Detection of bladder cancer cells using quantitative interferometric label-free imaging flow cytometry.

Bladder cancer is one of the most common cancers with a high recurrence rate. Patients undergo mandatory yearly scrutinies, including cystoscopies, which makes bladder cancer highly distressing and costly. Here, we aim to develop a non-invasive, label-free method for the detection of bladder cancer cells in urine samples, which is based on interferometric imaging flow cytometry. Eight urothelial carcinoma and one normal urothelial cell lines, along with red and white blood cells, imaged quantitatively without staining by an interferometric phase microscopy module while flowing in a microfluidic chip, and classified by two machine-learning algorithms, based on deep-learning semantic segmentation convolutional neural network and extreme gradient boosting. Furthermore, urine samples obtained from bladder-cancer patients and healthy volunteers were imaged, and classified by the system. We achieved accuracy and area under the curve (AUC) of 99% and 97% for the cell lines on both machine-learning algorithms. For the real urine samples, the accuracy and AUC were 96% and 96% for the deep-learning algorithm and 95% and 93% for the gradient-boosting algorithm, respectively. By combining label-free interferometric imaging flow cytometry with high-end classification algorithms, we achieved high-performance differentiation between healthy and malignant cells. The proposed technique has the potential to supplant cystoscopy in the bladder cancer surveillance and diagnosis space.

Holographic virtual staining of individual biological cells.

Many medical and biological protocols for analyzing individual biological cells involve morphological evaluation based on cell staining, designed to enhance imaging contrast and enable clinicians and biologists to differentiate between various cell organelles. However, cell staining is not always allowed in certain medical procedures. In other cases, staining may be time-consuming or expensive to implement. Staining protocols may be operator-sensitive, and hence may lead to varying analytical results, as well as cause artificial imaging artifacts or false heterogeneity. We present a deep-learning approach, called HoloStain, which converts images of isolated biological cells acquired without staining by holographic microscopy to their virtually stained images. We demonstrate this approach for human sperm cells, as there is a well-established protocol and global standardization for characterizing the morphology of stained human sperm cells for fertility evaluation, but, on the other hand, staining might be cytotoxic and thus is not allowed during human in vitro fertilization (IVF). After a training process, the deep neural network can take images of unseen sperm cells retrieved from holograms acquired without staining and convert them to their stainlike images. We obtained a fivefold recall improvement in the analysis results, demonstrating the advantage of using virtual staining for sperm cell analysis. With the introduction of simple holographic imaging methods in clinical settings, the proposed method has a great potential to become a common practice in human IVF procedures, as well as to significantly simplify and radically change other cell analyses and techniques such as imaging flow cytometry.

Quality of life with tandem ureteral stents compared to percutaneous nephrostomy for malignant ureteral obstruction.

PURPOSE: Malignant ureteral obstruction (MUO) is treated with kidney decompression by a percutaneous nephrostomy (PCN) or internal ureteral stents. The objective of this study was to compare quality of life (QoL) with a PCN compared to tandem ureteral stents (TUS) in cases of MUO. METHODS: We reviewed the medical records of patients with MUO who were treated by PCN/TUS in our institution between June 2019 and May 2020. Patients were asked to fill out a QoL questionnaire, a tube-symptoms questionnaire, report a general health scale, and asked for a drain preference if they had experience with both drains. Scores of both groups were compared and predictors of all QoL and tube-symptoms measures were searched using multivariate analysis. RESULTS: Seventy-four patients with a PCN and 30 with TUS were included in the study. No statistically significant difference was found in all QoL and tube-symptoms measurements between the two drains. Type of drain was not found to be a predictor of QoL or tube-related symptoms. Eighty-four percent of patients (11/13) who have experience with both types of drains preferred TUS. CONCLUSION: TUS and PCN for relief of MUO have a negative and similar effect on various areas of QoL and urinary symptoms. Most patients who had experience with both types of drains preferred TUS over PCN. In this patient population with a grim prognosis, this negative effect must be communicated to patients, and calculated against the potential benefits of drainage.

Fascial dehiscence after radical cystectomy: Is abdominal exploration mandatory?

