adjusted ANOVA model. For a specific gene identified by the ANOVA, the relationship between that mutation and tumor recurrence was assessed using Cox regression. RESULTS: In immunohistochemically stained samples from a subcohort of 25 patients, the mean number of CD4+ cells was 42.2/400× field and the mean number of CD8+ cells was 69.8/400× field. Elevated CD8+ cell infiltration was found to be associated with the presence of a mutation in the gene encoding for DNA polymerase epsilon, POLE (51.6 cells/hpf in wild-type tumors vs 95.9 cells/hpf in mutant tumors; p = 0.0199). In a retrospective cohort of 173 patients, the presence of any mutation in POLE was found to be associated with a 46% reduction in hazard of progression (HR 0.54, 95% CI 0.311-0.952; p = 0.033). The most frequent mutation was a near-C-terminal nonsense mutation. CONCLUSIONS: A potential association was found between mutant POLE and both an increase in CD8+ cell infiltration and progression-free survival. The predominant mutation was found outside of the known exonuclease hot spot; however, it was still associated with a slight increase in mutational burden, CD8+ cell infiltration, and progression-free survival. Alterations in gene expression, resulting from alterations in POLE, may yield an increased presentation of neoantigens, and, thus, greater CD8+ cell-mediated apoptosis of neoplastic cells. These findings have suggested the utility of checkpoint inhibitors in the treatment of POLE-mutant meningiomas.


Asunto(s)
Neoplasias Meníngeas , Meningioma , Linfocitos T CD8-positivos , ADN Polimerasa II/genética , Humanos , Neoplasias Meníngeas/genética , Meningioma/genética , Mutación/genética , Recurrencia Local de Neoplasia , Supervivencia sin Progresión , Estudios Retrospectivos
4.
J Craniofac Surg ; 32(1): 16-20, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32890158

RESUMEN

BACKGROUND: Geometric morphometric analysis with Procrustes superimposition is an advanced computational tool that can be used to quantify dynamic changes in complex three-dimensional structures. The present study couples high resolution CT imaging with a Geometric Morphometric approach in order to further understand the complex dysmorphology that occurs in unilateral coronal synostosis (UCS). METHODS: Forty-one UCS patients and 41 age- and sex-matched controls received high-resolution CT imaging. Thirty-one anatomical landmarks were identified on each imaging set. A geometric morphometric workflow was used to perform a Procrustes superimposition to register landmarks into a common space. Procrustes-aligned landmarks were used to derive angle calculations, lengths, and other anatomical measurements. Three-dimensional coordinates were also used to perform a principal components analysis (PCA). RESULTS: Unilateral coronal synostosis patients exhibited significant angular deviation at the levels of the inferior skull base, mid-posterior fossa, and vertex. Both left- and right-sided UCS patients showed increased lengthening in the transverse (left-right) dimension, exhibiting increased length between the left and right EAC (P = 0.047). Conversely, UCS patients revealed shortening in the midline AP dimension as evidenced by the decreased Nasal root-Lambda (P < 0.0001) and Nasal root-superior dorsum sellae (P = 0.01) distances compared with controls. PCA revealed that 25.26% of variation in shape among the patients sampled to be driven by flattening of the skull and that18.93% of variation was driven by right-sided deformity and mediolateral expansion. CONCLUSIONS: Significant dysmorphology between UCS patients and controls was quantified using Geometric Morphometric approach, which may be useful in further characterizing the dynamic craniofacial changes in UCS.


Asunto(s)
Craneosinostosis , Craneosinostosis/diagnóstico por imagen , Humanos , Imagenología Tridimensional , Base del Cráneo/diagnóstico por imagen , Tomografía Computarizada por Rayos X
5.
J Arthroplasty ; 35(12): 3488-3497, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32739081

