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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).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.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.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.

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.

Anastomotic leakage (AL) occurs with some frequency in all types of colorectal cancer surgery and is associated with increased morbidity, mortality and recurrence rates. Complications might be prevented by monitoring intra-operative bowel perfusion at the anastomotic site. A pilot study concerning the objective and quantitative measurement of tissue perfusion by monitoring regional tissue saturation of oxygen (rSOThis study evaluated the ability of the INVOS™ system to predict AL after left-sided colorectal cancer surgery. rSOAmong 73 patients, 6 (8.2%) experienced AL. The rSOMonitoring the rSO

We used real-world and large-scale data to assess the clinical efficacy and safety of pembrolizumab in older patients with advanced urothelial carcinoma (UC).A total of 608 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. All patients were histologically diagnosed with pure UC. Using propensity score matching (PSM) (ECOG performance status, site of metastasis, hemoglobin level and neutrophil-to-lymphocyte ratio, 1:1 matching), the overall survival (OS) and adverse events (AEs) of patients75 and ≥75 years old were compared.The median follow-up (IQR) period was 16.1 (9.9-20.5) months. After PSM, there were 215 patients each in the aged75 years and aged ≥75-year-old groups. The median OS of all patients was estimated to be 10.4 months (95% confidence interval [CI] = 8.8-12.1). After PSM, the median OS was 7.8 months (95% CI = 5.2-10.4) in the75-year-old group and 10.4 months (95% CI = 7.3-13.5) in the ≥75-year-old group (P = 0.186). Any-grade AEs were more frequently reported in the ≥75-year-old group in comparison to the age75-year-old group (55.3% vs. 41.9%, P = 0.007), whereas there was no significant difference between the two groups in the incidence of grade ≥3 AEs (10.2% vs. 12.6%, P = 0.544). The objective response rate, defined as complete remission or a partial response, was 22.8% in the75-year-old group and 25.1% in the ≥75-year-old group (P = 0.651).The present study demonstrates that age does not affect the efficacy and safety of pembrolizumab treatment for advanced chemoresistant UC. Pembrolizumab treatment should not be avoided based on chronological age; however, close monitoring for the development of treatment-related AE should be considered for older patients.

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 (Utx

Pancreatic metastasis from renal cell carcinoma (RCC) is relatively rare. Surgical resection of the lesion is recommended if no residual tumor remains. Although there is no clear standard for surgical procedures, enucleation can be considered for small lesions. Lesion identification is important for enucleation, and contrast-enhanced ultrasound which takes advantage of the characteristics of hypervascular lesions was useful in a 68-year-old woman who underwent a left nephrectomy for RCC 11 years ago that was pathologically diagnosed as clear cell carcinoma. Recent computed tomography checkup showed a hypervascular tumor of 6 mm in the uncinated process and 10 mm in the pancreatic tail. Endoscopic ultrasonography-guided fine-needle aspiration was performed for the tail lesion, a diagnosis of clear cell carcinoma was made, and laparoscopic enucleation of the pancreatic tumors was performed aided by intraoperative contrast-enhanced ultrasound. The postoperative course was uneventful, and no pancreatic fistula occurred.

Introduction Cutaneous metastasis of urothelial carcinoma is uncommon. We experienced a case of cutaneous metastasis that emerged during chemotherapy and progressed rapidly during immunotherapy for bladder tumor with lymph node metastasis. Case presentation A 77-year-old female patient received chemotherapy using gemcitabine and cisplatin for bladder urothelial carcinoma with para-aortic and pelvic lymph node metastases (clinical stage T2N1M1). After eight courses of chemotherapy, skin rash appeared in the lower abdomen with leg edema caused by multiple lymphadenopathy. Skin biopsy revealed cutaneous metastasis of urothelial carcinoma. The cutaneous tumor progressed rapidly and the patient died 5 weeks after the start of second-line pembrolizumab treatment. Conclusion A patient with cutaneous metastasis of urothelial carcinoma that emerged during chemotherapy had poor prognosis and lack of efficacy of an immune checkpoint inhibitor.

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.

