Evaluating the Survival Benefits of Perioperative Chemotherapy in Frail and Morbid Muscle-Invasive Bladder Cancer Patients.

INTRODUCTION: Current guidelines endorse the use of perioperative chemotherapy (POC) in muscle-invasive bladder cancer (MIBC) to enhance the long-term overall survival (OS) compared to radical cystectomy (RC) alone. This study aims to assess the impact of POC on the OS in frail and morbid (F-M) patients undergoing RC. METHODS: A retrospective multicenter study of 291 patients who underwent RC between 2015 and 2019 was performed. Patients with both a Charlson comorbidity index ≥ 4 and Modified Frailty Index ≥ 2 were classified as the F-M cohort. We compared the clinical and pathological characteristics and outcomes of the F-M patients who received POC to those who underwent RC alone. Univariable and multivariable analyses were performed to identify the predictors of the OS. RESULTS: The F-M cohort included 102 patients. POC was administered to 44% of these patients: neoadjuvant (NAC) to 31%, adjuvant (AC) to 19%, and both to 6 (6%). The OS was significantly lower in the F-M cohort compared to in the healthier patients (median OS 42 months, p = 0.02). The F-M patients who received POC were younger, less morbid and had better renal function. Although POC was marginally associated with improved OS in the univariable analysis (p = 0.06), this was not significant in the multivariable analysis (p = 0.50). NAC was associated with improved OS in the univariable analysis (p = 0.004) but not after adjustment for competing factors (p = 1.00). AC was not associated with the OS. CONCLUSIONS: POC does not improve the OS in F-M patients undergoing RC. Personalized treatment strategies and further prospective studies are needed to optimize care in this unique vulnerable population.

Acute Toxicity and Early Prostate Specific Antigen Response After Two-Fraction Stereotactic Radiation Therapy for Localized Prostate Cancer Using Peri-Rectal Spacing - Initial Report of the SABR-Dual Trial.

PURPOSE: SABR-Dual is a phase-III trial with an initial phase-I safety cohort, of 2-fraction stereotactic radiotherapy (SABR) with optional magnetic resonance imaging (MRI)-based focal boost, using peri-rectal spacing, for localized prostate cancer. This represents the initial report from the phase-I non-randomized cohort. METHODS AND MATERIALS: Subjects had favorable intermediate risk (FIR) or low risk prostate adenocarcinoma, and gland volume <80 cc. All underwent radiopaque hydrogel spacer and fiducial marker placement before simulation (computed tomography and 3-tesla T2 MRI). The clinical target volume included the entire prostate, and in FIR patients, 1-2 cm of seminal vesicle. A 2-mm expansion was applied for planning target volume (PTV), and a dose of 27 Gy was prescribed to the PTV-prostate, 23 Gy to the PTV-seminal vesicle, with an optional 30 Gy simultaneous boost to an MRI-defined dominant lesion. Primary endpoint was 3-month patient-reported changes in quality of life based on the Expanded Prostate Cancer Index Composite-26, International Prostate Symptom Score, and Sexual Health Inventory for Men questionnaires. Secondary endpoints were 6-month quality of life, acute toxicity (using Common Terminology Criteria for Adverse Events version 5.0) and early Prostate specific antigen (PSA) response. RESULTS: Among the 20 patients in the phase-I cohort, 95% had FIR disease, and 50% received a simultaneous boost. At median follow-up of 8 months, a 3-month minimally clinically important change occurred in 1/20 (5%), 6/20 (30%), 2/20 (10%), 4/20 (20%), and 5/20 (25%) in urinary incontinence, urinary obstructive, bowel, sexual, and hormonal domains. There was a mean increase of 1 ± 5.4 in International Prostate Symptom Score and decrease of 1.8 ± 6.5 in Sexual Health Inventory for Men scores. Rates of grade 2 urinary and bowel toxicity were 10% and 0%, respectively, with no grade ≥3 toxicities. Mean PSA decrease at last follow-up was 70.4% ± 17.7%. CONCLUSION: This generalizable protocol of 2-fraction prostate SABR using peri-rectal spacing is a safe approach for ultra-hypofractionated dose-escalation, with minimal acute toxicity. Longer-term outcomes and direct comparison with standard 5-fraction SABR are being studied in the phase-III randomized portion of SABR-Dual.

SABR-Dual: a phase II/III trial of two-fraction versus five-fraction stereotactic radiotherapy for localized low- and favorable intermediate-risk prostate cancer.