BACKGROUND: Fascial dehiscence after radical cystectomy may have serious clinical implications. To optimize its management, we sought to describe accompanying intraabdominal findings of post-cystectomy dehiscence repair and determine whether a thorough intraabdominal exploration during its operation is mandatory. METHODS: We retrospectively reviewed a multi-institutional cohort of patients who underwent open radical cystectomy between 2005 and 2020. Patients who underwent exploratory surgery due to fascial dehiscence within 30 days post-cystectomy were included in the analysis. Data collected included demographic characteristics, the clinical presentation of dehiscence, associated laboratory findings, imaging results, surgical parameters, operative findings, and clinical implications. Potential predictors of accompanying intraabdominal complications were investigated. RESULTS: Of 1301 consecutive patients that underwent cystectomy, 27 (2%) had dehiscence repair during a median of 7 days post-surgery. Seven patients (26%) had accompanying intraabdominal pathologies, including urine leaks, a fecal leak, and an internal hernia in 5 (19%), 1 (4%), and 1 (4%) patients, respectively. Accompanying intraabdominal findings were associated with longer hospital stay [20 (IQR 17, 23) vs. 41 (IQR 29, 47) days, P = 0.03] and later dehiscence identification (postoperative day 7 [IQR 5, 9] vs. 10 [IQR 6, 15], P = 0.03). However, the rate of post-exploration complications was similar in both groups. A history of ischemic heart disease was the only predictor for accompanying intraabdominal pathologies (67% vs. 24%; P = 0.02). CONCLUSIONS: A substantial proportion of patients undergoing post-cystectomy fascial dehiscence repair may have unrecognized accompanying surgical complications without prior clinical suspicion. While cardiovascular disease is a risk factor for accompanying findings, meticulous abdominal inspection is imperative in all patients during dehiscence repair. Identification and repair during the surgical intervention may prevent further adverse, possibly life-threatening consequences with minimal risk for iatrogenic injury.

External Validation of Contact Surface Area as a Predictor of Postoperative Renal Function in Patients Undergoing Partial Nephrectomy.

PURPOSE: We sought to externally validate a mathematical formula for tumor contact surface area as a predictor of postoperative renal function in patients undergoing partial nephrectomy for renal cell carcinoma. MATERIALS AND METHODS: We queried a prospectively maintained kidney cancer database for patients who underwent partial nephrectomy between 2014 and 2016. Contact surface area was calculated using data obtained from preoperative cross-sectional imaging. The correlation between contact surface area and perioperative variables was examined. The correlation between postoperative renal functional outcomes, contact surface area and the R.E.N.A.L. (radius, exophytic/endophytic properties, nearness of tumor to collecting system or sinus, anterior/posterior, location relative to polar lines and tumor touches main renal artery or vein) nephrometry score was also assessed. RESULTS: A total of 257 patients who underwent partial nephrectomy had sufficient data to enter the study. Median contact surface area was 14.5 cm2 (IQR 6.2-36) and the median nephrometry score was 9 (IQR 7-10). Spearman correlation analysis showed that contact surface area correlated with estimated blood loss (rs = 0.42, p <0.001), length of stay (rs = 0.18, p = 0.005), and percent and absolute change in the estimated glomerular filtration rate (rs = -0.77 and -0.78, respectively, each p <0.001). On multivariable analysis contact surface area and nephrometry score were independent predictors of the absolute change in the estimated glomerular filtration rate (each p <0.001). ROC curve analysis revealed that contact surface area was a better predictor of a greater than 20% postoperative decline in the estimated glomerular filtration rate compared with the nephrometry score (AUC 0.94 vs 0.80). CONCLUSIONS: Contact surface area correlated with the change in postoperative renal function after partial nephrectomy. It can be used in conjunction with the nephrometry score to counsel patients about the risk of renal functional decline after partial nephrectomy.

Update on Renal Mass Biopsy.

Renal masses are diagnosed with an increasing frequency. However, a significant proportion of these masses are benign, and the majority of malignant tumors are biologically indolent. Furthermore, renal tumors are often harbored by the elderly and comorbid patients. As such, matching of renal tumor biology to appropriate treatment intensity is an urgent clinical need. Renal mass biopsy is currently a very useful clinical tool that can assist with critical clinical decision-making in patients with renal mass. Yet, renal mass biopsy is associated with limitations and, as such, may not be appropriate for all patients.