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.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.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%, p0.01), 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).Ra-223 could be used more safely and more effectively for CRPC patients with bone metastasis before than after DOC therapy.

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.

In hepatobiliary and pancreatic surgery, an understanding of hepatic artery anomalies is of great importance to surgeons. Cases of the proper hepatic artery originating from the superior mesenteric artery and the gastroduodenal artery originating from the celiac trunk are extremely rare. To our knowledge, there are no reports of these arterial variants being diagnosed before hepatobiliary and pancreatic surgery. A 73-year-old woman underwent subtotal stomach-preserving pancreaticoduodenectomy and lymphadenectomy for duodenal carcinoma. Preoperative vascular construction with 3-dimensional computed tomography showed variants of the proper hepatic artery and gastroduodenal artery. The proper hepatic artery originated from the superior mesenteric artery, and the gastroduodenal artery originated from the celiac trunk. Intraoperative findings and preoperative vascular construction from 3-dimensional computed tomography were found to be matched exactly; both the proper hepatic artery and gastroduodenal artery were preserved. By diagnosing a rare arterial variant preoperatively, we were able to perform the surgery safely. In hepatobiliary and pancreatic surgery, understanding any potential variation of the hepatic artery before surgery is crucial to ensure the best patient outcomes.

Objectives Anastomotic leakage is associated with severe morbidity, mortality, and functional defects. Its risk factors remain unclear. However, blood perfusion may be a potential major risk factor. It has been reported that the Agatston score is an index for blood flow perfusion evaluation. Therefore, we evaluated the clinical indicators associated with anastomotic leakage, including the Agatston score, in patients who underwent colorectal surgery. Methods We retrospectively analyzed 147 patients who underwent elective colorectal surgery with the double-staple technique anastomosis for colorectal cancer between April 2015 and March 2020. The primary outcome was the presence or absence of anastomotic leakage. Univariate and multivariate analyses were employed to identify pre- and intraoperative risk factors. Results Of the 147 patients analyzed, anastomotic leakage occurred in 12 (8.16%). Male gender, history of angina and myocardial infarction, preoperative white blood cell count, the Agatston score, extent of bleeding, operation time, and intraoperative fluid volume were significantly related to a higher incidence of anastomotic leakage in univariate analysis. Multivariate analysis demonstrated that the incidence of anastomotic leakage was high in patients with a high Agatston score. Conclusions The Agatston score can predict the incidence of anastomotic leakage in patients following colorectal surgery. Thus, perioperative measures to prevent anastomotic leakage are recommended when a high Agatston score is observed. A prospective trial is required to demonstrate, with a high level of evidence, that the Agatston score can be useful as a risk score for anastomotic leakage following colorectal surgery.

Background Submucosal fecalith(s) mimicking submucosal tumors of the gastrointestinal lumen are rare. Moreover, accurate preoperative diagnosis of these entities is exceedingly difficult, and the mechanism(s) of their formation remains unclear. Case presentation A 40-year-old woman visited the authors’ hospital due to lower abdominal pain and diarrhea. She had previously been treated for endometriosis. Laboratory investigation revealed increased C-reactive protein levels. Abdominal contrast-enhanced computed tomography revealed thickening of the appendix wall and dilation of the small intestine. The patient was diagnosed with paralytic ileus caused by appendicitis, and interval appendectomy was scheduled. She underwent laparoscopic-assisted appendectomy after conservative treatment. Partial cecal resection was selected due to the presence of an elastic mass in the cecum. The final pathological diagnosis was submucosal fecalith, not submucosal tumor. On day 5, the patient was discharged without any postoperative complications. Conclusions In cases of appendicitis with fecalith(s) that appear as submucosal tumor(s) on colonoscopy, submucosal fecalith mimicking submucosal tumor should be considered in the differential diagnosis.

