Relationship between Chemotherapy-Induced Diarrhea and Intestinal Microbiome Composition.

BACKGROUND AND AIM: Fluoropyrimidines (FPs) are key drugs in many chemotherapy regimens; however, recipients are often prone to diarrhea due to gastrointestinal toxicity. Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea. However, despite studies on chemotherapy-induced changes in the intestinal microbiome of humans, the relationship between dysbiosis and diarrhea is unclear. In this study, we aimed to investigate the relationship between chemotherapy-induced diarrhea and the intestinal microbiome. METHODS: We conducted a single-center prospective observational study. Twenty-three patients who received chemotherapy, including FPs as first-line chemotherapy for colorectal cancer, were included. Stool samples were collected before the start of chemotherapy and after one cycle of treatment to analyze intestinal microbiome composition and perform PICRUSt predictive metagenomic analysis. RESULTS: Gastrointestinal toxicity was observed in 7 of 23 patients (30.4%), diarrhea was observed in 4 (17.4%), and nausea and anorexia were observed in 3 (13.0%). In 19 patients treated with oral FPs, the α diversity of the microbial community decreased significantly following chemotherapy only in the diarrheal group. At the phylum level, the diarrheal group showed a significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Bacteroidetes with chemotherapy (p = 0.013 and 0.011, respectively). In the same groups, at the genus level, Bifidobacterium abundance was significantly decreased (p = 0.019). In contrast, in the non-diarrheal group, Actinobacteria abundance increased significantly with chemotherapy at the phylum level (p = 0.011). Further, Bifidobacterium, Fusicatenibacter, and Dorea abundance significantly increased at the genus level (p = 0.006, 0.019, and 0.011, respectively). The PICRUSt predictive metagenomic analysis revealed that chemotherapy caused significant differences in membrane transport in KEGG pathway level 2 and in 8 KEGG pathway level 3, including transporters and oxidative phosphorylation in the diarrhea group. CONCLUSION: Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs.

Therapeutic Drug Monitoring of Golimumab for the Prediction of Long-Term Clinical Remission in Patients with Ulcerative Colitis.

BACKGROUND AND AIMS: A considerable number of patients with ulcerative colitis (UC) who initially respond to golimumab (GLM), an anti-TNF-α antibody, gradually lose clinical response. Therapeutic drug monitoring has been proposed to optimize serum anti-TNF-α antibody concentrations before the loss of response; however, little is known about ideal serum GLM concentrations. We aimed to evaluate whether the serum GLM trough levels (TLs) early after the initiation of induction therapy affect the long-term outcomes in UC and to identify the early GLM TLs that should be targeted for better long-term outcomes. METHODS: Thirty-one patients were prospectively evaluated. The primary outcome was clinical remission at 54 weeks, and we measured the serum GLM TLs at weeks 6, 10, and 14. Receiver operating characteristic (ROC) curves were constructed to identify optimal GLM TL thresholds early after induction therapy that were associated with clinical remission at week 54. RESULTS: The GLM TL at week 14, but not at weeks 6 or 10, was significantly associated with clinical remission at week 54 (median [IQR] 1.6 [1.3-1.6] µg/mL vs. 0.9 [0.6-1.3] µg/mL; p = 0.04). The area under the ROC curve for GLM TLs at week 14 was 0.78. We identified a week-14 GLM TL of 1.1 µg/mL as the target threshold for achieving clinical remission at week 54. CONCLUSION: Our results demonstrate the value of early serum GLM TLs in predicting the long-term outcomes of GLM for patients with UC.

Risk Factors for Nephrotoxicity due to Tacrolimus Therapy for Ulcerative Colitis.