Dysfunctional voiding in adults.

Dysfunctional voiding is characterized by an intermittent and/or fluctuating flow rate due to involuntary intermittent contractions of the periurethral striated or levator muscles during voiding in neurologically normal women (International Continence Society definition). Due to the variable etiology, the diagnosis and treatment of DV is problematic. Frequently, the diagnosis is done at a late stage mainly due to non-specific symptoms and lack of awareness. The objectives of treatment are to normalize micturition patterns and prevent complications such as renal failure and recurrent infections. Treatment should be started as early as possible and a multidisciplinary approach is beneficial.

Strategies of Endoscopic Management of Upper Tract Urothelial Carcinoma among Endourologists: A Global Survey.

Up-to-date guidelines on the management of upper tract urothelial carcinoma (UTUC) are continuously published. We aim to assess the variability of diagnosis and treatment strategies in the endoscopic management of UTUC and adherence to European Association of Urology and National Comprehensive Cancer Network guidelines. A 15-question survey was designed to query practitioners on approaches to clinical practice and knowledge about endoscopic treatment indications and techniques. It was emailed to all members of the Endourologic Society through the society's office, and to all Israeli non-member endourologists. Eighty-eight urologists participated in the survey. Adherence to guidelines on indications for endoscopic management was only 51%. Most of the survey respondents (87.5%) use holmium laser for tumor ablation, and ~50% use forceps for biopsy while the other half use baskets. Only 50% stated that they would use Jelmyto® for specific indications. Most (80%) indicated that they repeat the ureteroscopy 3 months after the first one, and 52.3% continue with follow-up ureteroscopy every 3 months during the first year after diagnosis. There is vast variability among endourologists in the technical aspects of UTUC, the indications for endoscopic management, and adherence to the available guidelines for managing UTUC.

The role of malnutrition universal screening tool in predicting outcomes after radical cystectomy.

PURPOSE: The Malnutrition Universal Screening Tool integrates body mass index, unintentional weight loss and present illness to assess risk for malnutrition. The predictive role of 'MUST' among patients undergoing radical cystectomy is unknown. We investigated the role of 'MUST' in predicting postoperative outcomes and prognosis among patients after RC. MATERIALS AND METHODS: We conducted a multicenter retrospective analysis of 291 patients who underwent radical cystectomy in 6 medical centers between 2015 and 2019. Patients were stratified to risk groups according to the 'MUST' score [low risk (n = 242) vs. medium-to-high risk (n = 49)]. Baseline characteristics were compared between groups. Endpoints were 30-day postoperative complications rate, cancer-specific-survival and overall survival. Kaplan-Meier curves and Cox-regression analyses were used to evaluate survival and identify predictors of outcomes. RESULTS: Median age of the study cohort was 69 years (IQR 63-74). Median duration of follow up for survivors was 33 months (IQR 20-43). Thirty-day major postoperative complications rate was 17%. Baseline characteristics were not different between the 'MUST' groups, and there was no difference in early post-operative complication rates. CSS and OS were significantly lower (p ≤ 0.02) in the medium-to-high-risk group ('MUST' score≥1) with estimated 3-year CSS and OS rates of 60% and 50% compared to 76% and 71% in the low-risk group, respectively. On multivariable analysis, 'MUST'≥1 was an independent predictor of overall- (HR = 1.95, p = 0.006) and cancer-specific-mortality (HR = 1.74, p = 0.05). CONCLUSIONS: High 'MUST' scores are associated with decreased survival in patients after radical cystectomy. Thus, the 'MUST' score may serve as a preoperative tool for patient selection and nutritional intervention.

11-item modified frailty index and outcomes after radical cystectomy.