BACKGROUND: Dose-escalated radiotherapy is known to improve progression free survival in patients with localized prostate cancer, and recent advances have led to the standardization of ultrahypofractionated stereotactic ablative radiotherapy (SABR) delivered in just 5-fractions. Based on the known effectiveness of the accepted though invasive 2-fraction treatment method of high-dose-rate brachytherapy and given the ubiquity of prostate cancer, a further reduction in the number of treatments of external-beam SABR is possible. This study aims to evaluate the safety, efficacy, and non-inferiority of generalizable 2-fraction SABR compared to the current 5-fraction regimen. METHODS: 502 patients will be enrolled on this phase II/III randomized control trial. Eligible patients will have previously untreated low- or favorable intermediate-risk adenocarcinoma of the prostate. Patients will be randomized between standard SABR of 40 Gy in 5 fractions given every-other-day and 27 Gy in 2 fractions at least two days apart but completing within seven days. MRI-based planning, radiopaque hydrogel spacer insertion, and fiducial marker placement are required, and SABR will be delivered on either a standard CT-guided linear accelerator or MR-LINAC. The primary endpoint will be freedom from disease progression, with additional secondary clinical, toxicity, and quality of life endpoints. DISCUSSION: This study will be the largest prospective randomized trial, adequately powered to demonstrate non-inferiority, comparing 2-fraction SABR to standard 5-fraction SABR for localized prostate cancer. As the protocol does not obligate use of an MRI-LINAC or other adaptive technologies, results will be broadly generalizable to the wider community. TRIAL REGISTRATION: This trial is registered on Clinicaltrials.gov: ClinicalTrials.gov Identifier: NCT06027892.

Natural history and health care burden of non-curative treatment for muscle-invasive bladder cancer.

OBJECTIVE: Muscle-invasive bladder cancer is an aggressive disease. Yet, many patients, especially those with advanced age and multiple comorbidities, do not receive treatment with curative intent. We evaluated the disease course and health care burden of these patients. MATERIALS AND METHODS: Bi-center, retrospective analysis of patients diagnosed with muscle-invasive bladder cancer who did not undergo curative-intent treatment (radical cystectomy or trimodal therapy) between 2016 and 2021. Patient characteristics and treatment burden were described. Metastasis-free, cancer-specific, and overall survivals were evaluated using the Kaplan-Meier method. RESULTS: Sixty-six patients with a median age of 86 (IQR 78,90) were evaluated. The median follow-up for survivors was 29 months (IQR 9, 44). All patients were diagnosed with muscle-invasive bladder cancer, and 32 (48%) presented with clinical T3 and T4 disease. The median age adjusted Charlson comorbidity index at diagnosis was 7 (IQR 6,8). Treatment with curative intent was not provided due to comorbidities and low-performance status in 58 patients (88%) and patient refusal in 8 (12%). Two-year estimated metastasis-free survival, cancer-specific survival, and overall survival were 11%, 18%, and 12%, respectively. During follow-up, 7 patients (10%) were treated with chemotherapy, 4 (6%) received immunotherapy, 21 (32%) radiation, and 17 (26%) had emergent operations due to hematuria. Twenty-four patients (37%) required nephrostomy tubes, and 39 (59%) required an indwelling urinary catheter for various periods. Forty-three patients (65%) suffered from recurrent hematuria episodes. Overall, median emergency room visits were 4 (IQR 2, 6), and median hospital admission was 16 days (IQR 9, 29). CONCLUSIONS: Untreated muscle-invasive bladder cancer is associated with a limited lifespan and a high disease burden for the patient and health system. These data should be taken into consideration and portrayed to the patient when curative intent treatment is chosen to be avoided.

Assessing the Impact of Percutaneous Nephrostomy Presence on Neoadjuvant Treatment Quality in Patients With Muscle Invasive Bladder Cancer.

INTRODUCTION: Symptomatic hydronephrosis associated with muscle invasive bladder cancer (MIBC) necessitates percutaneous nephrostomy (PCN) insertion before neoadjuvant chemotherapy (NAC). This study assesses the impact of PCN presence on standard intended NAC quality, its related complications and outcome after radical cystectomy (RC). MATERIALS AND METHODS: The study comprises a retrospective, multicenter cohort of 193 consecutive RCs performed between 2016 and 2019. Eighty (42%) of these patients received NAC and were divided in 2 comparison groups by presence (n = 26; 33%) or absence (n = 54; 67%) of PCN. Endpoints included completion of adequate NAC treatment (cisplatin-based chemotherapy for at least 4 courses), complications during NAC, post-RC complications and hospital stay. RESULTS: Overall, patients with PCN (45/193; 23%) featured a higher referral rate to NAC (58% vs. 36%, P = .01), worse glomerular filtration rates (P < .001) and more adverse events (P = .04), in comparison to non-PCN patients. In the NAC cohort, PCN patients had less adequate treatment rates (54% vs. 85%, P = .005), and more infections (35% vs, 7%; P = .008) and hospitalizations (58% vs. 13%; P < .001) during chemotherapy. Post-RC outcome was similar for both comparison groups. PCN was an independent risk factor for inadequate NAC (OR = 3.9, P = .04), and infections (OR = 11.3, P = .01) and hospitalizations (OR = 7.5, P = .004) during NAC. CONCLUSIONS: PCN in MIBC patients is a significant risk factor for inadequate NAC and adverse events during treatment. This finding may quire the rationale of NAC, potentially leading to consideration of NAC avoidance and upfront RC in PCN patients. Further survival studies with long follow-up are needed for elucidating this issue.