BACKGROUND AND AIMS: The calcineurin inhibitor tacrolimus is reportedly effective for moderate/severe ulcerative colitis (UC); however, it is also reportedly associated with nephrotoxicity. We investigated the risk factors for tacrolimus-induced nephrotoxicity and whether renal impairment adversely affected the outcomes of tacrolimus treatment in patients with UC. METHODS: We conducted a retrospective study of 93 patients with UC who were administered tacrolimus leading to high trough levels (10-15 ng/mL) for 2 weeks and low trough levels (5-10 ng/mL) for 3 months. RESULTS: Acute kidney injury (AKI) occurred in 44 patients (47.3%) during tacrolimus treatment. Of these patients, 34 (36.6%) developed AKI during the high trough phase and 17 (18.3%) developed AKI when the trough value exceeded the original target value of 15 ng/mL. Multivariate logistic regression analysis revealed that the male sex was significantly associated with AKI (p = 0.002, AOR = 4.38, 95% CI [1.69-11.3]). Clinical remission rate after 4, 8, 12, and 24 weeks of tacrolimus treatment in patients with AKI was lower than that in patients without AKI. Six patients (6.5%) had chronic kidney disease (CKD) after tacrolimus treatment completion, and all patients with CKD developed AKI during treatment. The median duration of treatment with no improvement in AKI was significantly longer in patients with CKD than in those without CKD (p = 0.016). CONCLUSION: We revealed the risk factors for tacrolimus-induced nephrotoxicity. Renal impairment occurrence adversely affected the tacrolimus treatment outcome; therefore, it is important to carefully administer tacrolimus to prevent renal impairment.

[Management of Internal Ureteral Stent (Double J-Stent) Occlusion].

Occlusion of internal ureteral stents commonly called double-J (DJ) stent leads to renal dysfunction, urinary tract infection, and difficulty in replacing the stent. We investigated the cause of stent occlusion and whether DJ stent occlusion persisted with change in the type of stent. The internal ureteral stent, Bird® Inlay™ Optima or Boston Scientific® Tria™, was inserted in 43 ureters of 33 patients who underwent replacement more than three times between September 2017 and June 2020. We defined stent occlusion as follows: a guide wire could not be passed through a stent during the replacement. In the first occlusion, the type of stent was changed. In the second occlusion, the stent placement interval was shortened from 12-13 weeks to 6-8 weeks. The presence of urinary stone and insertion of a urethral catheter had a high risk of DJ stent occlusion. Stent occlusion was observed in 20 of the 43 ureters. After the type of stent in 20 ureters with stent occlusion was changed, there were no DJ stent occlusions in 16 of the 20 ureters. Nevertheless, in 4 of the 20 ureters, even if we changed the type, DJ stent occlusion was still present; hence, the replacement interval was shortened. Therefore, changing the type of stent may be a recommended intervention for DJ stent occlusion.

Periprostatic fat thickness quantified by preoperative magnetic resonance imaging is an independent risk factor for upstaging from cT1/2 to pT3 in robot-assisted radical prostatectomy.

OBJECTIVES: To analyze the correlation between periprostatic fat thickness on multiparametric magnetic resonance imaging and upstaging from cT1/2 to pT3 in robot-assisted radical prostatectomy. METHODS: We retrospectively evaluated data from men with cT1/2 prostate cancer treated with robot-assisted radical prostatectomy at Nara Prefecture General Medical Center, Nara, Japan, between March 2013 and December 2017. We calculated the periprostatic fat thickness and subcutaneous thickness from preoperative multiparametric magnetic resonance imaging. We divided the cohort into two groups for analysis. Group 1 included patients upstaged from clinical to pathological stage, whereas group 2 included those without upstaging. RESULTS: Data on 220 patients meeting the inclusion criteria were included in the analysis. A total of 36 patients were upstaged from clinical T1 or T2 to pathological T3, whereas 184 patients were not upstaged. The upstaging was associated with prostate volume, Gleason score, prostate-specific antigen density, periprostatic fat thickness, Prostate Imaging Reporting and Data System score based on univariate analysis. Multivariate analysis showed prostate volume (P = 0.03, odds ratio 0.958, 95% confidence interval 0.921-0.996), Gleason score (P = 0.022, odds ratio 2.676, 95% confidence interval 1.153-6.213) and periprostatic fat thickness (P = 0.004, odds ratio 1.26, 95% confidence interval 1.079-1.471) as independent risk factors of upstaging. CONCLUSIONS: Prostate volume, Gleason score and periprostatic fat thickness on multiparametric magnetic resonance imaging are significantly associated with and independent risk factors for upstaging from cT1/2 to pT3 in patients undergoing robot-assisted radical prostatectomy.