RESUMEN

BACKGROUND: The role of preoperative laboratory values for risk stratification following joint arthroplasty is currently ambiguous. In order to improve upon existing risk stratification within joint arthroplasty, this study sought to define novel phenotypes of total hip or total knee arthroplasty patients based entirely on preoperative laboratory measures. These phenotypes ("clusters") were compared to elucidate statistically and clinically significant differences in outcomes. METHODS: A total of 134,252 patients were gathered from the National Surgical Quality Improvement Program database between 2005 and 2015. "K-means" with 3 clusters was applied using 9 preoperative laboratory values: sodium, blood urea nitrogen (BUN), creatinine, albumin, bilirubin, white blood cell count, hematocrit, platelet count, and international normalized ratio of prothrombin values (INR). Outcome measures included 30-day readmissions, severe adverse events, and discharge to nonhome. RESULTS: Cluster 2 was characterized by elevated preoperative BUN, creatinine, and INR and demonstrated almost twice the rate of adverse events (3.52% vs 2.20% and 2.22%), 30-day readmissions (6.39% vs 3.31% and 3.71%), and discharge to nonhome (47.97% vs 30.50% and 35.85%). Cluster 3 was characterized by a slightly higher risk of discharge to nonhome than cluster 1 and was overwhelmingly female (79.5% female, 35.8% discharge to nonhome). Cluster 1 represents the lowest-risk subgroup, experiencing the lowest rates of readmissions, adverse events, and discharge to nonhome. CONCLUSION: Preoperative laboratory values, namely BUN, creatinine, and INR, are useful in identifying patients at risk of adverse outcomes. This analysis supports the existing surgical literature pushing for preoperative hydration as a targeted intervention to expedite recovery.


Asunto(s)
Artroplastia de Reemplazo de Cadera , Medicare , Anciano , Artroplastia de Reemplazo de Cadera/efectos adversos , Análisis por Conglomerados , Femenino , Humanos , Masculino , Alta del Paciente , Readmisión del Paciente , Complicaciones Posoperatorias , Factores de Riesgo , Estados Unidos/epidemiología
6.
Endosc Int Open ; 12(1): E36-E42, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38188926

RESUMEN

Introduction The anti-cholinergic agent hyoscine-N-butylbromide (HBB) is used in gastrointestinal (GI) endoscopy to decrease motility and facilitate endoscopic procedures. Data from clinical studies to support this practice is limited especially for therapeutic procedures. Likewise, patterns of use among endoscopist are largely unclear. This study sought to assess usage of HBB among German-speaking endoscopists. Material and Methods We conducted an anonymous online survey among endoscopists in German-speaking countries. Results A total of 207 physicians participated in the survey. The majority (76.9%) were experienced endoscopists and 92.3% of respondents use HBB at least occasionally during procedures. The reported median stated frequency of HBB use varied greatly between different types of procedures and increased with the complexity of the procedure being performed. HBB was rarely used in diagnostic esophagogastroduodenoscopies (EGD) (median stated frequency 1% of procedures), while use frequency was significantly higher in EGD with endoscopic mucosal resection (EMR) (10%; p=0.002) and EGD with endoscopic submucosal dissection (ESD) (20%; p<0.001). Similarly, use frequency during diagnostic colonoscopy was lower (5%) compared to colonoscopy with EMR (20%, p=0.005) or ESD (42.5%, p<0.001). The highest use frequency was reported for ERCP (50%). The most frequently stated reason to use HBB was facilitation of the procedure (80.6%) followed by increasing diagnostic yield (58.3%). Conclusion German-speaking endoscopists commonly use HBB, most frequently to facilitate complex therapeutic procedures. Given there is almost no data supporting HBB use in therapeutic endoscopy, we suggest that more research is needed to evaluate benefits and risks of this practice.

7.
JCO Precis Oncol ; 8: e2300661, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39151107

RESUMEN

PURPOSE: The purpose of this study was to elucidate the relationship between the tumor microenvironment (TME) and cellular diversity in bladder cancer (BLCA) progression, leveraging single-cell RNA sequencing (scRNA-seq) data to identify potential prognostic biomarkers and construct a prognostic model for BLCA. METHODS: We analyzed scRNA-seq data of normal and tumor bladder cells from the Gene Expression Omnibus (GEO) database to uncover crucial markers within the bladder TME. The study compared gene expression in normal versus tumor bladder cells, identifying differentially expressed genes. These genes were subsequently assessed for their prognostic significance using patient follow-up data from The Cancer Genome Atlas. Prognostic models were constructed using Least Absolute Shrinkage and Selection Operator and multivariate Cox regression analyses, focusing on eight genes of interest. The predictive performance of the model was also tested against additional GEO data sets (GSE31684, GSE13507, and GSE32894). RESULTS: The prognostic model demonstrated reliable prediction of patient outcomes. Validation through gene set enrichment analysis and immune cell infiltration assessment supported the model's efficacy. The results from both the univariate and multivariate analyses suggest that the risk score is an independent prognostic factor with a hazard ratio of 2.97 (95% CI, 2.28 to 3.9, P < .001). In the validation cohort, the AUC at 1, 2, and 3 years is 0.74, 0.74, and 0.72, respectively. CONCLUSION: Our findings proposed biomarkers with prognostic potential, laying the groundwork for future in vitro validation and therapeutic exploration. This contributes to a deeper understanding of the genes associated with bladder TME and may improve prognostic precision in BLCA management.


