Characterizing Psychological Resources and Resilience in Patients With Bladder Cancer: Associations With Frailty and Quality of Life.

PURPOSE: Resilience, the ability to maintain or restore baseline function after a stressor, remains unexplored in patients with bladder cancer. Our objective was to demonstrate the feasibility of prospectively characterizing baseline resilience, related psychological resources, and frailty in patients with bladder cancer and evaluate associations with quality-of-life and mental health outcomes over time. MATERIALS AND METHODS: We enrolled patients with bladder cancer (N = 67, September 2020-July 2021) into a prospective, observational, cohort study. At intake, patients completed validated assessments of frailty domains and psychological resources (resilience, psychological capital, self-compassion, and thriving, collectively PsyResources). Validated quality-of-life surveys were completed at 2 weeks, 3 months, and 6 months after treatment selection. Correlation matrices were constructed to quantify correlations between baseline PsyResources and frailty measures (reported with Spearman correlation coefficient [ρ]). Associations between PsyResources and quality-of-life outcomes were evaluated with linear regression. RESULTS: The median age was 71 years (83.6% male), and 77.6% had muscle-invasive bladder cancer (cN+: 21%, M1: 7.6%). Baseline PsyResources were inversely correlated with the Geriatric Depression Scale (ρ = -0.50 to 0.65, P < .0001). Higher baseline PsyResources were associated with improved global symptoms and emotional function and decreased anxiety and depression over time (B: -0.17 to -2.5; P < .05). CONCLUSIONS: We present the first prospective characterization of baseline PsyResources in patients with bladder cancer. We observed positive correlations with improved mental health and quality-of-life outcomes over time. Ongoing work is exploring the relationship between resilience, frailty domains, and their role in functional recovery after treatment. Future work is needed to understand associations between PsyResources and treatment tolerance, recovery trajectories, and oncologic outcomes.

Pathological Effects of Apalutamide in Lower-risk Prostate Cancer: Results From a Phase II Clinical Trial.

PURPOSE: Active surveillance is a safe and effective strategy for men with lower-risk prostate cancer who want to avoid local therapy; however, many patients on active surveillance progress to active treatment (eg, prostatectomy or radiation). We hypothesized that apalutamide would decrease active surveillance attrition rates through downstaging low-grade tumors. MATERIALS AND METHODS: This was an open-label, single-arm, phase II study testing 90 days of oral apalutamide 240 mg daily in men with low- to intermediate-risk prostate cancer on active surveillance. The primary objective was to determine the percentage of patients with a negative biopsy immediately following treatment. Secondary objectives were to assess long-term clinical outcomes, quality of life, safety, and biomarkers of response/resistance. RESULTS: Twenty-three patients enrolled and 22 completed 90 days of apalutamide with post-treatment biopsy. Fifteen (65%) had Grade Group 1 disease, and all others had Grade Group 2 disease. Seven (30%) had favorable- to intermediate-risk disease. Of 22 evaluable patients, 13 (59%) had no residual cancer on post-treatment biopsy. The median time to first positive biopsy was 364 days (95% CI: 91-742 days). The impact of apalutamide on quality of life was minimal and transient. Decipher risk classifier revealed a greater number of negative post-treatment biopsies in those with higher baseline genomic risk score (P = .01). CONCLUSIONS: The negative repeat biopsy rate following 90 days of apalutamide was high in men with prostate cancer followed on active surveillance. Apalutamide was safe, well tolerated, and had minimal impact on quality of life. Randomized studies evaluating the effects of apalutamide in men enrolled on active surveillance are warranted.

Targeting backdoor androgen synthesis through AKR1C3 inhibition: A presurgical hormonal ablative neoadjuvant trial in high-risk localized prostate cancer.