Inhibition of Heparanase Expression Results in Suppression of Invasion, Migration and Adhesion Abilities of Bladder Cancer Cells.

Heparan sulfate proteoglycan syndecan-1, CD138, is known to be associated with cell proliferation, adhesion, and migration in malignancies. We previously reported that syndecan-1 (CD138) may contribute to urothelial carcinoma cell survival and progression. We investigated the role of heparanase, an enzyme activated by syndecan-1 in human urothelial carcinoma. Using human urothelial cancer cell lines, MGH-U3 and T24, heparanase expression was reduced with siRNA and RK-682, a heparanase inhibitor, to examine changes in cell proliferation activity, induction of apoptosis, invasion ability of cells, and its relationship to autophagy. A bladder cancer development mouse model was treated with RK-682 and the bladder tissues were examined using immunohistochemical analysis for Ki-67, E-cadherin, LC3, and CD31 expressions. Heparanase inhibition suppressed cellular growth by approximately 40% and induced apoptosis. The heparanase inhibitor decreased cell activity in a concentration-dependent manner and suppressed invasion ability by 40%. Inhibition of heparanase was found to suppress autophagy. In N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer mice, treatment with heparanase inhibitor suppressed the progression of cancer by 40%, compared to controls. Immunohistochemistry analysis showed that heparanase inhibitor suppressed cell growth, and autophagy. In conclusion, heparanase suppresses apoptosis and promotes invasion and autophagy in urothelial cancer.

Preoperative predictive factors focused on inflammation-, nutrition-, and muscle-status in patients with upper urinary tract urothelial carcinoma undergoing nephroureterectomy.

OBJECTIVE: The present study evaluated the clinical relevance of an integrative preoperative assessment of inflammation-, nutrition-, and muscle-based markers for patients with upper urinary tract urothelial carcinoma (UTUC) undergoing curative nephroureterectomy (NUx). METHODS: The study enrolled 125 patients and the preoperative variables assessed included age, body mass index, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), serum fibrinogen level (Fib), C-reactive protein (CRP), modified Glasgow prognostic score, serum albumin level (Alb), prognostic nutritional index (PNI), skeletal muscle index (SMI), psoas muscle index (PMI), and peak expiratory flow (PEF). The correlations among the variables and their prognostic values after NUx were evaluated. RESULTS: Five inflammation markers (NLR, MLR, PLR, Fib and CRP) were positively correlated. Fib was positively correlated with NLR, PLR and CRP, but inversely correlated with SMI. PNI was inversely correlated with age and the four inflammation markers (p < 0.001). Age was not significantly correlated with the inflammation markers, but older age was associated with lower Alb, PNI, SMI, PMI, and PEF. Disease-specific survival was independently predicted by preoperative ipsilateral hydronephrosis and low PNI. Overall survival was independently associated with high Fib and low PNI. CONCLUSION: The preoperative inflammation-, nutrition-, and muscle-based markers would be useful risk assessment tools for UTUC.

[Migration of Hem-o-Lok Clips into the Urinary Bladder Used during Robot-Assisted Laparoscopic Prostatectomy].

Recently, robot-assisted laparoscopic prostatectomy (RALP) has become a widely accepted surgical alternative for the treatment of prostate cancer. The intravesical migration of clips is a rare surgical complication of RALP. From March2013 to July 2018, 320 patients underwent RALP at our hospital. Migration of a Hem-o-Lok clip into the urinary bladder occurred in 4 of the 320 patients (1.3%). We analyzed these 4 patients in terms of subjective symptoms, intra- and post-operative findings, site of the migrated clip, and its treatment. The mean duration from RALP to the diagnosis was 13.8 months (2-26 months). The main symptoms due to migrated clips were : narrowed urinary stream, perineal pain, gross hematuria, and painful urination. In all cases, the size of the migrated clip was medium-large, and the events developed on the side contralateral to the first assistant. The clips were transurethrally removed using a Holmium-laser in 2 patients, and spontaneous excretion was observed in 1. The remaining patient has been asymptomatic and is being conservatively observed. In order to prevent the migration of clips used during RALP, the size of the clips and direction of the clip tail may be important. The first assistant should place the clips carefully, especially on the contralateral side.