Asunto(s)
Análisis de la Célula Individual , Microambiente Tumoral , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Humanos , Microambiente Tumoral/genética , Pronóstico , Análisis de la Célula Individual/métodos , Análisis de Secuencia de ARN , Biomarcadores de Tumor/genética , Masculino , Femenino
8.
Neurosurgery ; 95(2): 392-399, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38421190

RESUMEN

BACKGROUND AND OBJECTIVES: Pituitary adenomas (PAs) are the most common intrasellar tumor. Clinically relevant adenomas have a prevalence of 1 per 1000 in the general population. Transsphenoidal surgery (TSS) is the most common surgical treatment and is the first-line management for most PAs. Most patients fare well postoperatively, but a subset of patients experience a prolonged length of stay (PLOS). In this article, we aim to identify demographic and clinical factors associated with PLOS after TSS for PA. METHODS: Patients with sellar pathologies surgically treated at a single tertiary center from March 1, 2009, to May 31, 2020, were retrospectively reviewed. All patients older than 18 years receiving nonemergent endoscopic TSS for pituitary adenoma were included. Clinical and demographic characteristics were analyzed using χ 2 -tests and student t -tests. For those factors with a P -value less than .01, multivariate logistic regression and negative binomial regression models were constructed to estimate the adjusted odds of PLOS across predictive factors. RESULTS: A total of 301 patients were included in the study. This cohort had an average age of 54.65 ± 15.06 years and an average body mass index of 29.47 ± 6.69. The median length of stay was 54.9 hours [25th-75th percentiles: 43.5-72.9]. Postoperative cerebrospinal fluid leak ( P < .01), postoperative diabetes insipidus (DI) ( P < .01), increased surgery duration ( P = .01), and elevated maximal tumor dimension ( P = .01) were predictive of PLOS in logistic regression. Increased surgery duration, previous pituitary radiation, intraoperative complications, and postoperative DI (all P < .01) were associated with increased rate of PLOS in negative binomial regression. CONCLUSION: Patients undergoing endoscopic TSS for PA resection demonstrate prolonged lengths of stay if they have higher tumor burden, have lengthier surgeries with intraoperative complications, or develop postoperative complications such as cerebrospinal fluid leak or DI. Careful monitoring of these factors will allow for better resource optimization, reducing costs to both the hospital and the patient.


Asunto(s)
Adenoma , Tiempo de Internación , Neoplasias Hipofisarias , Complicaciones Posoperatorias , Humanos , Neoplasias Hipofisarias/cirugía , Masculino , Femenino , Persona de Mediana Edad , Tiempo de Internación/estadística & datos numéricos , Adenoma/cirugía , Adulto , Anciano , Factores de Riesgo , Estudios Retrospectivos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Neuroendoscopía/métodos , Pérdida de Líquido Cefalorraquídeo/epidemiología , Pérdida de Líquido Cefalorraquídeo/etiología , Procedimientos Neuroquirúrgicos/métodos , Procedimientos Neuroquirúrgicos/efectos adversos
9.
J Robot Surg ; 17(5): 2409-2414, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37432590

RESUMEN

Single-port (SP) robot-assisted laparoscopic partial nephrectomy (RAPN) is a promising new technique. The aim of this study was to compare surgical and oncological outcomes of SP-RAPN to the multi-port (MP) surgical platform. This is a retrospective, cohort-based study involving patients undergoing SP-RAPN between 2019 and 2020 at a single institution. Demographic, preoperative, surgical, and postoperative outcomes data were gathered and compared to a 1-to-1 matched MP cohort. A total of 50 SP and 50 matched MP cases were included. Length of surgery and ischemia time were not statistically significant between the two cohorts; however, estimated blood loss (EBL) was significantly lower in the SP group than in the MP (IQR 25-50 vs. IQR 50-100 mL, p = 0.002). No differences were seen in regard to the 30-day readmission rate, surgical margin status, pain scores, and complications between the two approaches. We found no statistically significant differences in positive margins, pain score, length of stay, or readmission rate between matched SP and MP patients. These data support the viability of the SP technique as an alternative to MP-RAPN when in the hands of experienced surgeons.


