Neoadjuvant Cisplatin-Based Chemotherapy Followed by Selective Bladder Preservation Chemoradiotherapy in Muscle-Invasive Urothelial Carcinoma of the Bladder: Post Hoc Analysis of Two Prospective Studies.

PURPOSE: Bladder preservation chemoradiotherapy (CRT) in patients with a clinical complete response (cCR) following cisplatin-based neoadjuvant chemotherapy (NAC) is a promising treatment strategy for muscle-invasive bladder urothelial carcinoma (MIBC). A combined analysis of raw data from two prospective phase II studies was performed to better evaluate the feasibility of selective bladder preservation CRT. MATERIALS AND METHODS: The analysis was based on primary efficacy data from two independent studies, including 76 MIBC patients receiving NAC followed by bladder preservation CRT. The efficacy data included metastasis-free survival (MFS) and disease-free survival (DFS). For the present analysis, starting point of survival was defined as the date of commencing CRT. RESULTS: Among 76 patients, 66 had a cCR following NAC. Sixty-four patients received gemcitabine and cisplatin (GC) combination chemotherapy in neoadjuvant setting, and 12 received nivolumab plus GC. Bladder preservation CRT following NAC was generally well-tolerated, with low urinary tract symptoms being the most common late complication. With a median follow-up of 64 months, recurrence was recorded in 43 patients (57%): intravesical only (n=20), metastatic only (n=16), and both (n=7). In 27 patients with intravesical recurrence, transurethral resection, and Bacillus Calmette-Guerin treatment was given to 17 patients. Salvage cystectomy was performed in 10 patients. Median DFS was 46.3 (95% confidence interval [CI], 25.1 to 67.5) months, and the median MFS was not reached. Neither DFS nor MFS appeared to be affected by any of the baseline characteristics. However, DFS was significantly longer in patients with a cCR than in those without (hazard ratio, 0.465; 95% CI, 0.222 to 0.976). CONCLUSION: The strategy of NAC followed by selective bladder preservation CRT based on the cCR is feasible in the treatment of MIBC. A standardized definition of cCR is needed to better assess disease status post-NAC.

Effects of poly (ADP-ribose) polymerase inhibitor treatment on the repair process of ischemic acute kidney injury.

Excessive activation of poly (ADP-ribose) polymerase (PARP) contributes to ischemic acute kidney injury (AKI). PARP inhibition has been shown to be beneficial in renal ischemia-reperfusion injury (IRI) in the early phase, but its role in the repair process remains unclear. The effects of JPI-289, a novel PARP inhibitor, during the healing phase after renal IRI were investigated. IRI was performed on 9-week-old male C57BL/6 mice. Saline or JPI-289 100 mg/kg was intraperitoneally administered once at 24 h or additionally at 48 h after IRI. Hypoxic HK-2 cells were treated with JPI-289. Renal function and fibrosis extent were comparable between groups. JPI-289 treatment caused more prominent tubular atrophy and proinflammatory intrarenal leukocyte phenotypes and cytokines/chemokines changes at 12 weeks after unilateral IRI. JPI-289 treatment enhanced gene expressions associated with collagen formation, toll-like receptors, and the immune system in proximal tubules and endothelial cells after IRI. JPI-289 treatment at 3 or 6 h after hypoxia facilitated proliferation of hypoxic HK-2 cells, whereas further treatment after 24 h suppressed proliferation. Delayed inhibition of PARP after renal IRI did not facilitate the repair process during the early healing phase but rather may aggravate renal tubular atrophy during the late healing phase in ischemic AKI.

Computed tomography-based prediction model for identifying patients with high probability of non-muscle-invasive bladder cancer.