Biological Behavior and Long-Term Outcomes of Carcinoma In Situ in Upper Urinary Tract Managed by Radical Nephroureterectomy.

PURPOSE: In patients with urothelial carcinoma CIS (carcinoma in situ) generally has a poor prognosis. However, to our knowledge the outcomes of pure/primary CIS and the behavior of CIS concomitant with pTa-pT4 upper tract urothelial carcinoma managed by nephroureterectomy have not been previously specified. We explored the biological and prognostic features of concomitant CIS compared with those of pure/primary CIS. MATERIALS AND METHODS: We queried a multicenter upper tract urothelial carcinoma database. Data from NUOG (Nishinihon Uro-Oncology Group) were analyzed, including patient gender, age, presence of bladder cancer and pT stage. Clinicopathological features were compared between the different subtypes. Cancer specific and overall survival, and the relative excess risk of death were estimated by CIS subtype. RESULTS: We identified 163 patients with CIS in the upper urinary tract, of whom pure/primary CIS was noted in 24.5%. In the concomitant CIS cohort the pathological diagnosis of the nonCIS region was pTa, pT1, pT2, pT3 and pT4 in 4.9%, 22.8%, 25.2%, 44.7% and 1.6% of patients, respectively. The sensitivity of a selective urine cytology test was higher in the pure/primary CIS group than in the concomitant CIS group (60.0% vs 37.4%). At a median followup of 32 months 10-year estimated mean cancer specific survival was 92.4 months (range 83.7 to 101.0) in the overall CIS cohort. Ten-year estimated mean cancer specific survival in patients with pure/primary CIS was significantly longer than in patients with concomitant carcinoma in situ (111.8 months, range 101.0 to 122.6 vs 85.89, range 75.3 to 96.5, log rank p = 0.007). CONCLUSIONS: Patients presenting with concomitant CIS have a worse outcome than those who present with pure/primary CIS, suggesting a need to differentiate these 2 entities in the treatment decision process.

Correlation of Immune Cells and Cytokines in the Tumor Microenvironment with Elevated Neutrophil-To-Lymphocyte Ratio in Blood: An Analysis of Muscle-Invasive Bladder Cancer.

We investigated the relationship between Neutrophil-to-lymphocyte ratio (NLR) and the quantities of neutrophil elastase, CD3, Foxp3, and CD204 in tumor-infiltrating cells and circulating cytokines (IL-2, -6, -8, 17a, and TGF-ß) in muscle-invasive bladder cancer. IL-6 and IL-8 levels showed a significant correlation with NLR in blood and Foxp3+ cells around the tumor. After co-culture of peripheral blood cells with bladder cancer cell lines, the induction of regulatory T cell (Treg) was higher in T24 whose IL-6 and IL-8 levels were higher. High NLR correlates with increased IL-6 and IL-8 and Treg expression.

Outcomes of subsequent non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin after radical nephroureterectomy for upper urinary tract urothelial carcinoma.