BACKGROUND: Localized prostate cancers (PCs) may resist neoadjuvant androgen receptor (AR)-targeted therapies as a result of persistent intraprostatic androgens arising through upregulation of steroidogenic enzymes. Therefore, we sought to evaluate clinical effects of neoadjuvant indomethacin (Indo), which inhibits the steroidogenic enzyme AKR1C3, in addition to combinatorial anti-androgen blockade, in men with high-risk PC undergoing radical prostatectomy (RP). METHODS: This was an open label, single-site, Phase II neoadjuvant trial in men with high to very-high-risk PC, as defined by NCCN criteria. Patients received 12 weeks of apalutamide (Apa), abiraterone acetate plus prednisone (AAP), degarelix, and Indo followed by RP. Primary objective was to determine the pathologic complete response (pCR) rate. Secondary objectives included minimal residual disease (MRD) rate, defined as residual cancer burden (RCB) ≤ 0.25cm3 (tumor volume multiplied by tumor cellularity) and elucidation of molecular features of resistance. RESULTS: Twenty patients were evaluable for the primary endpoint. Baseline median prostate-specific antigen (PSA) was 10.1 ng/ml, 4 (20%) patients had Gleason grade group (GG) 4 disease and 16 had GG 5 disease. At RP, 1 (5%) patient had pCR and 6 (30%) had MRD. Therapy was well tolerated. Over a median follow-up of 23.8 months, 1 of 7 (14%) men with pathologic response and 6 of 13 (46%) men without pathologic response had a PSA relapse. There was no association between prostate hormone levels or HSD3B1 genotype with pathologic response. CONCLUSIONS: In men with high-risk PC, pCR rates remained low even with combinatorial AR-directed therapy, although rates of MRD were higher. Ongoing follow-up is needed to validate clinical outcomes of men who achieve MRD.

Histotripsy: The Next Generation of High-Intensity Focused Ultrasound for Focal Prostate Cancer Therapy.

This article reviews the most current methods and technological aspects of high-intensity focused ultrasound (HIFU), which is termed histotripsy. The rationale for focal therapy for prostate carcinoma rather than prostatectomy, which is being used extensively throughout Europe and Asia, is presented, and an argument for why HIFU is the modality of choice for primary therapy and recurrent disease is offered. The article presents a review of the technical advances including higher ultrasound beam energy than current thermal HIFU which allows for more accurate tissue targeting, less collateral tissue damage, and faster treatment times. Finally, the article presents a discussion about the advantage of ultrasound guidance for histotripsy in preference to magnetic resonance imaging guidance primarily based on cost, ease of application, and portability.

Does the Diagnosis of Bladder Cancer Lead to Higher Rates of Smoking Cessation? Findings from the Medicare Health Outcomes Survey.

PURPOSE: Smoking is the most common risk factor for bladder cancer and it is associated with adverse clinical outcomes. The bladder cancer diagnosis represents a teachable moment for smoking cessation. We investigated the likelihood of smoking cessation after bladder cancer diagnosis in a population database. MATERIALS AND METHODS: We evaluated the 1998 to 2013 SEER (Surveillance, Epidemiology and End Results)-MHOS (Medicare Health Outcomes Survey) data on all patients diagnosed with incident bladder cancer on whom survey data were available before and after diagnosis. We compared these patients to propensity matched noncancer controls and to a cohort of patients with incident renal cell carcinoma. Differences in smoking cessation were compared between the groups and multivariate logistic regression was performed to assess the likelihood of smoking cessation. RESULTS: We propensity matched 394 patients with newly diagnosed bladder cancer to 1,970 noncancer controls and compared them with 169 patients with incident renal cell carcinoma. Baseline smoking prevalence was more common in patients diagnosed with bladder cancer compared to renal cell carcinoma (16% vs 11%) but the difference was not significant. The smoking cessation rate in patients with bladder cancer was 27% compared with 21% in noncancer controls and 26% in patients with renal cell carcinoma (p = 0.30 and 0.90, respectively). There was no significant difference in the adjusted OR of quitting smoking in patients with bladder cancer vs those with renal cell carcinoma compared to noncancer controls (OR 1.3, 95% CI 0.7-2.5 vs OR 1.2, 95% CI 0.4-3.6). Independent predictors of smoking cessation in patients with bladder cancer included age (p = 0.03), African American race (p = 0.03) and college education (p = 0.01). CONCLUSIONS: Compared to propensity matched noncancer controls smoking cessation did not significantly differ after a diagnosis of bladder cancer. The proportion of individuals who quit was low overall, suggesting that improved efforts are needed to use this teachable moment in patients with bladder cancer.