Asunto(s)
Neoplasias Renales , Laparoscopía , Procedimientos Quirúrgicos Robotizados , Robótica , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Neoplasias Renales/cirugía , Neoplasias Renales/complicaciones , Estudios Retrospectivos , Complicaciones Posoperatorias/etiología , Resultado del Tratamiento , Nefrectomía/métodos , Laparoscopía/métodos , Dolor
10.
JAMA Netw Open ; 6(1): e2250974, 2023 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-36662528

RESUMEN

Importance: Preference signals were to be implemented in over 15 specialties during the 2022-2023 residency match. Analyzing results from the implementation of signals during the American Urological Association (AUA) urology match may inform future behavior. Objective: To characterize applicant and program signal usage and results in the Society of Academic Urology and AUA databases with respect to interview invites and rank list creation. Design, Setting, and Participants: This cohort study involved all applicants and residencies in the 2021-2022 AUA match with data analysis conducted in April through July 2022. Exposures: Five signals indicating interest. Main Outcomes and Measures: Using verified match and survey data reported by applicants and programs, a logistic regression was performed on applicant factors associated with obtaining an interview-the main outcome (using inclusion on rank list as a proxy): age, gender, degree (MD or DO), dispersal of signal, US senior status, racial minority group status, Latino ethnicity, international medical graduate status, presence of a home program, AUA geographic section, and US Medical Licensing Examination Step 1 score. Applicant signal dispersal strategies were stratified by applicant and program competitiveness, as well as program behavior upon receipt of signal with respect to extending interviews and rank list ordering of applicants. Results: A total of 2659 signals were sent by 553 candidates (mean [SD] age, 27.4 [2.9] years; 179 female [32.4%], 243 racial minority candidates [61.2%]) submitting rank lists for 364 positions at 143 programs. Programs received a median (IQR) of 352 (295-411) applications and were signaled to a median of 16 (8-26) times each. In a logistic regression estimating interview status, geographic proximity (OR, 3.25; 95% CI, 2.05-5.15; P = .001) and signal status (OR, 6.04; 95% CI, 3.50-10.40; P < .001) were associated with receiving an interview. Using multiple imputation by chained equations to impute missing data and broadening the data set, male gender (OR, 0.64; 95% CI, 0.45-0.92; P = .04) and international medical graduate status (OR, 0.35; 95% CI, 0.15-0.81; P = .04) were negative variables, while MD degree (OR, 2.36; 95% CI, 1.27-4.36; P = .02) and US senior status (OR, 1.91; 95% CI, 1.13-3.23; P = .04) were positive variables. Conclusions and Relevance: This study of the usage and trends of the newly added preference signals reported the most common strategies for signal dispersal; in an analysis of factors involved in obtaining an interview, geographic similarity between applicant and program and preference signal usage were associated with successful applications.


Asunto(s)
Internado y Residencia , Urología , Humanos , Masculino , Femenino , Estados Unidos , Adulto , Estudios de Cohortes , Encuestas y Cuestionarios , Grupos Minoritarios
11.
Urol Oncol ; 41(4): 207.e1-207.e7, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36764890

