Effect of HLA Genotype on Anti-PD-1 Antibody Treatment for Advanced Renal Cell Carcinoma in the SNiP-RCC Study.

Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC.

Paratesticular cellular angiofibroma: a case report.

INTRODUCTION: Paratesticular cellular angiofibroma is a rare benign mesenchymal tumor. The optimal management is surgical resection due to the difficulty of preoperative accurate diagnosis. CASE PRESENTATION: A 51-year-old Japanese male visited our hospital complaining of asymptomatic left scrotal swelling. Physical examination revealed a nontender elastic paratesticular mass (5.5 cm in diameter). Although testicular germ cell tumor was ruled out clinically, the possibility of malignant potential remained for the tumor. Since the patient consented to complete resection, a transinguinal radical orchiectomy was performed. The pathological diagnosis revealed cellular angiofibroma. The patient recovered without perioperative complications, and no apparent recurrence was observed at 5 years after surgery. CONCLUSION: The pathological findings were compatible for cellular angiofibroma. The tumor was successfully resected, and no apparent recurrence was observed at 5 years after surgery.

Bilateral long ureteral strictures were successfully replaced by ileum in inverse seven configuration: A case report.

INTRODUCTION AND IMPORTANCE: Ureteral stricture is a potential postoperative complication of pelvic surgery. Repair is performed in the intraoperative or postoperative phase for various reasons. Ileal reconstruction of ureter is considered for extensive and bilateral ureteral injuries. CASE PRESENTATION: A 44-year-old female presented to the hospital where she had undergone hysterectomy two months prior, with acute renal failure due to bilateral hydronephrosis. Radiological examination revealed bilateral distal ureteral stricture measuring 5 cm in length. After failed balloon-dilation, ileal reconstruction was successfully performed without perioperative complications; and she has remained free from hydronephrosis with normal renal function for four years. CLINICAL DISCUSSION: Ileal interposition can be used for reconstruction of long lengths or bilateral ureteral injuries. High success rates and low rates of complication have been reported, and the long-term outcome was also acceptable. Apparent ureteral injury was not observed in our case; however, narrowing of ureteral lumen due to submucosal and sub-adventitial edema was observed as a possible cause of strictures. Although, some minor occult injuries during hysterectomy, including thermal effect, ischemia or physical damage due to traction on the ureters were suggested, we were unable to conclusively determine the etiology. CONCLUSION: Ileal ureter replacement is a useful reconstruction, and the inverse seven configuration is suitable for long bilateral strictures of distal ureter.

Clinicopathological characteristics of adrenocortical carcinoma in the Kyushu-Okinawa area of Japan.

OBJECTIVE: Adrenocortical carcinoma is a rare condition, with limited comprehensive reports from Japan. This study aimed to review Japan's data on adrenocortical carcinoma by assessing information from 46 patients-with adrenocortical carcinoma across 10 Japanese university hospitals. METHODS: We conducted a retrospective multi-institutional analysis of the clinical characteristics of adrenocortical carcinoma in Japan. We evaluated data from 46 patients across 10 university hospitals over 10 years and analyzed the relationship between clinicopathological characteristics and overall survival. RESULTS: Five- and 10-year overall survival rates were 59% and 53%, respectively. Overall survival was significantly different among the tumor-node-metastasis system for adrenocortical carcinoma of the American Joint Committee on Cancer/International Union Against Cancer, with the worst prognosis in stage IV (p = 0.0044). In our cohort, neither the Weiss score nor the Ki-67 proliferation index correlated with overall survival. Adjuvant treatment did not yield improved overall survival, whereas resection of the primary tumor in stage IV disease was significantly associated with improved overall survival (p = 0.0262). Out of the cases evaluated for plasma hormones, plasma cortisol, aldosterone, testosterone, and DHEA-S levels were measured at 23%, 42%, 29%, and 62%, respectively, demonstrating higher levels than the upper normal limits. CONCLUSION: Patients with stage IV adrenocortical carcinoma had a poor prognosis; however, resection of the primary tumor in stage IV disease was associated with prolonged survival. The results of this study are expected to contribute to future treatment of adrenocortical carcinoma in Japan.

