RESUMEN
BACKGROUND AND OBJECTIVE: Predicting response to therapy for each patient's tumor is critical to improving long-term outcomes for muscle-invasive bladder cancer. This study aims to establish ex vivo bladder cancer patient-derived organoid (PDO) models that are representative of patients' tumors and determine the potential efficacy of standard of care and curated experimental therapies. METHODS: Tumor material was collected prospectively from consented bladder cancer patients to generate short-term PDO models, which were screened against a panel of clinically relevant drugs in ex vivo three-dimensional culture. Multiomic profiling was utilized to validate the PDO models, establish the molecular characteristics of each tumor, and identify potential biomarkers of drug response. Gene expression (GEX) patterns between paired primary tissue and PDO samples were assessed using Spearman's rank correlation coefficients. Molecular correlates of therapy response were identified using Pearson correlation coefficients and Kruskal-Wallis tests with Dunn's post hoc pairwise comparison testing. KEY FINDINGS AND LIMITATIONS: A total of 106 tumors were collected from 97 patients, with 65 samples yielding sufficient material for complete multiomic molecular characterization and PDO screening with six to 32 drugs/combinations. Short-term PDOs faithfully represent the tumor molecular characteristics, maintain diverse cell types, and avoid shifts in GEX-based subtyping that accompany long-term PDO cultures. Utilizing an integrative approach, novel correlations between ex vivo drug responses and genomic alterations, GEX, and protein expression were identified, including a multiomic signature of gemcitabine response. The positive predictive value of ex vivo drug responses and the novel multiomic gemcitabine response signature need to be validated in future studies. CONCLUSIONS AND CLINICAL IMPLICATIONS: Short-term PDO cultures retain the molecular characteristics of tumor tissue and avoid shifts in expression-based subtyping that have plagued long-term cultures. Integration of multiomic profiling and ex vivo drug screening data identifies potential predictive biomarkers, including a novel signature of gemcitabine response. PATIENT SUMMARY: Better models are needed to predict patient response to therapy in bladder cancer. We developed a platform that uses short-term culture to best mimic each patient's tumor and assess potential sensitivity to therapeutics.
RESUMEN
INTRODUCTION: Multidisciplinary tumor board meetings are useful sources of insight and collaboration when establishing treatment approaches for oncologic cases. However, such meetings can be time intensive and inconvenient. We implemented a virtual tumor board within the Michigan Urological Surgery Improvement Collaborative to discuss and improve the management of complicated renal masses. METHODS: Urologists were invited to discuss decision-making for renal masses through voluntary engagement. Communication was performed exclusively through email. Case details were collected and responses were tabulated. All participants were surveyed about their perceptions of the virtual tumor board. RESULTS: Fifty renal mass cases were reviewed in a virtual tumor board that included 53 urologists. Patients ranged from 20-90 years old and 94% had localized renal mass. The cases generated 355 messages, ranging from 2-16 (median 7) per case; 144 responses (40.6%) were sent via smartphone. All urologists (100%) who submitted to the virtual tumor board had their questions answered. The virtual tumor board provided suggestions to those with no stated treatment plan in 42% of cases, confirmed the physician's initial approach to their case in 36%, and offered alternative approaches in 16% of cases. Eighty-three percent of survey respondents felt the experience was "Beneficial" or "Very Beneficial," and 93% stated increased confidence in their case management. CONCLUSIONS: Michigan Urological Surgery Improvement Collaborative's initial experience with a virtual tumor board showed good engagement. The format reduced barriers to multi-institutional and multi-disciplinary discussions and improved the quality of care for selected patients with complex renal masses.