Chemotherapy regimen is associated with venous thromboembolism risk in patients with urothelial tract cancer.

OBJECTIVE: To assess the association of venous thromboembolism (VTE) with different chemotherapy regimens in patients with urothelial tract cancer. PATIENTS AND METHODS: We identified patients aged ≥66 years, diagnosed with urothelial tract cancer in the period 1998 to 2011 in the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database. The chemotherapy regimens analysed were gemcitabine/cisplatin (GC), methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), or gemcitabine/carboplatin (CarboG). Propensity scores for treatment regimen based on comorbidities, tumour characteristics, age, and year of diagnosis were calculated. VTE rates within 120 days of chemotherapy initiation were calculated. VTE risk stratified by chemotherapy regimen was modelled using multivariable logistic regression, adjusting for treatment propensity scores and additional demographic characteristics. Overall survival stratified by VTE and chemotherapy regimen was estimated using Kaplan-Meier methods and the log-rank test. RESULTS: Of 5594 identified patients, a VTE occurred in 13.0%. The VTE rates within 120 days of chemotherapy initiation were 15.3% for GC, 8.7% for MVAC, and 12.0% for CarboG. On multivariable analysis, MVAC (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.39-0.94) and CarboG (OR 0.71, 95% CI: 0.59-0.85) were associated with lower VTE risk compared with GC. VTE was associated with worse overall survival (P < 0.001). CONCLUSIONS: Compared with GC, MVAC and CarboG were associated with a lower rate of VTE. This finding suggests that gemcitabine may add to the increased thrombosis risk from cisplatin. Additionally, patients with a VTE had worse survival outcomes than those without a VTE. Analysis of the risk of blood clots with different chemotherapy regimens in patients with urothelial tract cancer showed that GC was associated with the highest rate. We also found that blood clots were associated with worse patient outcomes.

Health Related Quality of Life Following Radical Cystectomy: Comparative Analysis from the Medicare Health Outcomes Survey.

PURPOSE: Health related quality of life after radical cystectomy and ileal conduit is not well quantified at the population level. We evaluated health related quality of life in patients with bladder cancer compared with noncancer controls and patients with colorectal cancer using data from SEER (Surveillance, Epidemiology and End Results)-MHOS (Medicare Health Outcomes Survey). MATERIALS AND METHODS: SEER-MHOS data from 1998 to 2013 were used to identify patients with bladder cancer and those with colorectal cancer who underwent extirpative surgery with ileal conduit or colostomy creation, respectively. A total of 166 patients with bladder cancer treated with radical cystectomy were propensity matched 1:5 to 830 noncancer controls and compared with 154 patients with colorectal cancer. Differences in Mental and Physical Component Summary scores as well as component subscores were determined between patients with bladder cancer, patients with colorectal cancer and noncancer controls. RESULTS: SEER-MHOS patients were more commonly male and white with a mean ± SD age of 77 ± 6 years. Patients treated with radical cystectomy had significantly lower Physical Component Summary scores, select physical subscale scores and all mental subscale scores compared with noncancer controls. These findings were similar in the subset of 40 patients treated with radical cystectomy who had available preoperative and postoperative survey data. Global Mental Component Summary scores did not differ significantly between the groups. No significant differences were observed in global Mental Component Summary, Physical Component Summary or subscale scores between patients with bladder cancer and patients with colorectal cancer. CONCLUSIONS: Patients with bladder cancer who undergo radical cystectomy have significant declines in multiple components of physical and mental health related quality of life vs noncancer controls, which mirror those of patients with colorectal cancer. Further longitudinal study is required to better codify the effectors of poor health related quality of life after radical cystectomy to improve patient expectations and outcomes.