Hepatic and lung methotrexate-associated polymorphic lymphoproliferative disorders arising during postoperative follow-up of renal cell carcinoma: a case report.

INTRODUCTION: Methotrexate induces lymphoproliferative disorders on rare occasions; however, its pathogenesis remains unknown. A clinical diagnosis based on imaging studies alone is often difficult. CASE PRESENTATION: A 57-year-old Japanese woman was referred to our department for the evaluation of multiple lung and hepatic nodules that developed during methotrexate treatment for rheumatoid arthritis. Since she had a history of nephrectomy for localized renal cell carcinoma, multiple lung and hepatic metastases were initially considered. However, pathological diagnosis of the lung nodules (needle biopsy) revealed methotrexate-associated polymorphic-type lymphoproliferative disorders. After methotrexate discontinuation, continuous smooth shrinkage of the lung and liver lymphoproliferative disorders was observed. CONCLUSION: Methotrexate-associated lymphoproliferative disorders should be considered in the event of newly appearing neoplastic lesions, even during follow-up for renal cell carcinoma, if methotrexate is being administered.

Prolapse of duodenal bulb from esophageal hiatal hernia: A case report.

INTRODUCTION: The number of patients with hiatal hernia has increased. Paraesophageal and mixed hiatal hernias are absolute indications for surgical treatment due to the possibility of blood flow disturbances to the stomach and other organs. CASE PRESENTATION: A 77-year-old woman with a history of type IV esophageal hiatal hernia (under observation), multiple operations presented with a chief complaint of vomiting. She was diagnosed with a type IV esophageal hiatal hernia with incarceration of the duodenal bulb into the mediastinum. Although the incarceration was relieved with conservative treatment, the patient was at a high risk for recurrence; therefore, surgical hernia repair was performed. Intraoperatively, the hernia portal was severely dilated and the duodenal bulb was easily accessible to the mediastinum due to its high mobility. Fundoplication was performed using the Toupet procedure. No stenosis at the fundoplication site was observed on intraoperative upper gastrointestinal endoscopy. DISCUSSION: The causes of prolapse and incarceration of the duodenal bulb into the mediastinum were speculated to be weakening of the tissue due to aging, adhesion of the omentum to the hernia portal due to chronic prolapse of the stomach toward the mediastinum, increased intra-abdominal pressure due to a rounded back, and anatomical shortening of the distance between the esophageal hiatus and the duodenal bulb. The Toupet method was used as it is associated with a lower incidence of dysphagia. CONCLUSION: Further investigation is needed to determine the best surgical technique.

Epithelioid Angiomyolipoma with Tumor Thrombus into Inferior Vena Cava Presurgically Treated with Combination Therapy of Pembrolizumab and Axitinib: A Case Report.

Epithelioid angiomyolipoma (EAML) is a rare variant of AML with malignant potential. It is occasionally difficult to distinguish EAML from renal cell carcinoma (RCC) on imaging. A 72-year-old woman was admitted to our hospital for the treatment of a left renal tumor with relatively high blood flow and a tumor thrombus extending to the inferior vena cava, suggesting RCC. The patient underwent presurgical combination therapy with axitinib and pembrolizumab. This treatment significantly shortened the thrombus, and radical nephrectomy was performed. The pathological findings were compatible with EAML, and the treatment effects were observed. We report a case treated pre-surgically with a combined therapy of pembrolizumab and axitinib, with a favorable response as a treatment option for EAML.

Clinical factors for tumor response, progression, and survival in nivolumab for advanced renal cell carcinoma in the SNiP-RCC study.

BACKGROUND: This study is part of the SNPs in Nivolumab PD-1 inhibitor for RCC (SNiP-RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients. METHODS: We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression-free survival (PFS), overall survival (OS), and treatment-related grade ≥ 3 (serious adverse events [SAEs]). RESULTS: We included 222 patients. The median age was 69 years (interquartile range 62-74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS. CONCLUSION: The SNiP-RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy.

A case of hyperammonemia occurring during treatment of metastatic renal cell carcinoma with axitinib.