PURPOSE: To investigate computed tomography (CT)-based prediction model for identifying patients with high probability of non-muscle-invasive bladder cancer (NMIBC). METHODS: This retrospective study evaluated 147 consecutive patients who underwent contrast-enhanced CT and surgery for bladder cancer. Using corticomedullary-to-portal venous phase images, two independent readers analyzed bladder muscle invasion, tumor stalk, and tumor size, respectively. Three-point scale (i.e., from 0 to 2) was applied for assessing the suspicion degree of muscle invasion or tumor stalk. A multivariate prediction model using the CT parameters for achieving high positive predictive value (PPV) for NMIBC was investigated. The PPVs from raw data or 1000 bootstrap resampling and inter-reader agreement using Gwet's AC1 were analyzed, respectively. RESULTS: Proportion of patients with NMIBC was 81.0% (119/147). The CT criteria of the prediction model were as follows: (a) muscle invasion score < 2; (b) tumor stalk score > 0; and (c) tumor size < 3 cm. From the raw data, PPV of the model for NMIBC was 92.7% (51/55; 95% confidence interval [CI] 82.4-98.0) in reader 1 and 93.3% (42/45; 95% CI 81.7-98.6) in reader 2. From the bootstrap data, PPV was 92.8% (95% CI 85.2-98.3) in reader 1 and 93.4% (95% CI 84.9-99.9) in reader 2. The model's AC1 was 0.753 (95% CI 0.647-0.859). CONCLUSION: The current CT-derived prediction model demonstrated high PPV for identifying patients with NMIBC. Depending on CT findings, approximately 30% of patients with bladder cancer may have a low need for additional MRI for interpreting vesical imaging-reporting and data system.

Effects of Treating Subclinical Rejection 2 Weeks After Kidney Transplantation, as Determined by Analyzing 1-Year Histologic Outcomes.

Subclinical rejection (SCR) is associated with chronic allograft nephropathy. Therefore, early detection and treatment of SCR through a protocol biopsy (PB) can reduce the incidence of pathologic changes. This study evaluates the impact of early detection and treatment of SCR using a routine PB 2 weeks after kidney transplantation (KT) by examining histologic outcomes 1 year later. We reviewed 624 KT recipients at the Samsung Medical Center between August 2012 and December 2018. Protocol biopsy was planned 2 weeks and 1 year after transplantation. We compared the histologic changes between the 2 biopsies. After a propensity score matching analysis, we divided the patients into 2 groups: the proven normal group (n = 256) and the rejection group (n = 96) at the PB taken 2 weeks post-transplant. The rejection group showed no significant difference from the normal group in the flow of graft function or the Kaplan-Meier curve for graft survival. In the histologic outcomes, the pathologic differences between the groups significantly improved between the 2 time points. Treating SCR through a PB 2 weeks after KT can contribute to the maintenance of graft function and improve histologic changes 1 year after KT.

Comparison of Metastatic Patterns Among Neuroendocrine Tumors, Neuroendocrine Carcinomas, and Nonneuroendocrine Carcinomas of Various Primary Organs.

BACKGROUND: Both neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) exhibit neuroendocrine differentiation and are classified as neuroendocrine neoplasms (NENs). NECs and nonneuroendocrine neoplasms (non-NENs), such as adenocarcinoma, have similar mutational profiles. The purpose of this study was to identify differences in metastatic patterns and to identify the key factor causing these differences by simultaneously comparing the metastatic patterns of NETs, NECs and non-NENs from various primary organs. METHODS: We retrieved data for 4,223 patients with NENs and 41,637 patients with non-NENs arising at various primary sites from an institutional database and then compared NET, NEC, and non-NEN metastatic patterns. RESULTS: NETs and NECs showed generally similar metastatic patterns. Most NEN patients had a higher liver organotrophic metastasis rate, lower lung organotrophic metastasis rate, and lower pleural/peritoneal organotrophic metastasis rate than non-NEN patients. Some differences were characteristics of specific organs. Some of these site-specific differences were not caused by NENs but by non-NENs, including a higher bone organotrophic metastasis rate for medullary thyroid carcinoma and a lower bone organotrophic metastasis rate for pulmonary NEN. Other differences were probably caused by NENs, including a higher bone organotrophic metastasis rate for colorectal NETs. Uterine cervical NEC showed unique patterns of metastasis compared to NEN from other sites. CONCLUSION: Significant differences between the metastatic patterns of NENs and non-NENs were detected. The multigene program that causes neuroendocrine differentiation might be associated with organotropic metastasis.