Release of Cell-free MicroRNA Tumor Biomarkers into the Blood Circulation with Pulsed Focused Ultrasound: A Noninvasive, Anatomically Localized, Molecular Liquid Biopsy.

Purpose To compare the abilities of three pulsed focused ultrasound regimes (that cause tissue liquefaction, permeabilization, or mild heating) to release tumor-derived microRNA into the circulation in vivo and to evaluate release dynamics. Materials and Methods All rat experiments were approved by the University of Washington Institutional Animal Care and Use Committee. Reverse-transcription quantitative polymerase chain reaction array profiling was used to identify candidate microRNA biomarkers in a rat solid tumor cell line. Rats subcutaneously grafted with these cells were randomly assigned among three pulsed focused ultrasound treatment groups: (a) local tissue liquefaction via boiling histotripsy, (b) tissue permeabilization via inertial cavitation, and (c) mild (<10°C) heating of tissue, as well as a sham-treated control group. Blood specimens were drawn immediately prior to treatment and serially over 24 hours afterward. Plasma microRNA was quantified with reverse-transcription quantitative polymerase chain reaction, and statistical significance was determined with one-way analysis of variance (Kruskal-Wallis and Friedman tests), followed by the Dunn multiple-comparisons test. Results After tissue liquefaction and cavitation treatments (but not mild heating), plasma quantities of candidate biomarkers increased significantly (P value range, <.0001 to .04) relative to sham-treated controls. A threefold to 32-fold increase occurred within 15 minutes after initiation of pulsed focused ultrasound tumor treatment, and these increases persisted for 3 hours. Histologic examination confirmed complete liquefaction of the targeted tumor area with boiling histotripsy, in addition to areas of petechial hemorrhage and tissue disruption by means of cavitation-based treatment. Conclusion Mechanical tumor tissue disruption with pulsed focused ultrasound-induced bubble activity significantly increases the plasma abundance of tumor-derived microRNA rapidly after treatment. © RSNA, 2016 Online supplemental material is available for this article.

Prostate Cancer Expression Profiles of Cytoplasmic ERß1 and Nuclear ERß2 are Associated with Poor Outcomes following Radical Prostatectomy.

PURPOSE: Existing data regarding the expression of estrogen receptors (ERs) and prostate cancer outcomes have been limited. We evaluated the relationship of expression profiles of ERß subtypes and the ER GPR30 (G-protein-coupled receptor-30) with patient factors at diagnosis and outcomes following radical prostatectomy. MATERIALS AND METHODS: Tissue microarrays constructed using samples from 566 men with long-term clinical followup were analyzed by immunohistochemistry targeting ERß1, ERß2, ERß5 and GPR30. An experienced pathologist scored receptor distribution and staining intensity. Tumor staining characteristics were evaluated for associations with patient characteristics, recurrence-free survival and prostate cancer specific mortality following radical prostatectomy. RESULTS: Prostate cancer cells had unique receptor subtype staining patterns. ERß1 demonstrated predominantly nuclear localization while ERß2, ERß5 and GPR30 were predominantly cytoplasmic. After controlling for patient factors intense cytoplasmic ERß1 staining was independently associated with time to recurrence (HR 1.7, 95% CI 1.1-2.6, p = 0.01) and prostate cancer specific mortality (HR 6.6, 95% CI 1.8-24.9, p = 0.01). Intense nuclear ERß2 staining was similarly independently associated with prostate cancer specific mortality (HR 3.9, 95% CI 1.1-13.4, p = 0.03). Patients with cytoplasmic ERß1 and nuclear ERß2 co-staining had significantly worse 15-year prostate cancer specific mortality than patients with expression of only cytoplasmic ERß1, only nuclear ERß2 and neither ER (16.4%, 4.3%, 0.0% and 2.0 %, respectively, p = 0.001). CONCLUSIONS: Increased cytoplasmic ERß1 and nuclear ERß2 expression is associated with worse cancer specific outcomes following radical prostatectomy. These findings suggest that tumor ERß1 and ERß2 staining patterns provide prognostic information on patients treated with radical prostatectomy.