Introduction: Although the incidence of hyperammonemia as an adverse event of tyrosine kinase inhibitors is quite low, several cases of tyrosine kinase inhibitor associated hyperammonemia have been reported. We report a case of hyperammonemia, that occurred during combined treatment with axitinib and pembrolizumab in a metastatic renal cell carcinoma patient without hepatic disorder or liver metastases. Case presentation: A 77-year-old Japanese woman was diagnosed with metastatic renal cell carcinoma and was treated with pembrolizumab and axitinib. Both agents were subsequently discontinued due to hyperammonemia with hypothyroidism. After recovery, the patient resumed single-agent therapy with axitinib. However, hyperammonemia and hypothyroidism occurred again, suggesting axitinib-inducible adverse event. After nephrectomy, a lower dose of axitinib was restarted and continued safely for residual metastases under prophylactic treatment with aminoleban, lactulose, and levothyroxine. Conclusion: The rare occurrence of hyperammonemia should be considered during treatment with VEGFR- targeted tyrosine kinase inhibitor including axitinib, and supportive prophylactic medication may be useful.

Real-world treatment outcomes of patients with penile cancer in the Kyushu-Okinawa area of Japan in the pre-guideline era.

OBJECTIVES: To understand the real-world outcomes for patients with penile cancer in the Kyushu-Okinawa area before the introduction of practice guidelines in Japan. METHODS: We retrospectively collected medical information on patients with penile squamous cell carcinoma and penile intraepithelial neoplasia at 12 university hospitals and their affiliated hospitals in the Kyushu-Okinawa area from January 2009 to December 2020. Patients with unknown clinical stage were excluded. Patient background characteristics and survival, as well as pretreatment factors involved in survival, were investigated. RESULTS: A total of 196 patients were included. Patients with clinical stage 0, I, IIA, IIB, IIIA, IIIB and IV comprised 9.7, 26.0, 22.4, 2.6, 10.7, 14.3 and 14.3%, respectively. The median follow-up was 26 months, and the mean 5-year overall survival and cancer-specific survival rates were 74.3 and 79.8%, respectively. On univariate analysis, tumor diameter ≥ 30 mm, penile shaft tumor, Eastern Cooperative Oncology Group performance status ≥ 1, cT ≥ 3, cN ≥ 2 and cM1 were associated with significantly poorer cancer-specific survival. On multivariate analysis, pretreatment factors of cN ≥ 2 (hazard ratio, 32.5; 95% confidence interval, 5.08-208; P = 0.0002), Eastern Cooperative Oncology Group performance status ≥ 1 (4.42; 1.79-10.9; P = 0.0012) and cT ≥ 3 (3.34; 1.11-10.1; P = 0.0319) were identified as independent prognostic factors. CONCLUSIONS: The study revealed basic data for future penile cancer treatment and research, including survival rates according to clinical stages, and identified cN ≥ 2, Eastern Cooperative Oncology Group performance status ≥ 1 and cT ≥ 3 at initial diagnosis as independent prognostic factors. Evidence for penile cancer in Japan is particularly scarce, and future large-scale prospective studies are warranted.

Identification of the α2 chain of interleukin-13 receptor as a potential biomarker for predicting castration resistance of prostate cancer using patient-derived xenograft models.

BACKGROUND: Several treatment strategies use upfront chemotherapy or androgen receptor axis-targeting therapies for metastatic prostate cancer. However, there are no useful biomarkers for selecting appropriate patients who urgently require these treatments. METHODS: Novel patient-derived xenograft (PDX) castration-sensitive and -resistant models were established and gene expression patterns were comprehensively compared. The function of a gene highly expressed in the castration-resistant models was evaluated by its overexpression in LNCaP prostate cancer cells. Protein expression in the tumors and serum of patients was examined by immunohistochemistry and ELISA, and correlations with castration resistance were analyzed. RESULTS: Expression of the α2 chain of interleukin-13 receptor (IL13Rα2) was higher in castration-resistant PDX tumors. LNCaP cells overexpressing IL13Rα2 acquired castration resistance in vitro and in vivo. In tissue samples, IL13Rα2 expression levels were significantly associated with castration-resistant progression (p < 0.05). In serum samples, IL13Rα2 levels could be measured in 5 of 28 (18%) castration-resistant prostate cancer patients. CONCLUSION: IL13Rα2 was highly expressed in castration-resistant prostate cancer PDX models and was associated with the castration resistance of prostate cancer cells. It might be a potential tissue and serum biomarker for predicting castration resistance in prostate cancer patients.