OBJECTIVES: To describe the clinicopathological characteristics and prognosis of subsequent non-muscle-invasive bladder cancer (NMIBC) after radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC), and particularly its response to intravesical Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: An observational study was conducted in 1463 patients with UTUC who had undergone RNU and in 1555 patients with primary NMIBC. Of the 1463 patients with UTUC, 256 (17%) subsequently developed NMIBC (UTUC-NMIBC group) and were available for the analysis. The clinicopathological background and outcomes, including intravesical recurrence-free survival and bladder progression-free survival, were compared between the patients with UTUC-NMIBC and the patients with primary NMIBC treated with intravesical BCG. Propensity score matching was performed to adjust for the potential differences in the backgrounds of the two groups. To validate the utility of the CUETO scoring model in the UTUC-NMIBC group, risk scores were calculated and compared with the published probabilities for recurrence and progression. RESULTS: Compared with the unadjusted primary NMIBC group (n = 352), the UTUC-NMIBC group (n = 75) were found to have a worse prognosis for intravesical recurrence and progression, before propensity score matching. After propensity score matching for potential confounding factors, however, a worse prognosis was observed only for intravesical recurrence. The validation test of the CUETO scoring model for the UTUC-NMIBC group showed a significant difference in the rate of intravesical recurrence and progression for the 0-4 and 5-6 score groups between the UTUC-NMIBC group and the CUETO risk table reference data. CONCLUSION: Compared with the primary NMIBC group, the UTUC-NMIBC group had a worse prognosis after intravesical BCG, especially with regard to intravesical recurrence. This suggests that patients with UTUC-NMIBC are inherently poor responders to BCG exposure. An optimal treatment strategy and risk scoring model to select patients for adjuvant intravesical BCG, chemotherapy or immediate radical cystectomy should be established.

Tadalafil, a phosphodiesterase type 5 inhibitor, improves bladder blood supply and restores the initial phase of lower urinary tract dysfunction in diabetic rats.

AIMS: To investigate the effect of tadalafil on bladder blood flow and lower urinary tract function in a rat model of diabetes. MATERIALS AND METHODS: We studied female Sprague-Dawley rats and induced diabetes in some using a single intraperitoneal injection of streptozotocin. We divided the rats into nondiabetes (ND), diabetes (D), and diabetes with tadalafil (DT) groups. The rats were raised for an additional 7 weeks after diabetes induction. The DT group received oral tadalafil (2 mg/kg/day) for 7 days before the experiments. At 7 weeks after diabetes induction, we performed cystometry, resected the bladders for immunohistochemistry (hypoxia-inducible factor-1α [HIF-1α] and 8-oxo-2'-deoxyguanosine [8-OHdG] staining), and measured bladder blood supply using a laser blood flow meter. RESULTS: The opening pressure, when the urethra opens and urine flow starts, was significantly lower in the DT group than in the D group (24.9 ± 5.9 vs 43.6 ± 12.3 cmH2 O). The inter-contraction interval was significantly longer in the D group than in the ND and DT groups (1566.2 ± 168.7 vs 702.9 ± 165.2 and 787.4 ± 148.8 s). Immunohistochemistry showed positive staining of the urothelial layer for both HIF-1α and 8-OHdG in the D group, but not in the ND or DT groups. Bladder blood flow was significantly lower in the D group than in the ND or DT groups. CONCLUSIONS: Tadalafil improves bladder blood supply and lower urinary tract function in diabetic rats. Tadalafil may be a promising drug that restores lower urinary tract dysfunction in the early phase of diabetes.

Clinical utility of bioelectrical impedance analysis in patients with locoregional muscle invasive or metastatic urothelial carcinoma: a subanalysis of changes in body composition during neoadjuvant systemic chemotherapy.

PURPOSE: The aim of this study was to determine the clinical utility of bioelectrical impedance analysis (BIA) in a cohort of patients with advanced urothelial carcinoma (UC). METHODS: We prospectively evaluated body composition in 35 patients with locoregional muscle invasive (≥ T2 and N0-2M0) or metastatic UC. Body composition was evaluated using multifrequency BIA at baseline (n = 35) and during chemotherapy in patients receiving neoadjuvant chemotherapy (n = 14). The BIA-predicted body composition index was compared with the computed tomography-measured muscle index and the prognostic nutrition index. Changes in body composition during neoadjuvant chemotherapy were recorded and compared with the incidence of hematological adverse events. RESULTS: There was a significant correlation between the BIA-predicted skeletal muscle index and the computed tomography-measured skeletal muscle index (P = 0.004), while there was no significant correlation between the prognostic nutrition index and the BIA-predicted nutrition index. After the completion of 3 cycles of neoadjuvant chemotherapy, the skeletal muscle index showed a significant decrease (P = 0.016), while the total body fat mass (P = 0.025), body fat percentage (P = 0.013), and body mass index (P = 0.004) showed a significant increase (a tendency toward "sarcopenic obesity"). Patients who experienced grade 2-3 anemia during neoadjuvant chemotherapy showed a significantly lower increase in body mass index compared with patients who did not experience high-grade toxicities (P = 0.032). CONCLUSIONS: BIA could contribute to other methods of nutrition and muscle assessment for pretreatment risk stratification in patients with UC. Further study of a larger cohort is required to elucidate the clinical impact of changes in body composition during chemotherapy.