Histotripsy methods in mechanical disintegration of tissue: towards clinical applications.

In high intensity focused ultrasound (HIFU) therapy, an ultrasound beam is focused within the body to locally affect the targeted site without damaging intervening tissues. The most common HIFU regime is thermal ablation. Recently there has been increasing interest in generating purely mechanical lesions in tissue (histotripsy). This paper provides an overview of several studies on the development of histotripsy methods toward clinical applications. Two histotripsy approaches and examples of their applications are presented. In one approach, sequences of high-amplitude, short (microsecond-long), focused ultrasound pulses periodically produce dense, energetic bubble clouds that mechanically disintegrate tissue. In an alternative approach, longer (millisecond-long) pulses with shock fronts generate boiling bubbles and the interaction of shock fronts with the resulting vapour cavity causes tissue disintegration. Recent preclinical studies on histotripsy are reviewed for treating benign prostatic hyperplasia (BPH), liver and kidney tumours, kidney stone fragmentation, enhancing anti-tumour immune response, and tissue decellularisation for regenerative medicine applications. Potential clinical advantages of the histotripsy methods are discussed. Histotripsy methods can be used to mechanically ablate a wide variety of tissues, whilst selectivity sparing structures such as large vessels. Both ultrasound and MR imaging can be used for targeting and monitoring the treatment in real time. Although the two approaches utilise different mechanisms for tissue disintegration, both have many of the same advantages and offer a promising alternative method of non-invasive surgery.

Prostate histotripsy: evaluation of prostatic urethral treatment parameters in a canine model.

OBJECTIVE: To assess the impact of histotripsy treatment parameters (pulse number and pulse-repetition frequency [PRF]) on the efficiency of histotripsy induced homogenisation of the prostatic urethra. MATERIALS AND METHODS: In all, 34 transabdominal prostate histotripsy treatments were applied along a perpendicular plane traversing the prostatic urethra of 21 dogs. Prostate histotripsy was applied with (i) escalating pulse number with fixed PRF or (ii) at fixed pulse number with varying PRFs. The development of urethral homognisation ≤14 days of histotripsy was evaluated endoscopically and confirmed histologically. RESULTS: Within 14 days of histotripsy 50%, 83%, 83%, and 100% of dogs receiving 12 500, 25 000, 50 000, and 100 000 pulses/mm of treatment path (delivered at 500 Hz PRF), respectively developed prostatic urethral disintegration. Delivery of 100 000 pulses/mm was required to achieve urethral disintegration in all dogs within 24 h of histotripsy treatment. Increasing histotripsy PRF from 50 to 500 to 2000 Hz while applying a constant dose of 25 000 pulses/mm treatment was associated with increased rate of urethral disintegration (50% vs 75% vs 100% at 14 days, respectively). CONCLUSIONS: Increasing the number of histotripsy pulses and/or increasing the PRF of histotripsy treatment applied to the urethra may improve the rate and efficiency of prostatic urethral disintegration in the canine model. This understanding will aid in the development of treatment strategies for prostate histotripsy for benign prostatic hyperplasia in human trials.

Validation of Urostomy Parastomal Herniation Incisional Prevention Strategies.