New transperineal ultrasound-guided biopsy for men in whom PSA is increasing after Miles' operation.

OBJECTIVES: Currently, a prostate biopsy is guided by transrectal ultrasound (US) alone. However, this biopsy cannot be performed in men without an anus. The aim of this study was to show the outcomes of a new transperineal US (TPUS)-guided biopsy technique in patients who underwent Miles' operation. METHODS: Between April 2009 and March 2022, TPUS-guided biopsy was consecutively conducted in 9 patients (median, 71 years; range, 61-78 years) with high prostate-specific antigen values (22.60 ng/mL; 6.19-69.7 ng/mL). Their anuses were all removed due to rectal cancer. TPUS-guided biopsy was performed according to information on prostate magnetic resonance imaging. The technical success rate, cancer detection rate, and complication rate were recorded. Tumor sizes were compared between benign and cancer groups using an unpaired t-test with Welch's correction. RESULTS: The new TPUS-guided biopsy was successfully performed in all patients. Cancer was detected in 77.8% (7/9) of the patients. These were all categorized as PI-RADS 5. Among them, the detection rate of significant cancer (Gleason score 7 or higher) was 66.7% (6/9). The median tumor size was 2.4 cm (1.7-3.1 cm). However, two patients were diagnosed with benign tissue with PI-RADS 3 or PI-RADS 4. Their median tumor size was 1.0 cm (0.8-1.2 cm). There was significant difference between the cancer and benign groups (p = 0.037) in terms of tumor size. Neither post-biopsy bleeding nor infections occurred. CONCLUSIONS: New TPUS-guided biopsy technique may contribute to detecting large PI-RADS 5 prostate cancer in men after Miles' operation.

Fat Loss in Patients with Metastatic Clear Cell Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors.

The purpose of this study was to determine the prognostic impact of fat loss after immune checkpoint inhibitor (ICI) treatment in patients with metastatic clear cell renal cell carcinoma (ccRCC). Data from 60 patients treated with ICI therapy for metastatic ccRCC were retrospectively analyzed. Changes in cross-sectional areas of subcutaneous fat (SF) between the pre-treatment and post-treatment abdominal computed tomography (CT) images were expressed as percentages and were divided by the interval between the CT scans to calculate ΔSF (%/month). SF loss was defined as ΔSF < -5%/month. Survival analyses for overall survival (OS) and progression-free survival (PFS) were performed. Patients with SF loss had shorter OS (median, 9.5 months vs. not reached; p < 0.001) and PFS (median, 2.6 months vs. 33.5 months; p < 0.001) than patients without SF loss. ΔSF was independently associated with OS (adjusted hazard ratio (HR), 1.49; 95% confidence interval (CI), 1.07-2.07; p = 0.020) and PFS (adjusted HR, 1.57; 95% CI, 1.17-2.12; p = 0.003), with a 5%/month decrease in SF increasing the risk of death and progression by 49% and 57%, respectively. In conclusion, Loss of SF after treatment initiation is a significant and independent poor prognostic factor for OS and PFS in patients with metastatic ccRCC who receive ICI therapy.

Five-gene signature for the prediction of response to immune checkpoint inhibitors in patients with gastric and urothelial carcinomas.

BACKGROUND: Ample evidence supports the potential of programmed death-ligand 1 (PD-L1) expression, detected by immunohistochemistry, as a predictive biomarker for immunotherapy in patients with advanced cancers. To predict the response to immune checkpoint inhibitors in patients with gastric and urothelial carcinomas, we aimed to replace PD-L1 combined positive score (CPS) with CD274 mRNA in the original four-gene signature and PD-L1 CPS model developed by us. METHOD: We used quantitative real-time polymerase chain reaction (qRT-PCR) to measure the expression levels of five target genes in a cohort of 49 patients (33 with gastric cancer and 16 with urothelial carcinoma) who had received immunotherapy and whose therapeutic responses were available. The predictive performance was evaluated using R package maxstat. RESULTS: Cutoff values of mRNA expression level were measured using the log-rank statistics for progression-free survival (PFS). Based on these cutoffs, immunotherapy responses were predicted and sorted into responder (n = 12, 24.5%) and non-responder (n = 37, 75.5%) groups. The median PFS values of predicted responders and non-responders were 14.8 months (95% confidence interval [CI]: 0-34.7) and 4.7 months (95% CI: 1.0-8.4, p = 0.02), respectively. Among the 12 predicted responders, 10 had microsatellite-stable tumors with a low tumor mutational burden. The actual clinical responses (complete and partial) were higher in the responder group than those in the non-responder group: 83.3% and 16.2%, respectively. CONCLUSION: We modified a predictive biomarker for CD274 mRNA expression to predict the response to immunotherapy in patients with gastric or urothelial carcinomas.