Effect of genetic polymorphisms on outcomes following nivolumab for advanced renal cell carcinoma in the SNiP-RCC trial.

BACKGROUND: Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. METHODS: This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. RESULTS: A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. CONCLUSION: This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.

Possible role of combined therapy targeting MET and pro-HGF activation for renal cell carcinoma: analysis by human HGF-producing SCID mice.

MET is a high-affinity receptor tyrosine kinase of HGF (hepatocyte growth factor). HGF is secreted as an inactive single-chain precursor (pro-HGF), which requires proteolytic activation for conversion to an active form. HGF activator inhibitor (HAI)-2 is a transmembrane Kunitz-type serine protease inhibitor, which inhibits all pro-HGF-activating enzymes. In RCC, increased expression of MET and decreased expression of HAI-2 were reported to be poor prognostic factors. In the current study, we tried to inhibit the growth of RCC cells by dual inhibition of both MET phosphorylation and pro-HGF-activation using MET inhibitor and HAI-2 overexpression. A transgenic mouse model which expressed human HGF (HGF mouse) was used for in vivo analysis to evaluate the HGF/MET signaling axis accurately. Initially, doxycycline-induced HAI-2 overexpression RCC cells (786-O-HAI2) were prepared. The cells were cultured with pro-HGF, and inhibitory effect of MET inhibitor (SCC244) and HAI-2 was evaluated by phosphorylation of MET and cell proliferation. Next, the cells were subcutaneously implanted to HGF mice and the growth inhibition was determined by SCC244 and HAI-2. Single use of each inhibitor showed significant inhibition in MET phosphorylation, migration and proliferation of 786-O-HAI2 cells; however, the strongest effect was observed by combined use of both inhibitors. Although in vivo analysis also showed apparent downregulation of MET phosphorylation and growth inhibition in combined treatment, statistical significance was not observed compared with single use of MET inhibitor. Combined treatment with MET-TKI and HAI-2 suggested to consider as a candidate for new strong therapy for RCC.

Protocadherin B9 Is Associated with Human Esophageal Squamous Cell Carcinoma Progression.

INTRODUCTION: Esophageal cancer is the sixth leading cause of cancer-related death worldwide. However, molecular targeted therapy and novel therapeutic targets are needed for esophageal squamous cell cancer (ESCC). In a previous study, we reported that protocadherin (PCDH) B9 plays an important role in several cancers. Therefore, in this study, we examined the clinical significance of PCDHB9 expression in ESCC. METHODS: PCDHB9 expression was examined using immunohistochemistry in 128 cases and using quantitative reverse transcription-polymerase chain reaction in 16 cases of ESCC. PCDHB9 function in ESCC cells was examined using RNA interference. RESULTS: High PCDHB9 expression was identified in 5 of 16 (31.3%). In total, 51 (40%) ESCC cases showed strong PCDHB9 expression, whereas nonneoplastic mucosa rarely showed its expression. High PCDHB9 expression was significantly associated with T classification, N grade, and stage in ESCC. In ESCC cell lines, PCDHB9 knockdown affected cell growth, migration, and adhesion. Further, the expression of integrin (ITG) A3, ITGA4, ITGA5, ITGB1, ITGB6, vimentin, snail family transcriptional repressor 1, and cadherin 2 (NCAD) was significantly reduced and cadherin 1 was significantly increased in PCDHB9 knockdown ESCC cells. CONCLUSION: These results suggest that PCDHB9 plays a tumor-promoting role and is a potential biomarker and therapeutic target in ESCC.

Validation of appendiceal stump invagination in laparoscopic appendectomy.