Spectrophotometric photodynamic diagnosis of prostate cancer cells excreted in voided urine using 5-aminolevulinic acid.

To evaluate the feasibility of photodynamic diagnosis using 5-aminolevulinic acid (PDD-ALA) for detection of prostate cancer (PCa) cells in urine samples after prostate massage in patients who were suspected to have PCa. One hundred and eighty-nine patients with abnormal digital rectal examination and/or an elevated prostate-specific antigen (PSA) level who underwent initial prostate biopsy were recruited. After prostate massage, the first 60 mL of voided urine was collected. For PDD-ALA, 50 mL was used. The rest of collected urine was used for polymerase chain reaction (PCR) of PSA and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). After incubation for 2 h, the intensity was measured at 635 nm under a 405-nm wavelength excitation. The results of PDD-ALA were compared with those of an initial transrectal ultrasound (TRUS)-guided prostate biopsy. Overall, 126/189 (67%) samples that showed bands of both PSA and GAPDH on PCR in urine samples were analyzed. The area under the curve, sensitivity, and specificity of PDD-ALA were 0.74, 77, and 67%, respectively. The value of PDD-ALA was significantly higher in patients with Gleason scores of 6 (p = 0.03), 7 (p = 0.005), and 8-10 (p = 0.0002) than in those with negative biopsy results. In the multivariate analysis, high PSA density, abnormal findings on TRUS, and a high value of PDD-ALA were significant markers for prediction of positive biopsy results. PDD-ALA was useful to predict positive biopsy results in patients who underwent initial prostate biopsy with suspected PCa. This PCa-detection method has potential for clinical use.

Diagnostic and prognostic role of urinary collagens in primary human bladder cancer.

Collagen type 4 alpha 1 (COL4A1) and collagen type 13 alpha 1 (COL13A1) produced by urothelial cancer cells support the vital oncogenic property of tumor invasion. We investigated the diagnostic and prognostic capability of COL4A1 and COL13A1 in voided urine and compared the observed values with those of fragments of cytokeratin-19 (CYFRA21-1), nuclear matrix protein 22 (NMP-22), and voided urine cytology in bladder cancer (BCa). We collected voided urine samples from 154 patients newly diagnosed with BCa, before surgery and from 61 control subjects. Protein levels of COL4A1, COL13A1, CYFRA21-1, and NMP-22 in urine supernatants were measured using enzyme-linked immunosorbent assays. Diagnostic performance and optimal cut-off values were determined by receiver operating characteristic analysis. Urine levels of COL4A1, COL13A1, the combined values of COL4A1 and COL13A1 (COL4A1 + COL13A1), and CYFRA21-1 were significantly elevated in urine from patients with BCa compared to the controls. Among these biomarkers, the optimal cut-off value of COL4A1 + COL13A1 at 1.33 ng/mL resulted in 57.4%, 83.7%, 56.1%, 80.7%, and 91.7% sensitivity for low-grade tumors, high-grade tumors, Ta, T1, and muscle invasive disease, respectively. We evaluated the prognostic value of preoperative urine levels in 130 non-muscle invasive BCa samples after the initial transurethral surgery. A high urinary COL4A1 + COL13A1 was found to be an independent risk factor for intravesical recurrence. Although these data need to be externally validated, urinary COL4A1 and COL13A1 could be a potential diagnostic and prognostic biomarker for BCa. This easy-to-use urinary signature identifies a subgroup of patients with a high probability of recurrence and progression in non-muscle invasive and muscle invasive BCa.

Integrative Assessment of Pretreatment Inflammation-, Nutrition-, and Muscle-Based Prognostic Markers in Patients with Muscle-Invasive Bladder Cancer Undergoing Radical Cystectomy.