Asunto(s)
Neoplasias Renales , Mejoramiento de la Calidad , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Adulto Joven , Riñón/patología , Neoplasias Renales/cirugía , Encuestas y Cuestionarios , UrólogosRESUMEN
PURPOSE: To optimize recovery after radical cystectomy (RC), providers stress the importance of ambulation and adequate rest. However, little is known about the activity and sleep habits of patients undergoing RC. Therefore, we utilized a wearable physical activity monitor (PAM) in the perioperative period to provide the first objective data on physical activity and sleep habits for RC patients. MATERIALS AND METHODS: We prospectively identified patients ≥60 years old with planned RC. Participants completed a 4-week prehabilitation exercise program prior to surgery. They wore a PAM for 7-day intervals: at baseline, after prehabilitation, at postoperative day (POD) 30 and POD90. We tracked physical activity via metabolic equivalents (METs). METs were categorized by intensity: light (MET 1.5-<3), moderate (MET 3-<6), and vigorous (MET ≥6). We calculated daily step totals. We tracked hours slept and number of sleep awakenings. We correlated activity and sleep with self-reported quality of life (QOL). RESULTS: Forty-two patients completed prehabilitation and RC. Moderate intensity exercise decreased at POD30 (61 minutes/d at baseline, 30 minutes/d at POD30, Pâ¯=â¯0.005). Physical activity did not significantly differ for light or vigorous activity at any timepoint. RC did not significantly affect sleep. Sleep and physical activity were associated with mental and physical QOL, respectively. CONCLUSIONS: This is the first study utilizing patient-worn monitors in RC to track physical activity and sleep. This study gives patients and providers a better understanding of postcystectomy recovery expectations. With these results in mind, interventions may be implemented to optimize activity and sleep in the perioperative period.
Asunto(s)
Cistectomía , Neoplasias de la Vejiga Urinaria , Humanos , Persona de Mediana Edad , Cistectomía/métodos , Neoplasias de la Vejiga Urinaria/cirugía , Calidad de Vida , Ejercicio FísicoRESUMEN
This observer study investigates the effect of computerized artificial intelligence (AI)-based decision support system (CDSS-T) on physicians' diagnostic accuracy in assessing bladder cancer treatment response. The performance of 17 observers was evaluated when assessing bladder cancer treatment response without and with CDSS-T using pre- and post-chemotherapy CTU scans in 123 patients having 157 pre- and post-treatment cancer pairs. The impact of cancer case difficulty, observers' clinical experience, institution affiliation, specialty, and the assessment times on the observers' diagnostic performance with and without using CDSS-T were analyzed. It was found that the average performance of the 17 observers was significantly improved (p = 0.002) when aided by the CDSS-T. The cancer case difficulty, institution affiliation, specialty, and the assessment times influenced the observers' performance without CDSS-T. The AI-based decision support system has the potential to improve the diagnostic accuracy in assessing bladder cancer treatment response and result in more consistent performance among all physicians.
Asunto(s)
Sistemas de Apoyo a Decisiones Clínicas , Neoplasias de la Vejiga Urinaria , Inteligencia Artificial , Humanos , Tomografía Computarizada por Rayos X , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen , Neoplasias de la Vejiga Urinaria/terapia , UrografíaRESUMEN
Importance: No data exist on time to recovery of patient-reported and performance-related measures of functional independence after radical cystectomy (open or robotic). Objective: To determine recovery of functional independence after radical cystectomy and whether robot-assisted radical cystectomy (RARC) is associated with any advantage over open procedures. Design, Setting, and Participants: Data for this secondary analysis from the RAZOR (Randomized Open vs Robotic Cystectomy) trial were used. RAZOR was a phase 3 multicenter noninferiority trial across 15 academic medical centers in the US from July 1, 2011, to November 18, 2014, with a median follow-up of 2 years. Participants included the per-protocol population (n = 302). Data were analyzed from February 1, 2017, to May 1, 2021. Interventions: Robot-assisted radical cystectomy or open radical cystectomy (ORC). Main Outcomes and Measures: Patient-reported (activities of daily living [ADL] and independent ADL [iADL]) and performance-related (hand grip strength [HGS] and Timed Up & Go walking test [TUGWT]) measures of independence were assessed. Patterns of postoperative recovery for the entire cohort