Neoadjuvant Nivolumab Plus Gemcitabine/Cisplatin Chemotherapy in Muscle-Invasive Urothelial Carcinoma of the Bladder.

PURPOSE: The activity and safety of neoadjuvant nivolumab plus gemcitabine/cisplatin (N+GC) were tested in patients with muscle-invasive bladder urothelial carcinoma (MIBC). Materials and Methods: In a prospective phase II trial, patients with cT2-T4a N0 MIBC who were eligible for cisplatin and medically appropriate to undergo radical cystectomy (RC) were enrolled. Treatment with nivolumab 3 mg/kg on days 1 and 15 plus GC (cisplatin 70 mg/m2 on day 1, and gemcitabine 1,000 mg/m2 on days 1, 8, and 15) was repeated every 28 days up to 3 or 4 cycles, depending on the surgery schedules. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included pathologic downstaging (≤ ypT1), disease-free survival (DFS), and safety. RESULTS: Between September 2019 and October 2020, 51 patients were enrolled. Neoadjuvant N+GC was well tolerated. Among 49 patients who completed neoadjuvant N+GC, clinical complete response (cCR) was achieved in 59% of intent-to-treat (ITT) population. RC was performed in 34 (69%) patients. pCR was achieved in 24% (12/49) of ITT population and 35% (12/34) of RC patients. Median DFS was not reached. Over a median follow-up of 24 months, 12 patients experienced disease recurrence and were treated with palliative therapy or surgery. Although 12 patients declined surgery and were treated with concurrent chemoradiotherapy, DFS was longer in patients with cCR after neoadjuvant therapy than those without. Preoperative programmed death-ligand 1 (PD-L1) did not correlate with pCR or pathologic downstaging rates. CONCLUSION: Neoadjuvant N+GC was feasible and provided meaningful pathologic responses in patients with MIBC, regardless of baseline PD-L1 expression (ONO-4538-X41; CRIS.nih.go.kr, KCT0003804).

The Ring Study: an international comparison of PD-L1 diagnostic assays and their interpretation in non-small cell lung cancer, head and neck squamous cell cancer and urothelial cancer.

PD-L1 immunohistochemistry has been approved as a diagnostic assay for immunotherapy. However, an international comparison across multiple cancers is lacking. This study aimed to assess the performance of PD-L1 diagnostic assays in non-small cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC) and urothelial cancer (UC). The excisional specimens of NSCLC, HNSCC and UC were assayed by Ventana SP263 and scored at three sites in each country, including Australia, Brazil, Korea, Mexico, Russia and Taiwan. All slides were rotated to two other sites for interobserver scoring. The same cohort of NSCLC was assessed with Dako 22C3 pharmDx PD-L1 for comparison. The PD-L1 immunopositivity was scored according to the approved PD-L1 scoring algorithms which were the percentage of PD-L1-expressing tumour cell (TC) and tumour proportion score (TPS) by Ventana SP263 and Dako 22C3 staining, respectively. In NSCLC, the comparison demonstrated the comparability of the SP263 and 22C3 assays (cut-off of 1%, κ=0.71; 25%, κ=0.75; 50%, κ=0.81). The interobserver comparisons showed moderate to almost perfect agreement for SP263 in TC staining at 25% cut-off (NSCLC, κ=0.72 to 0.86; HNSCC, κ=0.60 to 0.82; UC, κ=0.68 to 0.91) and at 50% cut-off for NSCLC (κ=0.64 to 0.90). Regarding the immune cell (IC) scoring in UC, there was a lower correlation (concordance correlation coefficient=0.10 to 0.68) and poor to substantial agreements at the 1%, 5%, 10% and 25% cut-offs (κ= -0.04 to 0.76). The interchangeability of SP263 and 22C3 in NSCLC might be acceptable, especially at the 50% cut-off. In HNSCC, the performance of SP263 is comparable across five countries. In UC, there was low concordance of IC staining, which may affect treatment decisions. Overall, the study showed the reliability and reproducibility of SP263 in NSCLC, HNSCC and UC.