Association between Hidradenitis Suppurativa and Abnormalities in Semen Parameters and Sexual Function: A Pilot Study.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting patients of reproductive age. Although HS shares risk factors with male infertility, only 1 epidemiological study has evaluated this association. To further evaluate this potential association, findings on semen and hormonal analysis, testicular ultrasound, and the International Index of Erectile Function (IIEF-15) were compared between 28 men attending a tertiary HS clinic during the period April 2019 to April 2021, and 44 healthy controls, spouses of infertile women undergoing semen evaluation before in vitro fertilization. Patients with HS were divided based on the absence or presence of gluteal and genital lesions. Patients with HS were younger than controls (median 27 vs 34 years, p < 0.0004) and had a higher proportion of smokers (86% vs 33%, p < 0.0001). Semen parameters in patients with gluteal-genital lesions, specifically those with severe scrotal involvement necessitating surgery, were lower than the WHO reference values and significantly lower than in patients without gluteal-genital lesions and controls. Erectile dysfunction was reported by 93% of patients with HS. These findings suggest that spermatogenesis and sexual function may be impaired in young men with HS. Therefore, multidisciplinary management of HS should include their evaluation to identify patients who might benefit from semen cryopreservation and sexual treatment.

A clinical evaluation of an ex vivo organ culture system to predict patient response to cancer therapy.

Introduction: Ex vivo organ cultures (EVOC) were recently optimized to sustain cancer tissue for 5 days with its complete microenvironment. We examined the ability of an EVOC platform to predict patient response to cancer therapy. Methods: A multicenter, prospective, single-arm observational trial. Samples were obtained from patients with newly diagnosed bladder cancer who underwent transurethral resection of bladder tumor and from core needle biopsies of patients with metastatic cancer. The tumors were cut into 250 µM slices and cultured within 24 h, then incubated for 96 h with vehicle or intended to treat drug. The cultures were then fixed and stained to analyze their morphology and cell viability. Each EVOC was given a score based on cell viability, level of damage, and Ki67 proliferation, and the scores were correlated with the patients' clinical response assessed by pathology or Response Evaluation Criteria in Solid Tumors (RECIST). Results: The cancer tissue and microenvironment, including endothelial and immune cells, were preserved at high viability with continued cell division for 5 days, demonstrating active cell signaling dynamics. A total of 34 cancer samples were tested by the platform and were correlated with clinical results. A higher EVOC score was correlated with better clinical response. The EVOC system showed a predictive specificity of 77.7% (7/9, 95% CI 0.4-0.97) and a sensitivity of 96% (24/25, 95% CI 0.80-0.99). Conclusion: EVOC cultured for 5 days showed high sensitivity and specificity for predicting clinical response to therapy among patients with muscle-invasive bladder cancer and other solid tumors.

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.

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.

Prostate-specific antigen level association with COVID-19 infection and vaccination.

INTRODUCTION: The associations among SARS-CoV-2 infection, vaccination and total serum prostate serum antigen (PSA) levels in men undergoing screening for prostate cancer are unknown. METHODS: A retrospective analysis of data from a large health maintenance organization. Records of individuals aged 50 to 75 years with two serum PSA tests taken between March 2018 and November 2021 were included. Individuals with prostate cancer were excluded. Changes in PSA levels were compared between individuals who had at least 1 SARS-CoV-2 vaccination and/or infection between the two PSA tests and individuals who did not have an infection and were not vaccinated between the two PSA tests. Subgroup analyses were performed to assess the impact of the elapsed time between the event and the second PSA test on the results. RESULTS: The study and control groups included 6,733 (29%) and 16 286 (71%) individuals, respectively. Although the median time between PSA tests was shorter in the study vs. the control group (440 vs. 469 days, P<.001), PSA elevation between the tests was higher in the study group (0.04 vs. 0.02, P<.001). The relative risk for PSA elevation ≥1 ng/dL was 1.22 (95% CI 1.1, 1.35). Among individuals who were vaccinated, PSA increased by 0.03 ng/dL (IQR -0.12, 0.28) and 0.09 ng/dL (IQR -0.05, 0.34) after 1 and 3 doses, respectively (P<.001). Multivariate linear regression showed that SARS-CoV-2 events (ß 0.043; 95% CI 0.026-0.06) were associated with a greater risk for PSA elevation, after adjusting for age, baseline PSA and days between PSA tests. CONCLUSION: SARS-CoV-2 infection and vaccinations are associated with a slight increase in PSA, with the third anti-COVID vaccine dose having a more prominent impact, but its clinical significance is unknown yet. Any significant increase in PSA must be investigated and cannot be dismissed as secondary to SARS-CoV-2 infection or vaccination.