and comparisons between RARC and ORC were performed. Exploratory analyses to assess measures of independence across diversion type and to determine whether baseline impairments were associated with 90-day complications or 1-year mortality were performed. Findings: Of the 302 patients included in the analysis (254 men [84.1%]; mean [SD] age at consent, 68.0 [9.7] years), 150 underwent RARC and 152 underwent ORC. Baseline characteristics were similar in both groups. For the entire cohort, ADL, iADL, and TUGWT recovered to baseline by 3 postoperative months, whereas HGS recovered by 6 months. There was no difference between RARC and ORC for ADL, iADL, TUGWT, or HGS scores at any time. Activities of daily living recovered 1 month after RARC (mean estimated score, 7.7 [95% CI, 7.3-8.0]) vs 3 months after ORC (mean estimated score, 7.5 [95% CI, 7.2-7.8]). Hand grip strength recovered by 3 months after RARC (mean estimated HGS, 29.0 [95% CI, 26.3-31.7] kg) vs 6 months after ORC (mean estimated HGS, 31.2 [95% CI, 28.8-34.2] kg). In the RARC group, 32 of 90 patients (35.6%) showed a recovery in HGS at 3 months vs 32 of 88 (36.4%) in the ORC group (P = .91), indicating a rejection of the primary study hypothesis for HGS. Independent ADL and TUGWT recovered in 3 months for both approaches. Hand grip strength showed earlier recovery in patients undergoing continent urinary diversion (mean HGS at 3 months, 31.3 [95% CI, 27.7-34.8] vs 33.9 [95% CI, 30.5-37.3] at baseline; P = .09) than noncontinent urinary diversion (mean HGS at 6 months, 27.4 [95% CI, 24.9-30.0] vs 29.5 [95% CI, 27.2-31.9] kg at baseline; P = .02), with no differences in other parameters. Baseline impairments in any parameter were not associated with 90-day complications or 1-year mortality. Conclusions and Relevance: The results of this secondary analysis suggest that patients require 3 to 6 months to recover baseline levels after radical cystectomy irrespective of surgical approach. These data will be invaluable in patient counseling and preparation. Hand grip strength and ADL tended to recover to baseline earlier after RARC; however, there was no difference in the percentage of patients recovering when compared with ORC. Further study is needed to assess the clinical significance of these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT01157676.
Asunto(s)
Actividades Cotidianas , Cistectomía/métodos , Recuperación de la Función , Procedimientos Quirúrgicos Robotizados/métodos , Neoplasias de la Vejiga Urinaria/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Satisfacción del Paciente , Resultado del Tratamiento , Estados UnidosRESUMEN
We identified urothelial tract biopsy and resection specimens with keratinizing squamous metaplasia (KSM), nonkeratinizing squamous metaplasia (NKSM), and urothelial and squamous carcinomas over a 20-yr period, focusing on cases with neurogenic lower urinary tract dysfunction (NLUTD) and/or those with spatial or temporal variation in sampling. TERT promoter mutations as assessed via allele-specific polymerase chain reaction were surprisingly common in our testing cohort, identified not only in 15 (94%) invasive cancer foci but also in 13 (68%) examples of KSM and seven (70%) examples of NKSM. TERT promoter mutations were present in 23 foci from NLUTD specimens and 11 foci from bladder diverticula, including in foci of KSM, NKSM, and unremarkable urothelium from cases with no clinical association with previous, concurrent, or subsequent cancer. Our demonstration of temporally and spatially persistent TERT promoter mutation in examples of KSM and NKSM in cases of bladder cancer and in morphologically benign cases with neurogenic dysfunction suggests a molecular mechanism by which such pre-neoplastic lesions can potentially progress and develop into overt carcinoma. Given the interest in TERT promoter mutations as a potential biomarker for the development of bladder cancer, these findings possibly explain the association between conditions with chronic urinary bladder injury (such as the natural history of NLUTD) and higher risk of bladder cancer. TERT promoter mutations may represent an early event in bladder cancer tumorogenesis, and our findings expand on the clinical ramifications and predictive value of TERT promoter mutations in this context. PATIENT SUMMARY: Mutations in the TERT gene are the most common genetic changes in bladder cancer. We found that these mutations are also sometimes present in patients with chronic bladder irritation such as neurogenic bladder dysfunction and changes to the lining of the bladder that pathologists would consider "benign." This finding might explain why such conditions are associated with the development of bladder cancer.