INTRODUCTION: To investigate the association between modified frailty index (mFI) scores and radical cystectomy outcomes. MATERIALS AND METHODS: We conducted a multicenter retrospective analysis of 292 patients who underwent radical cystectomy between 2015 and 2019. The patients were stratified according to mFI scores (mFI 0-1 vs. mFI ≥2). Baseline characteristics were compared between groups. The primary endpoints were cancer-specific survival (CSS) and overall survival (OS), and the secondary endpoint was the 30-day postoperative complication rate. RESULTS: One group included 164 patients with mFI 0-1 and the other included 128 patients with mFI ≥2. The cohort's median age was 69 years, and median follow-up for survivors was 33 months. Thirty-day major postoperative complication rate was 19%. Ninety patients (31%) died during the study period, 70 of them (24%) from bladder cancer. Older age, male sex, lower kidney function, and diversion to an ileal conduit were significantly more common in the mFI ≥2 group. The postoperative complication rates were comparable between groups, but the CSS and OS were significantly lower in the frailer group (p = 0.007 and p = 0.03, respectively). An mFI score ≥ 2 emerged as an independent risk factor for cancer-specific death (hazard ratio [HR] = 1.7, p = 0.03) and overall-mortality (HR = 1.8, p = 0.008). DISCUSSION: High mFI scores are associated with shorter CSS and OS after radical cystectomy. Healthcare providers should be encouraged to calculate frailty preoperatively for judicious patient selection in light of the predicted outcomes.

A machine learning model for predicting surgical intervention in renal colic due to ureteral stone(s) < 5 mm.

A 75-89% expulsion rate is reported for ureteric stones ≤ 5 mm. We explored which parameters predict justified surgical intervention in cases of pain caused by < 5 mm ureteral stones. We retrospectively reviewed all patients with renal colic caused by ureteral stone < 5 mm admitted to our urology department between 2016 and 2021. Data on age, sex, body mass index, the presence of associated hydronephrosis/stranding on images, ureteral side, stone location, medical history, serum blood count, creatinine, C-reactive protein, and vital signs were obtained upon admission. XGboost (XG), a machine learning model has been implemented to predict the need for intervention. A total of 471 patients (median age 49, 83% males) were reviewed. 74% of the stones were located in the distal ureter. 160 (34%) patients who sustained persistent pain underwent surgical intervention. The operated patients had proximal stone location (56% vs. 10%, p < 0.001) larger stones (4 mm vs. 3 mm, p < 0.001), longer length of stay (3.5 vs. 3 days, p < 0.001) and more emergency-room (ER) visits prior to index admission (2 vs. 1, p = 0.007) compared to those who had no surgical intervention. The model accuracy was 0.8. Larger stone size and proximal location were the most important features in predicting the need for intervention. Altogether with pulse and ER visits, they contributed 73% of the final prediction for each patient. Although a high expulsion rate is expected for ureteral stones < 5 mm, some may be painful and drawn out in spontaneous passage. Decision-making for surgical intervention can be facilitated by the use of the present prediction model.

The Effects of Surgical Approaches and Enhanced Recovery Protocols on the Cost Effectiveness of Radical Cystectomy.

Enhanced recovery protocols and robotic approaches to radical cystectomy are known to reduce perioperative complications; however, the most cost-effective strategy is unknown. We aim to assess the cost effectiveness of radical cystectomy with different surgical techniques and perioperative treatment protocols. We performed a meta-analysis of studies comparing open radical cystectomy (ORC), robotic assisted radical cystectomy (RARC) using extracorporeal (ECUD) or intracorporeal urinary diversion (ICUD) and enhanced recovery after surgery (ERAS) protocols. Operative time, transfusion, complication, Ileus, length of stay and re-admission rates were extracted. US costs for surgery, treatment, hospitalization and complications were obtained from the literature. Israeli costs were obtained from hospital administrative data. Two cost effectiveness models (US and Israel) were developed. The two most cost-effective strategies in both models were ORC with ERAS and RARC with ICUD and ERAS. RARC with ERAS produced the two most effective strategies with ICUD being dominant over ECUD. All strategies implementing the ERAS protocol were more effective than their parallel non-ERAS strategies. RARC with ICUD and ERAS is cost effective compared to ORC. ERAS protocol improves treatment effectiveness and lowers overall costs. ICUD was shown to be more effective and less costly in comparison to ECUD.

Classification of tissue biopsies by Raman spectroscopy guided by quantitative phase imaging and its application to bladder cancer.