OBJECTIVE: To evaluate simulated parastomal herniation forces in in vitro abdominal fascial models. Our group previously illustrated how incision type may play a consequential role in bowel herniation force generated across an incision using several abdominal fascia models. We sought to (1) Confirm findings in fresh human tissue, (2) Assess correlation between herniation force and incision size, and (3) Determine whether incision type impacts drainage in a simulated ex vivo ileal conduit. MATERIALS AND METHODS: Axial tension force (N) of herniation was measured using our previously published protocol, pulling a Foley catheter balloon 3.8 cm diameter affixed to a dynamometer through silicone/fascial incisions ranging 3-5.8 cm. We simulated ileal conduits using bovine small intestine with stoma matured through human fascia using 3.0 cm linear or cruciate incisions. The conduit's caudal end was catheterized and filled at 20 mL/min. Drainage was measured by pad weight change. Two-sided α < 0.05 was used to reject the null hypothesis. RESULTS: Mean (±SD) herniation forces in fresh human fascia varied significantly across linear longitudinal, linear transverse, and cruciate incisions (20.9 ± 3.7, 23.3 ± 8.8, and 8.9 ± 3.8 N, respectively [P = .011]). Fresh human fascial linear incisions 3 cm in diameter had a herniation force of 22.1 ± 6.3 vs 3.5 ± 0.7 N for 5.8 cm incisions when herniating a 3.8 cm balloon (P = .002). All observations were similar in silicone. In simulated ileal conduit, mean drainage: 70.8 ± 3.6 vs 82.1 ± 9.7 mL (linear vs cruciate) after 100 mL instilled, respectively (P = .05). CONCLUSION: This ex vivo study further suggests incision type has predictable influence on herniation force. These data support standardization of urostomy construction techniques and evaluating the clinical impact of stomal maturation techniques on parastomal hernia rates.

Chronic Glucocorticoid Use and Risk for Advanced Prostate Cancer at Presentation: A SEER-Medicare Cohort Study.

BACKGROUND: Examine the relationship between exposure to systemic glucocorticoids (steroids) and advanced prostate cancer (PCa) at presentation. Prior work suggested that steroid use may be associated with increased PCa risk. MATERIALS AND METHODS: We queried the linked SEER-Medicare database (2004-2015) to identify PSA screened patients diagnosed with PCa. Criteria for screening included a PSA lab test or DRE exam in both the 12 month and 13 to 36 month periods prior to diagnosis of PCa. Steroid exposure was determined using Medicare Part D and groups were divided based on duration of use in the 3 years prior to diagnosis: controls with no exposure, <30 days, 30 days - 1 year, 1 to 2 years, and >2+ years. Advanced PCa was defined as systemic metastases or regional lymph node metastasis at presentation. Risk estimates for advanced PCa at presentation for steroid exposure groups vs. controls were assessed with univariable and multivariable logistic regression models. RESULTS: We identified 22,920 PSA screened patients diagnosed with PCa of which 29% used glucocorticoids in the exposure period. The mean (SD) duration for glucocorticoid use (in days) among all steroid users was 76.7 days (192.1). On univariable and multivariable analyses, > 2 years of steroid exposure was associated with significantly increased risk for advanced PCa (OR 2.06, 95% CI 1.35-3.14 and OR 1.74, 95% CI 1.12-2.69, respectively). CONCLUSION: In this population-based PSA-screened cohort, prolonged steroid use was associated with increased risk of advanced PCa at diagnosis. With the widespread use of glucocorticoids, it is important to consider the role steroids may play in PCa pathogenesis.

Treatment Planning and Aberration Correction Algorithm for HIFU Ablation of Renal Tumors.

High-intensity focused ultrasound (HIFU) applications for thermal or mechanical ablation of renal tumors often encounter challenges due to significant beam aberration and refraction caused by oblique beam incidence, inhomogeneous tissue layers, and presence of gas and bones within the beam. These losses can be significantly mitigated through sonication geometry planning, patient positioning, and aberration correction using multielement phased arrays. Here, a sonication planning algorithm is introduced, which uses the simulations to select the optimal transducer position and evaluate the effect of aberrations and acoustic field quality at the target region after aberration correction. Optimization of transducer positioning is implemented using a graphical user interface (GUI) to visualize a segmented 3-D computed tomography (CT)-based acoustic model of the body and to select sonication geometry through a combination of manual and automated approaches. An HIFU array (1.5 MHz, 256 elements) and three renal cell carcinoma (RCC) cases with different tumor locations and patient body habitus were considered. After array positioning, the correction of aberrations was performed using a combination of backpropagation from the focus with an ordinary least squares (OLS) optimization of phases at the array elements. The forward propagation was simulated using a combination of the Rayleigh integral and k-space pseudospectral method (k-Wave toolbox). After correction, simulated HIFU fields showed tight focusing and up to threefold higher maximum pressure within the target region. The addition of OLS optimization to the aberration correction method yielded up to 30% higher maximum pressure compared to the conventional backpropagation and up to 250% higher maximum pressure compared to the ray-tracing method, particularly in strongly distorted cases.