RESUMEN

PURPOSE: Examine patient, tumor, and treatment characteristics effect on the disparity between black and white patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy (RC). METHODS: 1,286 black patients in the 2004 to 2016 National Cancer Database fit inclusion criteria. A tapered match was performed from 17,374 white patients sequentially matched to the black cohort on demographics (age, gender, insurance, income, education, county, diagnosis year), presentation (demographic variables, stage, grade, tumor size, Charlson score), and treatment (demographic and presentation variables, lymph node count, hospital volume, neoadjuvant chemotherapy [NAC], treatment delay), creating 3 matched cohorts. Chi-square and Kruskal-Wallis tests were used to compare cohorts. Kaplan-Meier analysis was used to compare 5-year overall survival (OS). RESULTS: 5-year OS rate was 40.4% and 35.6% for unmatched white and black cohorts (P < 0.001), respectively. Following demographics and presentation match, 5-year OS rate for white patients decreased to 39.2% (P = 0.003) and 39.10% (P = 0.019), respectively. After treatment match, 5-year OS rate decreased to 36.7% for white patient (P = 0.32). Following presentation match, 7.2% of black patients vs. 5.8% of white patients had treatment delay, and 10.1% of black patients vs. 11.2% of white patients received NAC. The treatment match resulted in a 0.3% difference between groups for treatment delay and NAC. CONCLUSIONS: Our analysis demonstrates that disparity between black and white patients with muscle-invasive bladder cancer exists in demographic-, presentation-, and treatment-related variables. Treatment variables may be a large contributing factor to survival disparities. Further research is needed to identify social, biological, and organizational inputs that contribute to these disparities.


Asunto(s)
Población Negra , Cistectomía , Disparidades en el Estado de Salud , Neoplasias de la Vejiga Urinaria , Población Blanca , Humanos , Quimioterapia Adyuvante , Cistectomía/métodos , Cistectomía/mortalidad , Terapia Neoadyuvante , Invasividad Neoplásica , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/etnología , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/terapia , Bases de Datos Factuales/estadística & datos numéricos
12.
Bladder Cancer ; 9(2): 125-139, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38993289

RESUMEN

BACKGROUND: For decades, immunotherapies have been integral for the treatment and management of bladder cancer, with immune checkpoint inhibitors (ICIs) transforming patient care in recent years. However, response rates are poor to T cell-targeted ICIs such as programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) blocking antibodies, framing a critical need for complementary immunotherapies. Promising strategies involve harnessing the activation potential of natural killer (NK) cells. They quickly exert their antitumor activity via signaling through germline-encoded activating receptors and are rapidly sensitized to new tissue microenvironments via their regulation by polymorphic HLA class I, KIR and NKG2A receptors. OBJECTIVE: In this review, we examined the roles of currently available NK-targeted antitumor treatment strategies such as engineered viral vectors, small-molecule IMiDs, NK agonist antibodies, interleukins, and chimeric antigen receptor (CAR) NK cells, and their potential for improving the efficacy of immunotherapy in the treatment of bladder cancer. METHODS: Through review of current literature, we summarized our knowledge of NK cells in solid tumors and hematologic malignancies as their roles pertain to novel immunotherapies already being applied to the treatment of bladder cancer or that offer rationale for considering as potential novel immunotherapeutic strategies. RESULTS: NK cells play a critical role in shaping the tumor microenvironment (TME) that can be exploited to improve T cell-targeted immunotherapies. CONCLUSIONS: Emerging evidence suggests that NK cells are a prime target for improving antitumor functions in immunotherapies for the treatment of bladder cancer. Further research into profiling NK cells in settings of immunotherapies for bladder cancer could help identify patients who might maximally benefit from NK cell-targeted immunotherapies and the various approaches for exploiting their antitumor properties.

13.
Urol Oncol ; 41(11): 457.e1-457.e7, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37863743

RESUMEN

INTRODUCTION: Perioperative management of patients undergoing radical cystectomy and urinary diversion utilizing both open and minimally invasive techniques have routinely included the use of drains in the operative field. We herein demonstrate the safety of robotic-assisted radical cystectomy (RARC) without the routine use of postoperative drains. METHODS: Patients who underwent drainless RARC with intracorporeal urinary diversion between 2017 and 2022 at our institution were reviewed. Baseline and clinical characteristics as well as perioperative and postoperative outcomes were analyzed. The primary study outcome was incidence of postoperative urinary leak or intra-abdominal infectious collections within 90 days of RARC. A univariate and multivariable logistic regression analysis was performed to determine associations between study variables and the primary outcome. RESULTS: Of 381 patients, 298 (78.2%) were male and median age and BMI were 68 (63, 76) and 26.2 [23.0, 29.8], respectively. Overall 30 and 90-day complication rates were 39.6% and 50.4%, respectively. Twenty-one (5.5%) patients experienced a urine leak or intra-abdominal infectious collections. Sub-group analysis of patients who experienced the primary outcome demonstrated median postoperative day of presentation was day 19, and this group required 16 total additional procedures. On multivariable logistic regression analysis, only prior radiation therapy was associated with the development of the primary outcome of urinary leak or intra-abdominal infectious collection (odds ratio: 15.12, 95% confidence interval [1.52-156.8], p = 0.02). CONCLUSION: Drainless RARC with totally intracorporeal urinary diversion achieved competitive perioperative and complications outcomes compared to prior open and robotic series. In the context of a larger enhanced recovery after surgery protocol in RARC patients, the routine use of drains may be safely omitted.