Patterns of Extrathoracic Metastasis in Lung Cancer Patients.

Metastasis is a major cause of death in lung cancer patients. Therefore, a deeper understanding of the metastatic mechanisms is important for developing better management strategies for lung cancer patients. This study evaluated the patterns of extrathoracic metastases in lung cancer. We retrieved data for 25,103 lung cancer patients from an institutional database and then evaluated the impacts of clinicopathologic factors on metastasis patterns. We found that 36.5% of patients had extrathoracic metastasis. Younger patients had a significantly higher extrathoracic metastasis rate in most histologic subtypes. Metastases to the bone (58.3%), central nervous system (CNS) (44.3%), liver (26.6%) and adrenal gland (18.3%) accounted for 85.5% of all extrathoracic metastases. Patients with nonmucinous adenocarcinoma had significantly higher bone metastasis rate. Patients with small cell carcinoma and large cell neuroendocrine carcinoma (LCNEC) had significantly higher liver metastasis rates. Further, patients with LCNEC also had a significantly lower bone metastasis rate, and patients with squamous cell carcinoma had a significantly lower CNS metastasis rate. Patients with multiple cancers had similar patterns of metastasis compared to patients with only lung cancer. In conclusion, different histologic subtypes of lung cancer have different metastatic patterns. Our study might help clinicians decide on follow-up strategies.

Recoverability of Diabetic Nephropathy of Donor Kidney After Kidney Transplantation.

Some kidney donors have diabetes, and little of their natural course of diabetic nephropathy (DN) is known. The aim of this study was to analyze the changes in pathologic lesions in the diabetic donor kidney after KT by performing protocol biopsy two weeks and one year after KT. This retrospective study included 103 patients who underwent KT, with kidneys from donors with a history of diabetes mellitus (DM). Among them, data of 34 patients who underwent biopsy two weeks and one year after KT were reviewed. Biopsy specimens were reviewed using light microscopy and electron microscopy. Glomerular basement membrane (GBM) thickness at 2 weeks and 1 year was compared. Biopsy showed that DN occurred in 29 of the 34 patients. Only trivial histological changes were observed in 22 patients (64.7%), including 5 patients who did not show DN. At one year after transplantation, there was no change in the DN histologic class in 26 patients (76.5%), and there was no statistically significant difference in the change in GBM thickness. This pattern was observed regardless of the recipient's DM or glycemic control. With this understanding, clinicians can use kidneys from DM donors with more comfort, thereby reducing the kidney discard rate.

Clinical value of urinary cytokines/chemokines as prognostic markers in patients with crescentic glomerulonephritis.

Crescentic glomerulonephritis (CrGN) usually requires urgent immunosuppressive treatment. However, aggressive immunosuppressive treatment is often difficult because of the patients' medical conditions or comorbidities. Prognostic markers including urinary cytokines/chemokines as noninvasive biomarkers were explored in CrGN patients. This prospective cohort study included 82 patients with biopsy-confirmed CrGN from 2002 to 2015 who were followed up for 5 years. Urine and serum cytokines/chemokines on the day of kidney biopsy were analyzed in 36 patients. The median age was 65 years and 47.6% were male. Baseline estimated glomerular filtration rate (eGFR) and interstitial fibrosis and tubular atrophy (IFTA) scores were identified as significant prognostic factors. Among patients with cytokines/chemokines measurement, increased IL-10 level was identified as an independent predictor of good prognosis, and increased levels of urinary MCP-1 and fractalkine tended to be associated with good prognosis after adjusting for baseline eGFR and IFTA score. However, semiquantitative analysis of intrarenal leukocytes did not show prognostic value predicting renal outcome or correlation with urinary cytokines/chemokines. This study supports the clinical importance of baseline eGFR and IFTA scores and suggests potential usefulness of urinary IL-10, MCP-1, and fractalkine as prognostic markers for predicting renal outcomes in patients with CrGN.