A comparative study of histotripsy parameters for the treatment of fibrotic ex-vivo human benign prostatic hyperplasia tissue.

Histotripsy is a noninvasive focused ultrasound therapy that mechanically fractionates tissue to create well-defined lesions. In a previous clinical pilot trial to treat benign prostatic hyperplasia (BPH), histotripsy did not result in consistent objective improvements in symptoms, potentially because of the fibrotic and mechanically tough nature of this tissue. In this study, we aimed to identify the dosage required to homogenize BPH tissue by different histotripsy modalities, including boiling histotripsy (BH) and cavitation histotripsy (CH). A method for histotripsy lesion quantification via entropy (HLQE) analysis was developed and utilized to quantify lesion area of the respective treatments. These data were correlated to changes in mechanical stiffness measured by ultrasound shear-wave elastography before and after treatment with each parameter set and dose. Time points corresponding to histologically observed complete lesions were qualitatively evaluated and quantitatively measured. For the BH treatment, complete lesions occurred with > = 30 s treatment time, with a corresponding maximum reduction in stiffness of -90.9 ± 7.2(s.d.)%. High pulse repetition frequency (PRF) CH achieved a similar reduction to that of BH at 288 s (-91.6 ± 6.0(s.d.)%), and low-PRF CH achieved a (-82.1 ± 5.1(s.d.)%) reduction in stiffness at dose > = 144 s. Receiver operating characteristic curve analysis showed that a > ~ 75% reduction in stiffness positively correlated with complete lesions observed histologically, and can provide an alternative metric to track treatment progression.

Advancing Boiling Histotripsy Dose in Ex Vivo And In Vivo Renal Tissues Via Quantitative Histological Analysis and Shear Wave Elastography.

OBJECTIVE: In the context of developing boiling histotripsy (BH) as a potential clinical approach for non-invasive mechanical ablation of kidney tumors, the concept of BH dose (BHD) was quantitatively investigated in porcine and canine kidney models in vivo and ex vivo. METHODS: Volumetric lesions were produced in renal tissue using a 1.5-MHz 256-element HIFU-array with various pulsing protocols: pulse duration tp = 1-10 ms, number of pulses per point ppp = 1-15. Two BHD metrics were evaluated: BHD1 = ppp, BHD2 = tp × ppp. Quantitative assessment of lesion completeness was performed by their histological analysis and assignment of damage score to different renal compartments (i.e., cortex, medulla, and sinus). Shear wave elastography (SWE) was used to measure the Young's modulus of renal compartments in vivo vs ex vivo, and before vs after BH treatments. RESULTS: In vivo tissue required lower BH doses to achieve identical degree of fractionation as compared to ex vivo. Renal cortex (homogeneous, low in collagen) was equal or higher in stiffness than medulla (anisotropic, collagenous), 5.8-12.2 kPa vs 4.7-9.6 kPa, but required lower BH doses to be fully fractionated. Renal sinus (fatty, irregular, with abundant collagenous structures) was significantly softer ex vivo vs in vivo, 4.9-5.1 kPa vs 9.7-15.2 kPa, but was barely damaged in either case with any tested BH protocols. BHD1 was shown to be relevant for planning the treatment of renal cortex (sufficient BHD1 = 5 pulses in vivo and 10 pulses ex vivo), while none of the tested doses resulted in complete fractionation of medulla or sinus. Post-treatment SWE imaging revealed reduction of tissue stiffness ex vivo by 27-58%, increasing with the applied dose, and complete absence of shear waves within in vivo lesions, both indicative of tissue liquefaction. CONCLUSION: The results imply that tissue resistance to mechanical fractionation, and hence required BH dose, are not solely determined by tissue stiffness but also depend on its composition and structural arrangement, as well as presence of perfusion. The SWE-derived reduction of tissue stiffness with increasing BH doses correlated with tissue damage score, indicating potential of SWE for post-treatment confirmation of BH lesion completeness.