We focused on the availability of an omnidirectional camera and head-mount display (HMD). If the laparoscope is an omnidirectional camera, captured images are sent to the HMD worn by the operator in real time. The operator can thus view the image as they like without moving the camera and obtain a 360° view intuitively. However, the surgical system that can be used for actual laparoscopic operations has not yet been developed. In this study, we aimed to show that an omnidirectional camera and HMD would be useful in laparoscopic surgery.Eleven medical students and twelve surgical residents (Surgeons group) participated in this study. We created an experimental box with five marks randomly attached inside the box, and the inside cannot be seen from the outside. We measured the time it took to identify all marks between conventional laparoscope and substitute system in each group.In the substitute system, the time required for the task was significantly shorter than with conventional laparoscopy in each group.An omnidirectional camera and HMD may be a useful new device for laparoscopic surgery. This system may help improve the safety of laparoscopic surgery.

Highlights • Colon MiNEN, in this case, adenocarcinoma and NET G1 is a rare tumor. • Preoperative diagnosis of MiNEN is difficult, and detailed observation of histopathology is important. • Prognosis depends on the more aggressive components of adenocarcinoma or NET., Introduction Neuroendocrine tumor (NET) that develops in the right-sided colon is relatively rare. Coexistence of adenocarcinoma and NET is extremely rare, and such cases are called mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). Presentation of case Colonoscopy in an 85-year-old woman for an anemia examination indicated laterally spreading tumor-nongranular (LST-NG) in the transverse colon. Colonoscopy and endoscopic ultrasonography (EUS) showed that the depth of the tumor invasion was deep submucosal. The tumor localization was diagnosed as transverse colon close to the hepatic curvature by enema. Computed tomography (CT) showed no obvious lymph node or distant metastasis. Based on these findings, laparoscopic transverse colectomy with D2 lymphadenectomy was performed. Pathologically, most of the tumor was well-differentiated tubular adenocarcinoma, but some solid follicles of polygonal tumor cells with poor nuclear atypia were observed. Immunostaining was positive for synaptophysin and diagnosed as NET G1. This tumor consisted of adenocarcinoma and neuroendocrine tumor, so we diagnosed it as MiNEN and classified the tumor as fT1N0M0 fStage I (TNM Classification of Malignant Tumors, 8th Edition). Since it was an early stage cancer, postoperative adjuvant therapy was not performed. No recurrence has yet been noted. Discussion Although MiNEN is extremely rare, the detailed pathological specimen observation and diagnosis are important because long-term follow-up after surgery is needed, as is the adequate selection of postoperative adjuvant therapy. Conclusion It is important to elucidate the mechanisms involved in the coexistence of NET and adenocarcinoma and to apply these findings to future medical care.

An 86-year-old man who presented with frequent hematochezia with mild anemia on blood tests was admitted to our hospital. Colonoscopy exhibited a submucosal tumor-like lesion in the lower rectum. CT and MRI showed blood flow into the lesion, but not tumor component. Angiography of the superior rectal artery and left internal iliac artery showed vascular hyperplasia and nidus. Thus, rectal arteriovenous malformation was diagnosed. If bleeding from arteriovenous malformation was out of control, surgical resection was necessary. However, due to the age of the patient, we performed transcatheter arterial embolization and abdominoperineal resection was not needed. Embolization from the left superior rectal artery, middle rectal artery and inferior rectal artery was performed to control the bleeding and to avoid surgery. After embolization, he was followed up for 10 months in our hospital without recurrence.

Miyazaki Urological Cancer Database (MUCD) is a web-based database containing background, treatment, and prognosis of patients with prostate, renal, and urothelial cancers diagnosed in Miyazaki. We entered information on patients diagnosed with urothelial carcinoma from 2014 to 2018 at 4 of the 17 facilities that diagnose urothelial carcinoma in Miyazaki Prefecture. We analyzed the overall survival for bladder cancer and upper urinary tract cancer, and examined its correlation with the presence of symptoms, urine cytology, and clinical TNM classification. There were 487 patients with urothelial carcinoma, comprising 372 (76%) with bladder cancer and 115 (24%) with upper tract urinary cancer. In the bladder cancer group, 301 (81%) patients had symptomatic disease and 119 (32%) had positive urine cytology. The stage according to the TNM classification was Ta-1N0, T2-4N0, N1-2M0 and M1 in 248 (67%), 94 (26%), 19 (5%) and 11 (3%) patients, respectively. In the upper urinary tract cancers group, 89 (76%) had symptomatic disease and 41 (36%) had positive urine cytology. The stage according to the TNM classification was Ta-1N0, T2-4N0, N1-2M0 and M1 in 45 (39%), 37 (32%), 11 (10%) and 22 (19%) patients, respectively. The 3-year survival rates for bladder and upper urinary tract cancer were 83.4% and 67.8%, respectively. TNM classification (≤T1 vs ≥T2≥) was significantly associated with overall survival (bladder cancer : HR＝7.07, 95% CI＝3.13-16.0, p＜0.0001 ; upper tract urinary cancer : HR＝6.33, 95% CI＝2.13-18.8, p＝0.0009). The prognosis of patients with urothelial carcinoma diagnosed in multiple institutions could be evaluated using MUCD. The clinical T stage was significantly associated with overall survival in patients with bladder cancer and patients with upper urinary tract cancer.