RESUMEN
PURPOSE: Our goal was to evaluate long-term safety and durability of response to UGN-101, a mitomycin-containing reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma. MATERIALS AND METHODS: In this open-label, single-arm, multicenter, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology and negative for-cause biopsy) 4-6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS: Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term followup; 23/41 patients (56%) remained in complete response after 12 months (95% CI 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs. CONCLUSIONS: Durability of response to UGN-101 with or without maintenance treatment is clinically meaningful, offering a kidney-sparing therapeutic alternative for patients with low-grade disease.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Carcinoma/tratamiento farmacológico , Mitomicina/administración & dosificación , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Anciano , Antibióticos Antineoplásicos/efectos adversos , Carcinoma/patología , Femenino , Humanos , Hidrogeles , Masculino , Persona de Mediana Edad , Mitomicina/efectos adversos , Clasificación del Tumor , Neoplasias de la Vejiga Urinaria/patología , Urotelio/efectos de los fármacosRESUMEN
OBJECTIVE: To evaluate MUSIC-KIDNEY's adherence to the American Urological Association (AUA) guidelines regarding the initial evaluation of patient's with clinical T1 (cT1) renal masses. METHODS: We reviewed MUSIC-KIDNEY registry data for patients with newly diagnosed cT1 renal masses to assess for adherence with the 2017 AUA guideline statements regarding recommendations to obtain (1) CMP, (2) CBC, (3) UA, (4) abdominal cross-sectional imaging, and (5) chest imaging. An evaluation consisting of all 5 guideline measures was considered "complete compliance." Variation with guideline adherence was assessed by contributing practice, management strategy, and renal mass size. RESULTS: We identified 1808 patients with cT1 renal masses in the MUSIC-KIDNEY registry, of which 30% met the definition of complete compliance. Most patients received care that was compliant with recommendations to obtain laboratory testing with 1448 (80%), 1545 (85%), and 1472 (81%) patients obtaining a CMP, CBC, and UA respectively. Only 862 (48%) patients underwent chest imaging. Significant variation exists in complete guideline compliance for contributing practices, ranging from 0% to 45% as well as for patients which underwent immediate intervention compared with initial observation (37% vs 23%) and patients with cT1b masses compared with cT1a masses (36% vs 28%). CONCLUSION: Complete guideline compliance in the initial evaluation of patients with cT1 renal masses is poor, which is mainly driven by omission of chest imaging. Significant variation in guideline adherence is seen across practices, as well as patients undergoing an intervention vs observation, and cT1a vs cT1b masses. There are ample quality improvement opportunities to increase adherence and decrease variability with guideline recommendations.
Asunto(s)
Adhesión a Directriz/estadística & datos numéricos , Neoplasias Renales/diagnóstico , Neoplasias Renales/patología , Abdomen/diagnóstico por imagen , Anciano , Recuento de Células Sanguíneas/estadística & datos numéricos , Femenino , Humanos , Neoplasias Renales/sangre , Masculino , Michigan , Persona de Mediana Edad , Estadificación de Neoplasias , Guías de Práctica Clínica como Asunto , Mejoramiento de la Calidad , Radiografía Torácica/estadística & datos numéricos , Sistema de Registros , Urinálisis/estadística & datos numéricosRESUMEN
PURPOSE: Utilization of neoadjuvant chemotherapy (NAC) for the management of muscle-invasive bladder cancer remains low. We sought to understand our practice of NAC use in order to design a quality improvement initiative geared towards optimizing medical oncology referral. MATERIALS AND METHODS: We identified 339 patients with ≥cT2 bladder cancer treated with radical cystectomy between 2012-2017 at our institution. We assessed the rate of referral to medical oncology, rate of NAC administration, as well as medical, patient and provider variables associated with NAC use. Bayesian logistic regression modeling identified variables associated with NAC use and chart review provided granular patient-level data. RESULTS: 85% (n=289) of patients were referred to medical oncology and 62.5% (n=212) received NAC. Renal insufficiency, hearing loss, and treating urologist were conclusively associated with lower odds of NAC use. 46 patients were not referred to medical oncology and 50% of these had medical contraindications to cisplatin cited as the reason for no referral. 38 patients met with medical oncology but did not receive NAC. 30 (79%) had comorbidities that impacted this decision with 15 (39%) ineligible based on impaired renal function. CONCLUSIONS: Despite the relatively high rates of medical oncology referral and NAC use in this cohort, there are still opportunities to improve the efficiency of this practice. Quality improvement initiatives could optimize the referral of patients with ≥T2 bladder cancer for consideration of cisplatin-based NAC and establish an important quality metric in the management of these patients.