A Comparative Study of Histotripsy Parameters for the Treatment of Fibrotic ex-vivo Human Benign Prostatic Hyperplasia Tissue.

Histotripsy is a noninvasive focused ultrasound therapy that mechanically fractionates tissue to create well-defined lesions. In a previous clinical pilot trial to treat benign prostatic hyperplasia (BPH), histotripsy did not result in consistent objective improvements in symptoms, potentially because of the fibrotic and mechanically tough nature of this tissue. In this study, we aimed to identify the dosage required to homogenize BPH tissue by different histotripsy modalities, including boiling histotripsy (BH) and cavitation histotripsy (CH). A method for histotripsy lesion quantification via entropy (HLQE) analysis was developed and utilized to quantify lesion area of the respective treatments. These data were correlated to changes in mechanical stiffness measured by ultrasound shear-wave elastography before and after treatment with each parameter set and dose. Time points corresponding to histologically observed complete lesions were qualitatively evaluated and quantitatively measured. For the BH treatment, complete lesions occurred with >=30s treatment time, with a corresponding maximum reduction in stiffness of -90.9±7.2(s.d.)%. High pulse repetition frequency (PRF) CH achieved a similar reduction to that of BH at 288s (-91.6±6.0(s.d.)%), and low-PRF CH achieved a (-82.1±5.1(s.d.)%) reduction in stiffness at dose >=144s. Receiver operating characteristic curve analysis showed that a >~75% reduction in stiffness positively correlated with complete lesions observed histologically, and can provide an alternative metric to track treatment progression.

Adjuvant Chemotherapy and Survival After Radical Cystectomy in Histologic Subtype Bladder Cancer.

OBJECTIVES: Patients with histologic subtype bladder cancer (HSBC) suffer worse outcomes than those with conventional urothelial carcinoma (UC). We sought to characterize the use of adjuvant chemotherapy (AC) in HSBC after radical cystectomy (RC) using the National Cancer Database (NCDB). MATERIALS AND METHODS: We retrospectively queried the NCDB (2006-2019) for patients with non-metastatic bladder cancer (BC) who underwent RC (N = 45,797). Patients were stratified by histologic subtype and receipt of AC. Multivariable logistic regression determined associations of demographic and clinicopathologic features with receipt of AC. Multivariable Cox regression evaluated associations between receipt of any AC and overall survival (OS). RESULTS: We identified 4,469 patients with HSBC classified as squamous, adenocarcinoma, small cell, sarcomatoid, micropapillary, or plasmacytoid. Squamous comprised 31% of the HSBC cohort, followed by small cells and micropapillary. Black patients were presented with a higher prevalence of adenocarcinoma (119/322, 37.0%). Use of AC was highest in plasmacytoid and small cell (30% each) and lowest in squamous (11%). Neuroendocrine histology was independently associated with greater odds of receiving AC (HR 1.6, 95% CI 1.37-1.87), while squamous cell histology was associated with lower odds (HR 0.61, 95% CI 0.53-0.71). On multivariable Cox regression analysis, treatment with AC was associated with significantly longer OS (HR 0.69, 95% CI 0.59-0.81) and for squamous, sarcomatoid, and micropapillary cohorts after stratified by subtype. CONCLUSIONS: AC was variably used among patients with HSBC and was associated with OS benefit in such patients.