Single-Dose Post-Office Fulguration Mitomycin C Instillation Appears to Improve Recurrence-Free Survival in Patients With Low-Grade Noninvasive Bladder Cancer.

INTRODUCTION: Perioperative instillation of mitomycin-C (MMC) has shown effectiveness in reducing the recurrence of low-grade non-muscle invasive bladder cancer (NMIBC). Data is lacking about the impact of single-dose MMC following office fulguration of low-grade urothelial carcinoma. We compared the outcomes of small-volume low-grade recurrent NMIBC in patients treated with office-fulguration - with and without an immediate single-dose instillation of MMC. PATIENTS AND METHODS: A retrospective analysis of medical records of patients with recurrent small-volume (≤1 cm) low-grade papillary urothelial cancer who underwent fulguration in a single institution between January 2017 and April 2021 either with or without instillation of post-fulguration MMC (40mg/50 mL). The primary outcome was recurrence-free survival (RFS). RESULTS: Of 108 patients (27% women) who underwent fulguration, 41% received intravesical MMC. The treatment and control groups had similar sex ratio, mean age, mass size, tumor multifocality and or tumor grade. Median RFS was 20 months (95% CI 4-36) in the MMC group and 9 months (95% CI 5-13) in the control group (P = .038). Multivariate Cox regression analysis showed that MMC instillation was associated with longer RFS (OR = 0.552, 95% CI 0.320-0.955, P = .034) and multifocality was associated with shorter RFS (OR = 1.866, 1.078-3.229, P = .026). A higher rate of grade 1-2 adverse events was observed in the MMC group (18.2%) vs. the control (6.8%, P = .048). No complications grade 3 or higher were observed. CONCLUSION: A single dose of MMC instilled after office fulguration is associated with longer RFS compared to patients who did not receive MMC after the procedure, with no associated high-grade complications.

Neoadjuvant 177Lu-PSMA-I&T Radionuclide Treatment in Patients with High-risk Prostate Cancer Before Radical Prostatectomy: A Single-arm Phase 1 Trial.

BACKGROUND: High-risk localized prostate cancer (HRLPC) has a substantial risk of disease progression despite local treatment. Neoadjuvant systemic therapy before definitive local therapy may improve oncological outcomes by targeting the primary tumor and micrometastatic disease. OBJECTIVE: To evaluate whether a lutetium-177 prostate-specific membrane antigen radioligand (LuPSMA) can be safely administered to patients with HRLPC before robot-assisted radical prostatectomy (RARP) and to describe immediate oncological outcomes. DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, single-arm clinical trial. Patients with HRLPC and elevated radioligand uptake on PSMA positron emission tomography/computed tomography were enrolled. Two or three LuPSMA radioligand doses (7.4 GBq) were given at 2-wk intervals. RARP with lymph node dissection was performed 4 wk after the last LuPSMA dose. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The rate of surgical complications, operative parameters, changes in functional and quality-of-life measures, and immediate oncological outcomes (histological findings and biochemical response) were measured. Data were analyzed descriptively. RESULTS AND LIMITATIONS: Fourteen patients participated (median age 67 yr). Prostate-specific antigen decreased by 17% (interquartile range [IQR] 9-50%) after two LuPSMA doses and 34% (IQR 11-60%) after three doses. Thirteen patients underwent RARP with no identifiable anatomical changes or intraoperative complications. Four patients (30%) had postoperative complications (pneumonia, pulmonary embolism, urinary leak with urinary tract infection). At 3 mo postoperatively, 12 patients (92%) required one pad or less. Final whole-mount pathology showed positive surgical margins (PSMs) in seven patients (53%) and downgrading to International Society of Urological Pathology grade group 3 in three patients (23%). Treatment-related effects included a clear vacuolated cytoplasm and pyknotic nuclei. CONCLUSIONS: LuPSMA followed by RARP appears to be surgically safe. While oncological outcomes are pending, continence recovery seems to be unaffected by LuPSMA treatment. PATIENT SUMMARY: We evaluated outcomes for patients with aggressive localized prostate cancer who received treatment with a radioactive agent before surgical removal of their prostate. This approach appears to be safe and feasible, but its therapeutic efficacy is still unknown.