RESUMEN
OBJECTIVES: To examine length of stay (LOS) and readmission rates for all minimally-invasive partial nephrectomy (MIPN) and MI radical nephrectomy (MIRN) performed for localized renal masses ≤7 cm in size (cT1RM) within 12 Michigan urology practices. Both RN and PN are commonly performed in treating cT1RM. Although technically more complex and associated with higher complication rates, Centers for Medicare & Medicaid Services considers MIPN an outpatient procedure and MIRN is inpatient. METHODS: We collected data for renal surgeries for cT1RM at MUSIC-KIDNEY practices between May 2017-February 2020. Data abstractors recorded clinical, radiographic, pathologic, surgical, and short-term follow-up data into the registry for cT1RM patients. RESULTS: Within MUSIC-KIDNEY, 807 patients underwent MI renal surgery at 12 practices. Median LOS for cT1RM patients after MIPN (nâ¯=â¯531, 66%) was 2 days and after MIRN (nâ¯=â¯276, 34%) was also 2 days. Among patients undergoing laparoscopic or robotic PN, 171 (32%), 230 (43%), and 130 (24%) stayed ≤1, 2, ≥3 days. Among patients undergoing laparoscopic or robotic RN, 81 (29%), 112 (41%), and 83 (30%) stayed ≤1, 2, ≥3 days. No significant difference was observed between MIPN and MIRN on LOS commensurate with outpatient surgery (≤1-day, ORâ¯=â¯0.97, Pâ¯=â¯0.87). CONCLUSIONS: Less than one-third of patients had a LOS ≤1-day and LOS was comparable for MIPN and MIRN. Centers for Medicare & Medicaid Services should be advised that MIPN is a more complex surgery than MIRN, most patients receiving a MIPN will require a ≥2-day hospital stay and it would be more appropriate to classify MIPN an inpatient procedure with MIRN.
Asunto(s)
Hospitalización , Neoplasias Renales/cirugía , Tiempo de Internación/estadística & datos numéricos , Nefrectomía/clasificación , Nefrectomía/métodos , Readmisión del Paciente/estadística & datos numéricos , Mejoramiento de la Calidad , Anciano , Femenino , Humanos , Laparoscopía , Masculino , Michigan , Persona de Mediana Edad , Procedimientos Quirúrgicos RobotizadosRESUMEN
BACKGROUND: In patients with haematuria, a fast, noninvasive test with high sensitivity (SN) and negative predictive value (NPV), which is able to detect or exclude bladder cancer (BC), is needed. A newly developed urine assay, Xpert Bladder Cancer Detection (Xpert), measures five mRNA targets (ABL1, CRH, IGF2, UPK1B, and ANXA10) that are frequently overexpressed in BC. OBJECTIVE: To validate the performance of Xpert in patients with haematuria. DESIGN, SETTING, AND PARTICIPANTS: Voided precystoscopy urine specimens were prospectively collected at 22 sites from patients without prior BC undergoing cystoscopy for haematuria. Xpert, cytology, and UroVysion procedures were performed. Technical validation was performed and specificity (SP) was determined in patients without BC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Test characteristics were calculated based on cystoscopy and histology results, and compared between Xpert, cytology, and UroVysion. RESULTS AND LIMITATIONS: We included 828 patients (mean age 64.5 yr, 467 males, 401 never smoked). Xpert had an SN of 78% (95% confidence interval [CI]: 66-87) overall and 90% (95% CI: 76-96) for high-grade (HG) tumours. The NPV was 98% (95% CI: 97-99) overall. The SP was 84% (95% CI: 81-86). In patients with microhaematuria, only one HG patient was missed (NPV 99%). Xpert had higher SN and NPV than cytology and UroVysion. Cytology had the highest SP (97%). In a separate SP study, Xpert had an SP of 89% in patients with benign prostate hypertrophy and 92% in prostate cancer patients. CONCLUSIONS: Xpert is an easy-to-use, noninvasive test with improved SN and NPV compared with cytology and UroVysion, representing a promising tool for identifying haematuric patients with a low likelihood of BC who might not need to undergo cystoscopy. PATIENT SUMMARY: Xpert is an easy-to-perform urine test with good performance compared with standard urine tests. It should help identify (micro)haematuria patients with a very low likelihood to have bladder cancer.