We report a case of Stauffer syndrome-like findings in a patient with metastatic renal carcinoma treated by surgery and molecular targeted therapy. The patient was a 58-year-old woman diagnosed with renal carcinoma with multiple metastases. She had hepatosplenomegaly and hepatic dysfunction with elevated serum liver enzyme and IL-6 levels. Treatment with temsirolimus and axitinib reduced the size of the local and metastatic tumors and simultaneously improved the hepatosplenomegaly. The local tumor was excised by laparoscopic nephrectomy, treated with axitinib and then with nivolumab. With the reduction in the metastatic tumor size, serum liver enzyme and IL-6 levels decreased. It was suggested that molecular targeted therapy is an effective treatment when the findings of metastatic renal cell carcinoma, are similar to those of Stauffer syndrome.

Highlights • Inguinal bladder hernia (IBH) is a rare condition that is difficult to diagnose preoperatively. • 16% of IBHs are diagnosed postoperatively due to bladder injury and leakage. • Preoperative diagnosis of IBHs is important to lessen postoperative complications. • Transabdominal preperitoneal approach can significantly reduce the risk of bladder damage., Introduction Inguinal bladder hernia (IBH) is a rare condition that is difficult to diagnose preoperatively based only on physical examination; 16% of IBHs are diagnosed postoperatively due to complications. Presentation of case We report the case of a 56-year-old man who presented with left inguinal swelling and increased frequency of urination since eight years. Physical examination demonstrated a 6 × 4 cm non-reducible left inguinal bulge with mild tenderness on palpation. Computed tomography revealed a left inguinal hernia containing a portion of the urinary bladder. He was diagnosed with IBH and transabdominal preperitoneal (TAPP) repair was performed. We confirmed a left internal inguinal hernia and incised the peritoneum from the outside of the left inguinal ring. The preperitoneal space was dissected toward the Retzius space, and the prolapsed bladder was examined. The adhesion with the surroundings was carefully dissected and the bladder was reduced into the abdomen. Indigo carmine was injected through a urinary catheter, which confirmed that no bladder damage had occurred. After the mesh was positioned to cover the myopectineal orifice, it was fixed to the Cooper’s ligaments, interior side, lateral side, and ventral side. The postoperative course was uneventful, and the patient is now free of symptoms and recurrence two months after surgery. Conclusion TAPP repair is a useful treatment for IBH. Preoperative diagnosis of IBH is important to lessen postoperative complications.

Because of the small numbers of cases in single centers, the indications for and survival benefits of adrenalectomy for adrenal metastasis remain unclear. We evaluated the outcomes of laparoscopic adrenalectomy for patients with adrenal metastasis. We retrospectively analyzed the records of 67 patients who underwent laparoscopic adrenalectomy for metastatic disease from 2003 to 2017 at 11 hospitals. Associations of clinical, surgical, and pathologic features with overall survival (OS) and positive surgical margins were evaluated using univariate and multivariate Cox regression analyses and univariate logistic regression analysis. Lung cancer (30%) and renal cell carcinoma (30%) were the most common primary tumor types. Intraoperative complications were observed in seven patients (10%) and postoperative complications in seven (10%). The surgical margin was positive in 10 patients (15%). The median OS was 3.8 years. Univariate analysis showed that the tumor size, episodes of extra-adrenal metastasis before adrenalectomy, extra-adrenal metastasis at the time of adrenalectomy, and positive surgical margins were significantly associated with shorter OS (p = 0.022, p = 0.005, p