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.

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.

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 [...].

Association between early change in neutrophil-to-lymphocyte ratio after radical cystectomy and treatment outcomes.

OBJECTIVES: To evaluate the associations of peri-operative neutrophil-to-lymphocyte ratio (NLR) and change in NLR with survival after radical cystectomy. PATIENTS AND METHODS: We retrospectively reviewed a multicentre cohort of patients with bladder cancer who underwent radical cystectomy between 2010 and 2020. Preoperative NLR, postoperative NLR, delta-NLR (postoperative minus preoperative NLR) and NLR change (postoperative divided by preoperative NLR) were calculated. Patients were stratified based on elevation of preoperative and/ or postoperative NLR above the median values. Multivariable Cox regression models were used to evaluate the associations of peri-operative NLR and NLR change with survival. RESULTS: The study cohort included 346 patients with a median age of 69 years. The median (interquartile range) preoperative NLR, postoperative NLR, delta-NLR and NLR change were 2.55 (1.83, 3.90), 3.33 (2.21, 5.20), 0.43 (-0.50, 2.08) and 1.2 (0.82, 1.96), respectively. Both preoperative and postoperative NLR were elevated in 110 patients (32%), 126 patients (36%) had an elevated preoperative or postoperative NLR, and 110 patients (32%) did not have an elevated NLR. On multivariable analysis, increased preoperative and postoperative NLR were significantly associated with decreased survival. While delta-NLR and NLR change were not associated with outcome, patients with elevations in both preoperative and postoperative NLR had the worst overall (hazard ratio [HR] 2.97, 95% confidence interval [CI] 1.78, 4.95; P < 0.001) and cancer-specific survival rates (HR 2.41, 95% CI 1.3, 4.4; P = 0.004). CONCLUSIONS: Preoperative and postoperative NLR are significant predictors of survival after radical cystectomy; patients in whom both NLR measures were elevated had the worst outcomes. Future studies should evaluate whether an increase in NLR during long-term follow-up may precede disease recurrence.

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.

Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer.

Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To find new clinically relevant drug combinations for colorectal cancer (CRC), we prioritized the top five synergistic combinations from a large in vitro screen for ex vivo testing on 29 freshly resected human CRC tumors and found that only the combination of mitogen-activated protein kinase kinase (MEK) and proto-oncogene tyrosine-protein kinase Src (Src) inhibition was effective when tested ex vivo. Pretreatment phosphorylated Src (pSrc) was identified as a predictive biomarker for MEK and Src inhibition only in the absence of KRASG12 mutations. Overall, we demonstrate the potential of using ex vivo platforms to identify drug combinations and discover MEK and Src dual inhibition as an effective drug combination in a predefined subset of individuals with CRC.

Nutritional Status Impairment Due to Neoadjuvant Chemotherapy Predicts Post-Radical Cystectomy Complications.

BACKGROUND: Radical cystectomy (RC) is the standard treatment for muscle invasive bladder cancer (MIBC). Neoadjuvant chemotherapy (NAC) is associated with improved patient survival. The impact of NAC on nutritional status is understudied, while the association between malnutrition and poor surgical outcomes is well known. This study aims to examine the association between NAC, nutritional status impairment, and post-operative morbidity. MATERIALS AND METHODS: We included MIBC patients who underwent RC and received NAC from multiple academic centers in Israel. Cross-sectional imaging was used to measure the psoas muscle area and normalized it by height (smooth muscle index, SMI). Pre- and post-NAC SMI difference was calculated (represents nutritional status change). The primary outcomes were post-RC ileus, infection, and a composite outcome of any complication. Logistic regression models were fit to identify independent predictors of the outcomes. RESULTS: Ninety-one patients were included in the study. The median SMI change was -0.71 (-1.58, -0.06) cm2/m2. SMI decline was significantly higher in patients with post-RC complications (-18 vs. -203, p < 0.001). SMI change was an independent predictor of all complications, ileus, infection, and other complications. The accuracy of SMI change for predicting all complications, ileus, infection, and other complications was 0.85, 0.87, 0.75, and 0.86, respectively. CONCLUSIONS: NAC-related nutritional deterioration is associated with increased risk of complications after RC. Our results hint towards the need for nutritional intervention during NAC prior to RC.