Asunto(s)
ARN Mensajero/análisis , Urinálisis , Neoplasias de la Vejiga Urinaria , Cistoscopía , Femenino , Hematuria/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Vejiga Urinaria/diagnósticoAsunto(s)
Hernia/fisiopatología , Herniorrafia/efectos adversos , Herniorrafia/instrumentación , Obstrucción Intestinal/cirugía , Intestino Delgado/cirugía , Derivación Urinaria/efectos adversos , Dolor Abdominal , Anciano de 80 o más Años , Carcinoma in Situ/cirugía , Diagnóstico Diferencial , Humanos , Obstrucción Intestinal/complicaciones , Masculino , Radiografía Abdominal , Tomografía Computarizada por Rayos X , Neoplasias de la Vejiga Urinaria/complicaciones , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
OBJECTIVE: To assess the feasibility of a prehabilitation program for cystectomy patients and to determine the effectiveness of the program in improving strength and functional capacity in the peri-operative period. MATERIALS AND METHODS: This phase I/II study accrued patients ≥60 years old from January 2013 to October 2017 with biopsy-proven bladder cancer, Karnofsky performance score ≥70 and a sedentary baseline lifestyle to participate in a 4-week supervised preoperative exercise training program. Primary outcomes were feasibility and safety; secondary outcomes included changes in fitness, patient-reported QOL, peri-operative complications and readmissions. Student's ttests and Wilcoxon signed-rank test were performed. RESULTS: Fifty-four patients enrolled in the program. Successful completion, defined as patients who began the program and adhered to >70% of the sessions, was attained by 41 of 51 patients (80.4%, 90% CI [71%-90%]). There were no adverse events. Fitness and patient-reported QOL improved postintervention, with sustained improvements in general and mental health 90-days postsurgery. The primary limitation is no control group. CONCLUSION: Prehabilitation prior to cystectomy is feasible, safe, and results in improvements in patient strength, endurance and sustained improvements in patient-reported QOL from baseline. Efforts to further evaluate the impact of prehabilitation in this population in an expanded and randomized fashion are warranted.