Asunto(s)
Procedimientos Quirúrgicos Robotizados , Neoplasias de la Vejiga Urinaria , Derivación Urinaria , Humanos , Masculino , Femenino , Cistectomía/métodos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Procedimientos Quirúrgicos Robotizados/métodos , Neoplasias de la Vejiga Urinaria/complicaciones , Resultado del Tratamiento , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Tempo Operativo , Derivación Urinaria/métodos
14.
Asian J Urol ; 10(4): 446-452, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38024428

RESUMEN

Objective: We aimed to compare perioperative and oncologic outcomes for patients undergoing robotic-assisted radical cystectomy (RARC) with intracorporeal ileal conduit (IC) and neobladder (NB) urinary diversion. Methods: Patients undergoing RARC with intracorporeal urinary diversion between January 2017 and January 2022 at the Icahn School of Medicine at Mount Sinai, New York, NY, USA were indexed. Baseline demographics, clinical characteristics, perioperative, and oncologic outcomes were analyzed. Survival was estimated with Kaplan-Meier plots. Results: Of 261 patients (206 [78.9%] male), 190 (72.8%) received IC while 71 (27.2%) received NB diversion. Median age was greater in the IC group (71 [interquartile range, IQR 65-78] years vs. 64 [IQR 59-67] years, p<0.001) and BMI was 26.6 (IQR 23.2-30.4) kg/m2. IC group was more likely to have prior abdominal or pelvic radiation (15.8% vs. 2.8%, p=0.014). American Association of Anesthesiologists scores were comparable between groups. The IC group had a higher proportion of patients with pathological tumor stage 2 (pT2) tumors (34 [17.9%] vs. 10 [14.1%], p=0.008) and pathological node stages pN2-N3 (28 [14.7%] vs. 3 [4.2%], p<0.001). The IC group had less median operative time (272 [IQR 246-306] min vs. 341 [IQR 303-378] min, p<0.001) and estimated blood loss (250 [150-500] mL vs. 325 [200-575] mL, p=0.002). Thirty- and 90-day complication rates were 44.4% and 50.2%, respectively, and comparable between groups. Clavien-Dindo grades 3-5 complications occurred in 27 (10.3%) and 34 (13.0%) patients within 30 and 90 days, respectively, with comparable rates between groups. Median follow-up was 324 (IQR 167-552) days, and comparable between groups. Kaplan-Meier estimate for overall survival at 24 months was 89% for the IC cohort and 93% for the NB cohort (hazard ratio 1.23, 95% confidence interval 1.05-2.42, p=0.02). Kaplan-Meier estimate for recurrence-free survival at 24 months was 74% for IC and 87% for NB (hazard ratio 1.81, 95% confidence interval 0.82-4.04, p=0.10). Conclusion: Patients undergoing intracorporeal IC urinary diversion had higher postoperative cancer stage, increased nodal involvement, similar complications outcomes, decreased overall survival, and similar recurrence-free survival compared to patients undergoing RARC with intracorporeal NB urinary diversion.

15.
bioRxiv ; 2023 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-36778311