Expression of CD274 mRNA Measured by qRT-PCR Correlates With PD-L1 Immunohistochemistry in Gastric and Urothelial Carcinoma.

Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is widely used to predict the clinical responses to immune checkpoint inhibitors (ICIs). However, PD-L1 IHC suffers from the complexity of multiple testing platforms and different cutoff values caused by the current one drug-one diagnostic test co-development approach for ICIs. We aimed to test whether PD-L1 (CD274) mRNA expression levels measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) can represent PD-L1 IHC and predict responses to ICI. The FDA-approved PD-L1 IHC results with 22C3 pharmDx (gastric cancer) and SP142 (urothelial carcinoma) were compared with CD274 mRNA expression levels via qRT-PCR using the same formalin-fixed, paraffin-embedded tissue blocks from 59 gastric cancer and 41 urothelial carcinoma samples. CD274 mRNA expression was identified using three independent sets of primers and TaqMan® probes targeting exon 1-2, exon 3-4, and exon 5-6. CD274 mRNA levels in spanning exon 1-2, exon 3-4, and exon 5-6 junctions of CD274 correlated well with PD-L1 expression (r2=0.81, 0.65, and 0.59, respectively). The area under the curve of exon 1-2 was the highest (0.783), followed by exon 3-4 (0.701), and exon 5-6 (0.671) of the CD274 gene against the PD-L1 combined positive score cutoff of 10. When CD274 mRNA expression was matched for response to immunotherapy, the overall response rate was higher in patients with high CD274 mRNA levels with a cutoff of 0.0722 (gastric cancer) and 0.0480 (urothelial carcinoma) than in those with low CD274 mRNA expression (P < 0.001 and P = 0.018, respectively). These results show that CD274 mRNA levels predicted ICI responses in patients with gastric or urothelial carcinomas and could be used as alternatives for PD-L1 IHC.

A Retrospective Study of First-Line Therapy Involving Immune Checkpoint Inhibitors in Patients With Poor Risk Metastatic Renal Cell Carcinoma.

Purpose: Patients with International Metastatic RCC Database Consortium (IMDC) poor risk metastatic renal cell carcinoma (mRCC) rarely respond to first-line tyrosine kinase inhibitors (TKIs) including sunitinib, and carries a very poor prognosis. In recent years, combination therapy involving immune checkpoint inhibitors (ICIs) have demonstrated superior efficacy to sunitinib in poor risk disease. Materials and Methods: In a retrospective study using a cancer chemotherapy registry, 206 consecutive patients with mRCC in the first-line setting were identified between Oct 2019 and Dec 2020. Sixty-one patients had a poor risk mRCC, and were treated with TKI monotherapy (n=36), nivolumab plus ipilimumab (n=16), or pembrolizumab plus axitinib (n=9). Endpoints included overall survival (OS), progression-free survival (PFS), response rate (RR), and safety. Results: Patients' median age was 61 years and the median number of risk factors was 3 (range, 3-5). During a median 23.0 months of follow-up, the median OS was 24.3 months with ICI-based combinations and 14.8 months with TKI monotherapy, and the median PFS periods were 9.3 months and 3.4 months, respectively. An objective response occurred in 60% of the patients receiving ICI-based combinations and in 19% of those receiving TKI monotherapy (P=0.001). In the multivariate regression model, number of IMDC risk factors and the ICI-based combination therapy were independent prognostic factors for PFS. All-causality grade 3 or 4 adverse events were 44% for ICI-based combinations and 50% for TKI monotherapy. Conclusions: Among patients with poor risk mRCC, first-line ICI-based therapy showed significantly longer OS and PFS, as well as a higher RR, than TKI monotherapy.