OBJECTIVE: The present study evaluated the clinical relevance of an integrative preoperative assessment of inflammation-, nutrition-, and muscle-based markers for patients with muscle-invasive bladder cancer (MIBC) undergoing curative radical cystectomy (RC). METHODS: The analysis enrolled 117 patients and the variables included age, body mass index (BMI), neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI), Controlling Nutritional Status score, psoas muscle index (PMI), and peak expiratory flow (PEF). The correlations among the variables were evaluated and their prognostic values after RC were tested. RESULTS: Three inflammation markers (ratios of blood cell counts) were positively correlated (p < 0.0001). The PNI and the BMI were positively correlated (p = 0.04), although they were inversely correlated with the three inflammation markers (p < 0.0001). Age was not significantly correlated with the inflammation markers and PMI, although older age was associated with lower PNI and lower PEF. The disease-specific survival was independently predicted by T4 tumor, positive N status, and decreased PNI. Overall survival was independently predicted by T4 tumor, mGPS, and pretreatment sarcopenia status. CONCLUSIONS: The inflammation-, nutrition-, and muscle-based markers would be useful risk assessment tools for MIBC.

Clinical impact of postoperative loss in psoas major muscle and nutrition index after radical cystectomy for patients with urothelial carcinoma of the bladder.

BACKGROUND: Although the significance of preoperative nutritional status has been investigated, there is no report regarding the relationship of their postoperative changes on outcomes in patients who underwent radical cystectomy for bladder cancer. Here, we report the clinical impact of the change, from baseline, in nutritional status and volume of abdominal skeletal muscle mass and adipose tissue after radical cystetomy. METHODS: A retrospective analysis of 89 patients with bladder cancer, who underwent curative radical cystectomy, was conducted to assess the time course of change, from baseline, in body composition and nutritional status at 1, 3, 6, 12, and 24 months, after surgery. Skeletal muscle mass and abdominal adipose tissue mass were quantified by unenhanced computed tomography images. Two different nutritional indices, the Prognostic Nutritional Index and the Controlling Nutritional Status score were calculated from laboratory blood tests. We evaluated the prognostic value of the rate of change in the body composition and nutritional status after radical cystectomy. RESULTS: The cross-sectional area at the level of the third lumbar vertebra of the psoas major muscle and nutritional indices showed a transient deterioration at 1 and 3 months after radical cystectomy, with a return to baseline values from 6 to 24 months. A ≤ -10% loss in the area of the psoas muscle was associated with a shorter overall survival, compared to those with a > -10 change [hazard ratio (HR) 2.2, P = 0.02]. Multivariate analyzes identified sarcopenia status at baseline (HR 2.2, P = 0.03) and a ≤ -10% loss in the psoas muscle (HR 2.4, P = 0.02) were identified as independent prognostic factors for overall survival. A subanalysis of patients without sarcopenia identified a worse survival outcome for patients with a ≤ -10% loss in the psoas muscle (HR 2.6, P = 0.03) and ≤ - 5 change in the Prognostic Nutritional Index (HR 3.6, P = 0.01). CONCLUSION: Further research is required to establish appropriate rehabilitation protocols and nutritional interventions after radical cystectomy for maintaining skeletal muscle mass and nutrition status which could counteract physical deterioration and improve outcomes.

Transperineal template-guided saturation biopsy aimed at sampling one core for each milliliter of prostate volume: 103 cases requiring repeat prostate biopsy.

BACKGROUND: We evaluated the cancer detection rate of prostate cancer using transperineal template-guided saturation biopsy aimed at sampling one core for each milliliter of prostate volume for patients requiring repeated prostate biopsies. METHODS: In total, 103 consecutive patients with repeated prostate biopsies were enrolled in this retrospective study. The number of biopsy cores was defined by prostate volume. In principle, one biopsy core covered 1 mL of prostate volume. We used a prostate brachytherapy template with a 5-mm grid and adopted a transperineal needle biopsy. RESULTS: The median age, prostate-specific antigen level, and prostate volume were 69 (range, 37-83) years, 9.2 (range, 1.9-107) ng/mL, and 34.7 (range, 18-76.7) mL, respectively. The median number of biopsy cores was 37 (range, 18-75 cores). Fifty-three patients (51.5%) were diagnosed with prostate cancer. The Gleason score was 6, 7, and 8-10 in 24.5, 64.2 and 11.3% patients, respectively. Forty-two patients (79.2%) were diagnosed with clinically significant PCa. Acute urinary retention was detected in 2 patients (1.9%). CONCLUSIONS: Transperineal template-guided saturation biopsy with one core per milliliter of prostate volume helped achieve a high cancer detection rate and high significant cancer detection rate with acceptable biopsy-associated adverse events.