RESUMEN

CD40 is a central co-stimulatory receptor implicated in the development of productive anti-tumor immune responses across multiple cancers, including bladder cancer. Despite strong preclinical rationale, systemic administration of therapeutic agonistic antibodies targeting the CD40 pathway have demonstrated dose limiting toxicities with minimal clinical activity to date, emphasizing an important need for optimized CD40-targeted approaches, including rational combination therapy strategies. Here, we describe an important role for the endogenous IL-15 pathway in contributing to the therapeutic activity of CD40 agonism in orthotopic bladder tumors, with upregulation of trans-presented IL-15/IL-15Rα surface complexes, particularly by cross-presenting cDC1s, and associated enrichment of activated CD8 T cells within the bladder tumor microenvironment. In bladder cancer patient samples, we identify DCs as the primary source of IL-15, however, they lack high levels of IL-15Rα at baseline. Using humanized immunocompetent orthotopic bladder tumor models, we demonstrate the ability to therapeutically augment this interaction through combined treatment with anti-CD40 agonist antibodies and exogenous IL-15, including the fully-human Fc-optimized antibody 2141-V11 currently in clinical development for the treatment of bladder cancer. Combination therapy enhances the crosstalk between Batf3-dependent cDC1s and CD8 T cells, driving robust primary anti-tumor activity and further stimulating long-term systemic anti-tumor memory responses associated with circulating memory-phenotype T and NK cell populations. Collectively, these data reveal an important role for IL-15 in mediating anti-tumor CD40 agonist responses in bladder cancer and provide key proof-of-concept for combined use of Fc-optimized anti-CD40 agonist antibodies and agents targeting the IL-15 pathway. These data support expansion of ongoing clinical studies evaluating anti-CD40 agonist antibodies and IL-15-based approaches to evaluate combinations of these promising therapeutics for the treatment of patients with bladder cancer.

16.
Urology ; 181: 84-91, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37604253

RESUMEN

OBJECTIVE: To characterize first and second recurrence patterns using 26years of cohort-level follow-up and microsimulation modeling. METHODS: Patients diagnosed with nonmuscle-invasive bladder cancer in Stockholm County between 1995 and 1996 were included. Clinical, pathological, and longitudinal follow-up data were gathered. Logistic regressions, Kaplan Meier curves, and Cox proportional hazards models were run to generate assumptions for a microsimulation model, simulating first and second recurrence and progression for 10,000 patients. RESULTS: Three hundred eighty-six patients were included: 67.4% were male; >50% were TaLG; and 37.5% were American Urological Association high-risk. Median time to recurrence was 300days. Three patients had missing data. Cohort follow-up has been carried out for 26years. For simulated first-recurrences, low-risk patients recurred at 56.6% over 15years of follow-up, with 2.2% muscle-invasive (MI) progression; intermediate-risk patients recurred at 62.8%, with 4.3% MI progression; high-risk patients recurred at 48.7% over 15years, with MI progression at 14.3%. For second recurrences, 70.7%, 75.7%, and 84.7% of low, medium, and high-risk patients recurred. No patients were seen to have first recurrences after 9years, with low, but notable, rates beyond 5years. CONCLUSION: These data suggest that low-, intermediate-, and high-risk patients without recurrence at 5years may be potentially transitioned to less invasive monitoring.


Asunto(s)
Neoplasias de la Vejiga Urinaria , Humanos , Masculino , Femenino , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias de la Vejiga Urinaria/terapia , Músculos
17.
Eur Urol Focus ; 2023 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-37838593

RESUMEN

BACKGROUND: Enhanced recovery after surgery (ERAS) has significantly decreased the morbidity associated with radical cystectomy. However, infectious complications including sepsis, urinary tract (UTIs), wound (WIs), and intra-abdominal (AIs) infections remain common. OBJECTIVE: To assess whether intracorporeal urinary diversion (ICUD) and antibiogram-directed antimicrobial prophylaxis would decrease infections after robotic-assisted radical cystectomy (RARC). DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was performed of a prospectively maintained database of patients undergoing RARC between 2014 and 2022 at a tertiary care institution, identifying two groups based on adherence to a prospectively implemented modified ERAS protocol for RARC: modified-ERAS-ICUD and antibiogram-directed ampicillin-sulbactam, gentamicin, and fluconazole prophylaxis were utilized (from January 2019 to present time), and unmodified-ERAS-extracorporeal urinary diversion (UD) and guideline-recommended cephalosporin-based prophylaxis regimen were utilized (from November 2014 to June 2018). Patients receiving other prophylaxis regimens were excluded. INTERVENTION: ICUD and antibiogram-directed infectious prophylaxis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was UTIs within 30 and 90 d postoperatively. The secondary outcomes were WIs, AIs, and sepsis within 30 and 90 d postoperatively, and Clostridioides difficile infection (CDI) within 90 d postoperatively. RESULTS AND LIMITATIONS: A total of 396 patients were studied (modified-ERAS: 258 [65.2%], unmodified-ERAS: 138 [34.8%]). UD via a neobladder was more common in the modified-ERAS cohort; all other intercohort demographic differences were not statistically different. Comparing cohorts, modified-ERAS had significantly reduced rates of 30-d (7.8% vs 15.9%, p = 0.027) and 90-d UTIs (11.2% vs 25.4%, p = 0.001), and 30-d WIs (1.2% vs. 8.7%, p < 0.001); neither group had a WI after 30 d. Rates of AIs, sepsis, and CDI did not differ between groups. On multivariate regression, the modified-ERAS protocol correlated with a reduced risk of UTIs and WIs (all p < 0.01). The primary limitation is the retrospective study design. CONCLUSIONS: Utilization of ICUD and antibiogram-based prophylaxis correlates with significantly decreased UTIs and WIs after RARC. PATIENT SUMMARY: In this study of infections after robotic radical cystectomy for bladder cancer, we found that intracorporeal (performed entirely inside the body) urinary diversion and an institution-specific antibiogram-directed antibiotic prophylaxis regimen led to fewer urinary tract infections and wound infections at our institution.