Neoadjuvant chemotherapy with gemcitabine and cisplatin followed by selective bladder preservation chemoradiotherapy in muscle-invasive urothelial carcinoma of bladder.

PURPOSE: To assess the safety and efficacy of gemcitabine and cisplatin as neoadjuvant chemotherapy followed by selective bladder preservation chemoradiotherapy in muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: Patients with clinical T2-T4aN0M0 MIBC eligible for radical cystectomy and cisplatin-based chemotherapy were treated with gemcitabine 1,000 mg/m² on days 1, 8 and 15, and cisplatin 70 mg/m² on day 1 every 28 days for 3 cycles. After clinical re-staging with computed tomography scans and cystoscopy, patients with clinical complete response (CR) were eligible to proceed without cystectomy and receive bladder preservation chemoradiotherapy involving weekly cisplatin 10 mg/m² and up to 70.2 Gy of radiation. The primary endpoint of the present prospective phase II study was metastasis-free survival (MFS). RESULTS: Between Oct 2017 and Nov 2019, a total of 138 MIBC patients were enrolled and treated with neoadjuvant gemcitabine/cisplatin. Neoadjuvant chemotherapy was well-tolerated, with fatigue, nausea, and pruritus being the most commonly observed adverse events. After completion of planned neoadjuvant chemotherapy, 54 patients with a clinical CR and 10 patients who did not have CR but refused surgery received bladder preservation chemoradiotherapy. With a median follow-up duration of 34 months (95% confidence interval [CI], 32%-36%), the 3-year MFS rate in 64 chemoradiotherapy patients was calculated to be 70% (95% CI, 58%-82%). CONCLUSIONS: Neoadjuvant chemotherapy followed by selective bladder preservation chemoradiotherapy based on the clinical CR was feasible and efficacious in the treatment of MIBC.

Repair phase modeling of ischemic acute kidney injury: recovery vs. transition to chronic kidney disease.

The repair mechanism after ischemic acute kidney injury (AKI) involves complex immunologic processes, which determine long-term renal outcomes. Through investigating two murine ischemia-reperfusion injury (IRI) models: bilateral IRI (BIRI) and unilateral IRI (UIRI), we aimed to determine an appropriate murine model that could simulate the recovery phase of ischemic AKI. Changes in renal function, phenotypes of kidney mononuclear cells, renal fibrosis, and intrarenal cytokine/chemokine expression were serially analyzed up to 12 weeks after IRI. Plasma creatinine and BUN concentrations increased and remained elevated in the BIRI group until 7 days but decreased to comparable levels with the sham control group at 2 weeks after surgery and thereafter, whereas plasma creatinine and BUN concentrations remained unchanged in the UIRI group. Intrarenal total leukocytes, and effector memory and activated phenotypes of CD4 and CD8 T cells markedly increased in the postischemic kidneys in both IRI groups. Expression of proinflammatory cytokines/chemokines and TGF-ß1 was enhanced in the postischemic kidneys of both IRI groups with a higher degree in the UIRI group. Importantly, intrarenal immunologic changes of the BIRI group persisted until 6 weeks despite full functional recovery. The postischemic kidneys of the UIRI group showed earlier and more pronounced proinflammatory conditions as well as more severe atrophic and fibrotic changes compared to the BIRI group. These findings support the utility of longer follow-ups of BIRI and UIRI models for investigating the adaptive repair process, which facilitates recovery of ischemic AKI and maladaptive repair process may result in AKI to CKD transition, respectively.

Direct comparison of the next-generation sequencing and iTERT PCR methods for the diagnosis of TERT hotspot mutations in advanced solid cancers.