INTRODUCTION: There are various methods for appendiceal stump dissection, but the necessity for stump invagination remains unclear. This study aimed to assess the efficacy of appendiceal stump invagination in patients with acute appendicitis after laparoscopic appendectomy (LA). METHODS: We enrolled 327 patients with acute appendicitis who underwent LA between 2012 and 2020. Perioperative variables and surgical outcomes were analyzed between the invagination of the appendiceal stump and noninvagination groups. Propensity score-matched analysis (PSM) was performed. RESULTS: More patients experienced severe inflammation and severe intra-abdominal contamination in the noninvagination group than in the invagination group. Patients in the noninvagination group had an older age, higher body mass index, and poorer American Society of Anesthesiologists physical status than the invagination group. Severe inflammation in the noninvagination group was associated with longer hospital stays and poorer postoperative complications than in the invagination group. PSM analysis was performed to minimize bias in the two groups. After PSM analysis, there were no significant differences in surgical site infection, postoperative intra-abdominal abscess, Clavien-Dindo class ≥IIIa, or postoperative stay between the two groups. During the follow-up period, the postoperative adhesive ileus was not significantly different between the invagination and noninvagination groups. CONCLUSION: Invagination of the appendiceal stump during LA is not necessary to prevent short- and long-term complications. Even in cases dissected using a laparoscopic endostapler, the appendiceal stump per se is not related to postoperative adhesive ileus.

Clinical Phase I Study of TAS102/Irinotecan/Bevacizumab Combination Therapy in Japanese Patients With Unresectable Metastatic Colorectal Cancer (mCRC).

BACKGROUND: In this phase I study, we aimed to examine the safety of a triple combination (TAS-102/irinotecan/bevacizumab) therapy in patients with previously treated metastatic colorectal cancer (mCRC). METHODS: In the TAS-102 dose-escalation phase, we determined dose-limiting toxicity (DLT), estimated the maximum tolerated dose (MTD), and determined the recommended dose (RD); in the expansion phase, we evaluated safety. The RD was administered in advance for 10 patients. The TAS-102 dose was increased to 25-35 mg/m2 and administered orally twice on days 1-5 and 8-12. Irinotecan (100 mg/m2) and bevacizumab (5 mg/m2) were administered on days 1 and 15 of the treatment, respectively. RESULTS: Fifteen patients were enrolled in dose-escalation Levels 1-3, and ten in the expansion phase. A 30 mg/m2 TAS-102 dose at Level 2 was administered to three patients, with one presenting grade 4 neutropenia. A 35 mg/m2 TAS-102 dose at Level 3 was administered to five patients, with three patients presenting grade 4 neutropenia and grade 3 DLTs. We added three patients at Level 2 and set the MTD at 30 mg/m2, with no DLTs. The RD was fixed at 25 mg/m2, with no DLTs (N = 10) or treatment-related deaths. One patient showed complete response at Level 2, four presented partial response, and eleven individuals maintained stable disease for over four months. The median progression-free survival duration was 7.6 months, while the median overall survival period was 16.9 months. CONCLUSION: The TAS-102/irinotecan/bevacizumab combination therapy was safe, effective, and well-tolerated in patients previously treated with mCRC.

UTX deficiency in neural stem/progenitor cells results in impaired neural development, fetal ventriculomegaly, and postnatal death.

Recent studies have demonstrated that epigenetic modifications are deeply involved in neurogenesis; however, the precise mechanisms remain largely unknown. To determine the role of UTX (also known as KDM6A), a demethylase of histone H3K27, in neural development, we generated Utx-deficient mice in neural stem/progenitor cells (NSPCs). Since Utx is an X chromosome-specific gene, the genotypes are sex-dependent; female mice lose both Utx alleles (UtxΔ/Δ ), and male mice lose one Utx allele yet retain one Uty allele, the counterpart of Utx on the Y chromosome (UtxΔ/Uty ). We found that UtxΔ/Δ mice exhibited fetal ventriculomegaly and died soon after birth. Immunofluorescence staining and EdU labeling revealed a significant increase in NSPCs and a significant decrease in intermediate-progenitor and differentiated neural cells. Molecular analyses revealed the downregulation of pathways related to DNA replication and increased H3K27me3 levels around the transcription start sites in UtxΔ/Δ NSPCs. These results indicate that UTX globally regulates the expression of genes required for proper neural development in NSPCs, and UTX deficiency leads to impaired cell cycle exit, reduced differentiation, and neonatal death. Interestingly, although UtxΔ/Uty mice survived the postnatal period, most died of hydrocephalus, a clinical feature of Kabuki syndrome, a congenital anomaly involving UTX mutations. Our findings provide novel insights into the role of histone modifiers in neural development and suggest that UtxΔ/Uty mice are a potential disease model for Kabuki syndrome.