18.
Urol Case Rep ; 45: 102236, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36281436

RESUMEN

Germ cell tumors (GCT) are rare, frequently diagnosed in men aged 20-34 years old, and have a 95% 5-year relative survival rate. Metastasis from GCT has predictable spread to retroperitoneal lymph nodes. However, in cases of scrotal violation or tumor spillage, lymphatic drainage can be altered. Beyond the retroperitoneum, the most reported extra-nodal sites of metastases include the liver, lung, brain, and bone. Here we report a case of an unusual site of metastasis to the corpora cavernosa, as well as the complex reconstruction required to preserve sexual function.

19.
Trends Cancer ; 8(8): 698-710, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35581130

RESUMEN

Non-muscle invasive bladder cancer, a disease with the oldest immunotherapeutic standard of care, has seen recent improvements in treatment via the application of checkpoint blocking antibodies. Unfortunately, response rates to programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) blocking antibodies remain low despite stratification by biomarkers. Sharing common biology with T cells but lacking true antigen-specificity and responding earlier to tumorigenic threats, natural killer (NK) cells present an ideal target for combination immunotherapies. NK-targeted immunotherapies under clinical investigation, including anti-NKG2A antibodies, interleukin agonists, and engineered viral vectors, hold promise in altering the immunotherapeutic landscape in bladder cancer and will be the focus of this review.


Asunto(s)
Neoplasias de la Vejiga Urinaria , Anticuerpos Bloqueadores/uso terapéutico , Humanos , Inmunoterapia , Células Asesinas Naturales , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia
20.
Urol Oncol ; 40(4): 168.e21-168.e27, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35039217

RESUMEN

INTRODUCTION: Renal function impairment is often cited as a contraindication to continent diversion strategies. There is little evidence exploring renal function changes between continent and incontinent surgery in patients with preoperative chronic kidney disease (CKD), in particular CKD3B. METHODS: This was a retrospective review of two high-volume centers performing robotic assisted radical cystectomy (RARC) with orthotopic neobladder (ONB) or ileal conduit (IC) between 2014 to 2020. Patients were stratified based on CKD estimated glomerular filtration (eGFR) stage, which was estimated via the CKD-EPI equation. Postoperative renal function was compared for up to 60 months postoperative. Surgical, post-surgical, complications, and readmission data were gathered and compared between all patients RESULTS: 522 cystectomy patients, 430 with IC and 125 with ONB, were included. eGFR decline was statistically significant in a matched cohort of IC and ONB patients only at 3 months. There were no statistically significant differences between readmission rates, time to readmission, or complications. 34.6% of stage 3B patients had hydronephrosis on imaging prior to surgery, compared to 11.4%, 22.1% and 21.8% of CKD stage 1, 2, and 3A patients. CKD stage 3B had statistically and clinically improved eGFR through 24 months. CONCLUSION: ONB surgery may be a viable diversion strategy in patients previously thought to be contraindicated due to low renal function.


Asunto(s)
Insuficiencia Renal Crónica , Neoplasias de la Vejiga Urinaria , Derivación Urinaria , Reservorios Urinarios Continentes , Cistectomía/métodos , Femenino , Humanos , Masculino , Insuficiencia Renal Crónica/complicaciones , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/etiología , Neoplasias de la Vejiga Urinaria/cirugía , Derivación Urinaria/métodos
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