BACKGROUND: Mutations in the telomerase reverse transcriptase (TERT) promoter region have been proposed as novel mechanisms for the transcriptional activation of telomerase. Two recurrent mutations in the TERT promoter, C228T and C250T, are prognostic biomarkers. Herein, we directly compared the commercially available iTERT PCR kit with NGS-based deep sequencing to validate the NGS results and determine the analytical sensitivity of the PCR kit. METHODS: Of the 2032 advanced solid tumors diagnosed using the TruSight Oncology 500 NGS test, mutations in the TERT promoter region were detected in 103 cases, with 79 cases of C228T, 22 cases of C250T, and 2 cases of C228A hotspot mutations. TERT promoter mutations were detected from 31 urinary bladder, 19 pancreato-biliary, 22 hepatic, 12 malignant melanoma, and 12 other tumor samples. RESULTS: In all 103 TERT-mutated cases detected using NGS, the same DNA samples were also tested with the iTERT PCR/Sanger sequencing. PCR successfully verified the presence of the same mutations in all cases with 100% agreement. The average read depth of the TERT promoter region was 320.4, which was significantly lower than that of the other genes (mean, 743.5). Interestingly, NGS read depth was significantly higher at C250 compared to C228 (p < 0.001). CONCLUSIONS: The NGS test results were validated by a PCR test and iTERT PCR/Sanger sequencing is sensitive for the identification of the TERT promoter mutations.

Genomic Sequencing for Bladder Urothelial Carcinoma and Its Clinical Implications for Immunotherapy.

PURPOSE: This study aimed to explore the genomic and transcriptomic landscape of bladder cancer (BC) and its implication for treatment with an immune checkpoint inhibitor (ICI). MATERIALS AND METHODS: We analyzed whole-exome and -transcriptome sequences of tumor samples from 64 BC patients who underwent surgical resection with either transurethral resection or radical cystectomy. For exploratory purposes, programmed death-ligand 1 (PD-L1) expression was evaluated in a subset of patients (n=57) including those treated with ICI (n=8). RESULTS: We identified frequent molecular dysregulations in chromatin regulatory genes (KDM6A, ARID1A, MLL2, and STAG2) and recurrent copy number alterations. Thirty-five samples (54.7%) were PD-L1-positive (PD-L1 combined positive score ≥ 1) with a significantly higher exonic tumor mutational burden (TMB) compared to PD-L1-negative BC samples (p=0.010). We observed that various immune-responsive pathways, including the PD-L1 signaling pathway, were enriched significantly in PD-L1-positive BCs. Interestingly, genes in the CTLA4 pathway were enriched significantly in PD-L1-positive BC as well. Among eight patients who received ICI, progressive disease was confirmed in one patient, whose tumor had low exonic TMB, negative PD-L1 status, and a relatively colder microenvironment. CONCLUSION: Gaining new insights into the molecular landscape of BC will improve treatment strategies. Our analysis suggests a rationale for studying dual checkpoint inhibition against BC.

Risk Factors and Patterns of Locoregional Recurrence after Radical Nephrectomy for Locally Advanced Renal Cell Carcinoma.

PURPOSE: We aimed to investigate the risk factors and patterns of locoregional recurrence (LRR) after radical nephrectomy (RN) in patients with locally advanced renal cell carcinoma (RCC). MATERIALS AND METHODS: We retrospectively analyzed 245 patients who underwent RN for non-metastatic pT3-4 RCC from January 2006 to January 2016. We analyzed the risk factors associated with poor locoregional control using Cox regression. Anatomical mapping was performed on reference computed tomography scans showing intact kidneys. RESULTS: The median follow-up duration was 56 months (range, 1 to 128 months). Tumor extension to renal vessels or the inferior vena cava (IVC) and Fuhrman's nuclear grade IV were identified as independent risk factors of LRR. The 5-year actuarial LRR rates in groups with no risk factor, one risk factor, and two risk factors were 2.3%, 19.8%, and 30.8%, respectively (p < 0.001). The locations of LRR were distributed as follows: aortocaval area (n=2), paraaortic area (n=4), retrocaval area (n=5), and tumor bed (n=11). No LRR was observed above the celiac axis (CA) or under the inferior mesenteric artery (IMA). CONCLUSION: Tumor extension to renal vessels or the IVC and Fuhrman's nuclear grade IV were the independent risk factors associated with LRR after RN for pT3-4 RCC. The locations of LRR after RN for RCC were distributed in the tumor bed and regional lymphatic area from the bifurcation of the CA to that of the IMA.