Asunto(s)
Cistectomía/efectos adversos , Aptitud Física/fisiología , Ejercicio Preoperatorio/fisiología , Calidad de Vida , Neoplasias de la Vejiga Urinaria/cirugía , Anciano , Estudios de Factibilidad , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
OBJECTIVES: Empirically dosed enoxaparin is routinely given in the postoperative period for venous thromboembolism (VTE) prophylaxis after radical cystectomy (RC). Patient-specific factors may alter its pharmacokinetics, and it is unclear whether this leads to levels sufficient for antithrombosis. We sought to evaluate variability of anti-factor Xa levels in a cohort of RC patients receiving perioperative enoxaparin prophylaxis. MATERIAL AND METHODS: Patients undergoing RC at a single institution were placed on a postoperative pathway that included enoxaparin. An anti-factor Xa level was drawn 2 to 4 hours after the third dose. The target range for prophylaxis was 0.3 IU/ml to 0.5 IU/ml. RESULTS: The primary outcome was anti-factor Xa level. Demographics, operative time, hospital course, and 30-days post-operative VTE were compared by anti-factor Xa level group using univariate and multivariable analyses. Between January 2018 and 2019, 107 RC patients remained on pathway and were included in our analysis. Sixty-five (61%) were below target range for VTE prophylaxis. A single VTE event (0.9%) occurred in a subprophylactic individual. The subprophylactic group had a significantly higher body mass index (P < 0.01) than those within target range. CONCLUSIONS: Higher body mass index was associated with subprophylactic enoxaparin dosing after RC. Nearly two-thirds of patients had below target anti-factor Xa levels. This suggests that dosing could be further individualized, but given the low incidence of VTE, implications of dose-adjusted prophylaxis on VTE prevention remain unknown.
Asunto(s)
Anticoagulantes/administración & dosificación , Cistectomía/efectos adversos , Complicaciones Posoperatorias/prevención & control , Neoplasias de la Vejiga Urinaria/terapia , Tromboembolia Venosa/prevención & control , Anciano , Anticoagulantes/farmacocinética , Variación Biológica Poblacional , Índice de Masa Corporal , Quimioterapia Adyuvante/estadística & datos numéricos , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Monitoreo de Drogas/estadística & datos numéricos , Enoxaparina/administración & dosificación , Enoxaparina/farmacocinética , Femenino , Heparina/sangre , Humanos , Incidencia , Masculino , Terapia Neoadyuvante/estadística & datos numéricos , Cuidados Posoperatorios/métodos , Cuidados Posoperatorios/estadística & datos numéricos , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Resultado del Tratamiento , Tromboembolia Venosa/sangre , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiologíaRESUMEN
BACKGROUND: Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel. METHODS: In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5-15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient's renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4-6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128. FINDINGS: Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47-71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1-12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment. INTERPRETATION: Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients. FUNDING: UroGen Pharma.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Carcinoma/tratamiento farmacológico , Portadores de Fármacos , Neoplasias Renales/tratamiento farmacológico , Mitomicina/administración & dosificación , Urotelio/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/efectos adversos , Carcinoma/patología , Composición de Medicamentos , Femenino , Humanos , Hidrogeles , Israel , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Mitomicina/efectos adversos , Clasificación del Tumor , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Urotelio/patologíaRESUMEN
We evaluated the intraobserver variability of physicians aided by a computerized decision-support system for treatment response assessment (CDSS-T) to identify patients who show complete response to neoadjuvant chemotherapy for bladder cancer, and the effects of the intraobserver variability on physicians' assessment accuracy. A CDSS-T tool was developed that uses a combination of deep learning neural network and radiomic features from computed tomography (CT) scans to detect bladder cancers that have fully responded to neoadjuvant treatment. Pre- and postchemotherapy CT scans of 157 bladder cancers from 123 patients were collected. In a multireader, multicase observer study, physician-observers estimated the likelihood of pathologic T0 disease by viewing paired pre/posttreatment CT scans placed side by side on an in-house-developed graphical user interface. Five abdominal radiologists, 4 diagnostic radiology residents, 2 oncologists, and 1 urologist participated as observers. They first provided an estimate without CDSS-T and then with CDSS-T. A subset of cases was evaluated twice to study the intraobserver variability and its effects on observer consistency. The mean areas under the curves for assessment of pathologic T0 disease were 0.85 for CDSS-T alone, 0.76 for physicians without CDSS-T and improved to 0.80 for physicians with CDSS-T (P = .001) in the original evaluation, and 0.78 for physicians without CDSS-T and improved to 0.81 for physicians with CDSS-T (P = .010) in the repeated evaluation. The intraobserver variability was significantly reduced with CDSS-T (P < .0001). The CDSS-T can significantly reduce physicians' variability and improve their accuracy for identifying complete response of muscle-invasive bladder cancer to neoadjuvant chemotherapy.