We present a multimodal label-free optical measurement approach for analyzing sliced tissue biopsies by a unique combination of quantitative phase imaging and localized Raman spectroscopy. First, label-free quantitative phase imaging of the entire unstained tissue slice is performed using automated scanning. Then, pixel-wise segmentation of the tissue layers is performed by a kernelled structural support vector machine based on Haralick texture features, which are extracted from the quantitative phase profile, and used to find the best locations for performing the label-free localized Raman measurements. We use this multimodal label-free measurement approach for segmenting the urothelium in benign and malignant bladder cancer tissues by quantitative phase imaging, followed by location-guided Raman spectroscopy measurements. We then use sparse multinomial logistic regression (SMLR) on the Raman spectroscopy measurements to classify the tissue types, demonstrating that the prior segmentation of the urothelium done by label-free quantitative phase imaging improves the Raman spectra classification accuracy from 85.7% to 94.7%.

Laparoscopic Versus Robot-Assisted Pyeloplasty in Adults-A Single-Center Experience.

Background: Laparoscopic (LP) and robot-assisted pyeloplasty (RAP) are minimally invasive techniques for correcting uretero-pelvic junction obstruction (UPJO). We retrospectively compared the clinical outcomes of all adults who underwent RAP (n = 41) to those who underwent LP (n = 24) for UPJO at our institution between 2003−2022. Methods: Age, sex, body mass index, surgical side, past abdominal/endoscopic surgeries, pre- and postoperative renal scans, pre- and postoperative serum creatinine levels, operative time (OT), presence of crossing vessels, estimated blood loss, postoperative complications, length of hospital stay, time to JJ stent removal, follow-up length, and postoperative hydronephrosis were analyzed. Results: The groups were demographically comparable. The mean total and skin-to-skin OTs (minutes) were significantly longer in the RAP group than in the LP group (242.4 ± 55 vs. 161.4 ± 40 p < 0.001; 163.7 ± 41.8 vs. 124.3 ± 30.3 p = 0.006, respectively). Hospital stay (days) was shorter in the RAP group (3.3 ± 2.1 vs. 7.3 ± 2.5 p < 0.001). Postoperative complication rates were identical for both groups. The LP group had a significantly longer follow-up period (85.2 ± 73 vs. 19 ± 14 months p < 0.001). The success rates for the LP and RAP groups were 87.5% and 90.6% (p = 0.708). Conclusions: RAP achieves equivalent results to LP, in adult patients. A longer OT may be expected with the robotic system since it can handle more complicated cases.

Reply to Veerman et al. Comment on "Rosenzweig et al. Very Low Prostate PET/CT PSMA Uptake May Be Misleading in Staging Radical Prostatectomy Candidates. J. Pers. Med. 2022, 12, 410".

We thank the commenters for their important insights [...].

Very Low Prostate PET/CT PSMA Uptake May Be Misleading in Staging Radical Prostatectomy Candidates.

Purpose: to evaluate a unique subpopulation of radical prostatectomy (RP) candidates with "negative" prostate 68Ga-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) computed tomography (CT) imaging scans and to characterize the clinical implications of misleading findings. Materials and Methods: This case-control retrospective study compared the final histological outcomes of patients with "negative" pre-RP PSMA PET/CT prostate scans (with a prostate maximal standardized uptake value [SUVmax] below the physiologic uptake) to those with an "intense" prostatic tracer uptake (with a SUVmax above the physiologic uptake). The patients underwent an RP between March 2015 and July 2019 in five academic centers. Data on the demographics, comorbidities, prostate-specific antigen (PSA) and rectal exam findings, prior biopsies, imaging results, biopsies, and RP histology results were collected. Results: Ninety-seven of the 392 patients who underwent an RP had PSMA PET/CT imaging preoperatively. Fifty-two (54%) had a "negative" uptake (in the study group), and 45 (46%) had a "positive" uptake (in the control group). Only the lesion size and SUVmax values on the PSMA PET/CT differed between the groups preoperatively. On the histological analysis, only the ISUP score, seminal vesicles invasion, T stage, and positive margin rates differed between the groups (p < 0.05), while 50 (96%) study group patients harbored clinically significant disease (ISUP ≥ 2), with an extra-prostatic disease in 24 (46%), perineural invasion in 35 (67%), and positive lymph nodes in 4 (8%). Conclusions: Disease aggressiveness generally correlated with an intense PSMA uptake on the preoperative PSMA PET/CT, but a subpopulation of patients with clinically significant cancer and aggressive characteristics showed a deceptively weak PSMA uptake. These data raise a concern about the unqualified application of PSMA PET/CT for staging RP candidates.