Duodenal diverticula perforation caused by an impacted bezoar successfully treated by endoscopic drainage and lithotripsy: A case report and literature review.

Duodenal diverticula perforation due to an impacted bezoar is a rare disease. Surgical treatment is associated with high rates of complications and mortality; therefore, treatment strategies must be carefully decided. Endoscopic treatment offers significant benefits to patients over surgery.

Efficacy and Safety of Radium-223 for Castration-resistant Prostate Cancer With Bone Metastasis Before and After Docetaxel.

BACKGROUND/AIM: Radium-223 (Ra-223) therapy provides a survival benefit for castration-resistant prostate cancer (CRPC) patients with bone metastasis. The optimal timing of using Ra-223 has not been determined. We evaluated the efficacy and safety of Ra-223 before and after docetaxel (DOC) therapy. PATIENTS AND METHODS: We retrospectively reviewed 36 CRPC patients with bone metastasis who were treated with Ra-223 in our institution and satellite hospitals. Ra-223 was used before DOC (pre-DOC group) in 17 patients (47%) and after DOC (post-DOC group) in 19 patients (53%). The treatment completion rate of 6 cycles, progression-free survival (PFS), cause-specific survival (CSS) and occurrence rate of adverse events were compared between the groups. RESULTS: The median follow-up duration was 45 months. In the pre-DOC compared with the post-DOC group, treatment completion rate was significantly higher (94% vs. 52%, p<0.01), PFS was significantly longer (median: 8 vs. 5 months, p=0.024) and CSS was significantly longer (median: 32 vs. 15 months, p=0.028). The difference in CSS was significant in multivariate analysis. In the pre-DOC compared with the post-DOC group, the occurrence rate of grade ≥3 adverse events tended to be lower (6% vs. 36%, p=0.322), and the CSS tended to be longer (median: not reached vs. 45 months, p=0.208). CONCLUSION: Ra-223 could be used more safely and more effectively for CRPC patients with bone metastasis before than after DOC therapy.

Immune-related adverse events in urothelial cancer patients: Adjustment for immortal time bias.

To investigate the association between the onset, severity, and type of immune-related adverse events (irAEs) and the efficacy of pembrolizumab in patients with platinum-pretreated advanced urothelial carcinoma (UC), we retrospectively collected clinical datasets of 755 patients and conducted landmark analysis. Patients who survived for fewer than 3 months were excluded from the evaluation to reduce the immortal time bias. In total, 620 patients were evaluated, of whom 220 patients (35.5%) experienced grade ≥2 irAEs, including 134 patients with grade 2 irAEs and 86 with grade ≥3 irAEs. Propensity score matching extracted 198 patients with and without grade ≥2 irAEs. The onset of grade ≥2 irAEs was associated with longer median progression-free survival (PFS) (8.3 months vs. 4.5 months, p = 0.003) and overall survival (OS) (20.4 months vs. 14.3 months, p = 0.031) and a higher objective response rate (ORR) (44.8% vs. 30.2%, p = 0.004). Patients with grade 2 irAEs had significantly better oncological outcomes (PFS, OS, and ORR) than grade ≤1 and ≥3 irAEs. Patients with grade ≥3 irAEs had worse outcomes than grade 2 irAEs. Endocrine and skin irAEs were related with better survival outcomes, and the rate of severities was lower in these categories. In conclusion, the occurrence of irAEs, particularly low-grade irAEs, was predictive of pembrolizumab efficacy in patients with platinum-pretreated advanced UC.