Assessment of lower urinary symptom flare with overactive bladder symptom score and International Prostate Symptom Score in patients treated with iodine-125 implant brachytherapy: long-term follow-up experience at a single institute.

BACKGROUND: The aim of this study was to evaluate the combined use of the overactive bladder symptom score (OABSS) and International Prostate Symptom Score (IPSS) as an assessment tool for urinary symptom flare after iodine-125 (125I) implant brachytherapy. The association between urinary symptom flare and prostate-specific antigen (PSA) bounce was investigated. METHODS: Changes in the IPSS and OABSS were prospectively recorded in 355 patients who underwent seed implantation. The percentage distribution of patients according to the difference between the flare peak and post-implant nadir was plotted to define significant increases in the scores. The clinicopathologic characteristics, treatment parameters, and post-implant dosimetric parameters were compared between the non-flare and flare groups. PSA bounce was defined as an elevation of ≥0.1 ng/mL or ≥0.4 ng/mL compared to the previous lowest value, followed by a decrease to a level at or below the pre-bounce value. RESULTS: A clinically significant increase required an IPSS increase of at least 12 points and an OABSS increase of at least 6 points based on a time-course analysis of total scores and the QOL index. Assessment only by IPSS failed to detect 40 patients (11%) who had urinary symptom flare according to the OABSS. Univariate and multivariate analyses revealed that patients treated with higher biologically effective doses and those without diabetes mellitus had higher risks of urinary flare. There was no statistical correlation between the incidence and time of urinary symptom flare onset and that of a PSA bounce. CONCLUSIONS: To our knowledge, this is the first report to prove the clinical potential of the OABSS as an assessment tool for urinary symptom flare after seed implantation. Our findings showed that persistent lower urinary tract symptoms after seed implantation were attributed to storage rather than to voiding issues. We believe that assessment with the OABSS combined with the IPSS would aid in decision-making in terms of timing, selection of a treatment intervention, and assessment of the outcome.

Regulatory T Cells and Tumor-Associated Macrophages in the Tumor Microenvironment in Non-Muscle Invasive Bladder Cancer Treated with Intravesical Bacille Calmette-Guérin: A Long-Term Follow-Up Study of a Japanese Cohort.

The clinical significance of regulatory T cells (Treg) and tumor-associated macrophages (TAM) in the tumor microenvironment of human bladder cancer remains unclear. The aim of this study is to explore their relevance to oncological features in non-muscle invasive bladder cancer (NMIBC). We carried out immunohistochemical analysis of forkhead box P3 (FOXP3, Treg maker), CD204 (TAM marker), and interleukin-6 (IL6) using surgical specimens obtained from 154 NMIBC patients. The Treg and TAM counts surrounding the cancer lesion and IL6-positive cancer cell counts were evaluated against clinicopathological variables. We focused on the ability of the Treg and TAM counts around the cancer lesion to predict outcomes after adjuvant intravesical Bacille Calmette-Guérin (BCG) treatment. High Treg counts were associated with female patients, older age, T1 category, and high tumor grade. TAM count was significantly correlated with Treg count and with IL6-positive cancer cell count. In our analysis of 71 patients treated with BCG, high counts of Treg and TAM were associated with shorter recurrence-free survival, and the former was an independent predictor of recurrence. Poor response to intravesical BCG was associated with Treg and TAM in the tumor microenvironment. Disrupting the immune network can be a supplementary therapeutic approach for NMIBC patients receiving intravesical BCG.