Association between COVID-19 Burden, Population Vaccination Status, and Urologic Oncology Surgery Volume: A National Multicenter Cross-Sectional Study.

Initial deleterious effects of the COVID-19 pandemic on urologic oncology surgeries are well described, but the possible influence of vaccination efforts and those of pandemic conditions on surgical volumes is unclear. Our aim was to examine the association between changing vaccination status and COVID-19 burden throughout the pandemic and the volume of urologic oncology surgeries in Israel. This multi-center cross-sectional study included data collected from five tertiary centers between January 2019 and December 2021. All 7327 urologic oncology surgeries were included. Epidemiological data were obtained from the Israeli Ministry of Health database. A rising trend in total urologic oncology surgery volumes was observed with ensuing COVID-19 wave peaks over time (X2 = 13.184, df = 3, p = 0.004). Total monthly surgical volumes correlated with total monthly hospitalizations due to COVID-19 (R = -0.36, p = 0.015), as well as with the monthly average Oxford Stringency Index (R = -0.31, p = 0.035). The cumulative percent of vaccinations and of new COVID-19 cases per month did not correlate with total monthly urologic surgery volumes. Our study demonstrates the gradual acclimation of the Israeli healthcare system to the COVID-19 pandemic. However, hospitalizations due to COVID-19, as well as restriction stringency, correlate with lower volumes of urologic oncological surgeries, regardless of the population's vaccination status.

Tandem ureteral stents drainage lowers renal pelvis pressure in malignant ureteral obstruction: Experimental and computational models.

Malignant ureteral obstruction may lead to impaired renal function and requires drainage by a percutaneous nephrostomy tube or an internal ureteric stent. Usage of stiff tandem ureteral stents may decrease stent failure rates. In this paper we combined computational and in vitro models to examine the flow in a malignant ureteral obstruction (MUO) managed by 4 methods of drainage: single soft stent, single stiff stent, soft tandem ureteral stents, and stiff tandem ureteral stents. Pressure at the renal pelvis was the primary outcome of the computational and in vitro models. Different drainage modalities were compared using ANCOVA. Results of computational and in vitro models agreed completely. Drainage by stiff tandem ureteral stents provides lower renal pelvis pressure levels compared with single and soft stents (p < 0.001), especially for high levels of external pressure. Usage of stiff tandem ureteral stents may decrease stent-failure rates and postpone the need for percutaneous nephrostomy tube insertion.

Urologic oncology randomized controlled trials are frequently fragile - A review of the urology literature.

BACKGROUND: Randomized controlled trials (RCT) in urologic oncology are the basis of patient management. Considerable debate exists on the limitation of statistical reporting of randomized controlled trials. Fragility index (FI) is a measure of the number of events upon which the trials statistical results depend on. The FI is defined as the minimum number of patients whose status would have to change from a 'non-event' to 'event', in order to turn a statistically significant result to a non-significant result and vice versa. Our aim is to examine the FI of RCT's in urologic oncology published in the urology literature. MATERIAL AND METHODS: We exhaustively searched MEDLINE and EMBASE from January 1, 2016 to December 31 2019 for RCT's in urology journals. Only studies reporting dichotomous outcomes were included and FI was calculated for each outcome. The distributions of FI across different journals and types of outcome (primary/ secondary, significant/ non-significant) were assessed. We examined the correlation of FI with sample size and P-value. RESULTS: We identified 216 RCT's, 79 were eligible for analysis. Median FI was 3.0 (2.5, 6.0). One hundred and forty-six (89.6%) outcomes from 72 (94.7%) RCT's had a FI lower than 10 and 6 (3.7%) outcomes from 6 (7.9%) RCT's had a FI = 0. There was no statistically significant difference in FI between different types of outcomes. There was a modest correlation between the FI and the sample size (rs 0.50, P < 0.01) and a weak correlation between the FI the P value (rs 0.15 (P < 0.04)). CONCLUSIONS: Randomized controlled trials in urology journals that study dichotomous outcomes often report fragile results that should be regarded with caution. Reporting the FI alongside P values may enhance the interpretation and implementation of urologic oncology RCT's.