Purpose The number of patients on antiplatelet therapy (APT) who need surgery is increasing; however, it is unclear whether APT should be continued for abdominal surgery, particularly laparoscopic colorectal surgery. We investigated the safety of continuing APT for patients undergoing laparoscopic colorectal surgery. Methods We collected retrospective data from 529 patients who underwent laparoscopic colorectal surgery at Hiroshima University between January, 2013 and December, 2018. We analyzed information related to APT. Thirty-six pairs were matched by the propensity score method between patients on APT (APT+) and those not on APT (APT−). We compared the surgical outcomes of both groups. Results Among 463 patients eligible for the study, 48 were on APT for cerebrovascular or cardiovascular disease, and 36 continued to take aspirin. In the case-matched comparison, the amount of intraoperative blood loss in the APT+ group was not significantly higher than that in the APT− group, and the incidences of bleeding complications, thromboembolic complications, and other complications were not significantly different between the groups. Conclusion In a case-matched comparison, continuation of aspirin during laparoscopic colorectal surgery did not increase perioperative complications. In laparoscopic colorectal surgery, continuation of aspirin is an acceptable strategy for patients with thromboembolic risk caused by interruption of APT.

Introduction Erythropoietic protoporphyria (EPP) is a rare disorder caused by reduced ferrochelatase activity and shows incomplete autosomal dominant inheritance. Meticulous perioperative management can avoid characteristic complications. This report describes a case of a bleeding jejunal tumor in a patient with EPP. Presentation of case A 49-year-old man with a history of EPP was admitted to our department with abdominal distention and severe anemia. Contrast-enhanced computed tomography revealed an abdominal tumor measuring 5 cm, originating from the small bowel wall or mesentery. Tumor resection was planned after correction of anemia. Red blood cell transfusion restored his hemoglobin to acceptable levels; however, his liver function worsened. Institution of liver support therapy achieved gradual reduction in his elevated liver enzymes; however, hyperbilirubinemia persisted. He underwent tumor resection on the 12th day of hospitalization. Yellow filters were used to avoid operating room light-induced tissue injury. The tumor was located in the jejunum 30 cm from the Treitz ligament toward the anal aspect. The histopathological diagnosis was desmoid-type fibromatosis of the jejunum. Postoperatively, his hemoglobin levels were stabilized; however, his serum bilirubin level remained high. His serum bilirubin level gradually decreased following hemin injections (150 mg/day). Discussion Reducing heme synthesis and minimizing protoporphyrin generation are important perioperatively. Additionally, preventing operating room light-induced tissue burns and selecting appropriate anesthestic agents are important during surgery. Conclusion The institution of appropriate treatment and adequate intra- and perioperative measures can ensure safe surgery in patients with EPP even under emergency conditions.

Kozue Nakahara,1 Koji Yamasaki,1 Takahiro Nagai,1 Masato Fujii,1 Takahiro Akioka,1 Hiroki Takamori,1 Naoki Terada,1 Shoichiro Mukai,1 Yuichiro Sato,2 Toshiyuki Kamoto11Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; 2Section of Diagnostic Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, JapanBackground: Matriptase, which is a Type II transmembrane serine protease,has the potential to activate several growth factors, including pro-hepatocyte growth factor (HGF). A G protein-coupled transmembrane cell-surface receptor and a protease-activated receptor 2 (PAR-2) are also required for activation by matriptase. Activation of PAR-2 has been reported to induce the progression of various cancers. In a previous study, we evaluated the correlation between upregulation of MET phosphorylation with high matriptase expression and worse prognosis in patients with muscle invasive bladder cancer; however, expression of PAR-2, matriptase and MET in non-muscle invasive bladder cancer (NMIBC) has not been evaluated.Materials and methods: We retrospectively analyzed the expression of PAR-2, matriptase and MET using 55 paraffin-embedded specimens obtained from patients with NMIBC by immunohistochemistry.Results: MET was significantly expressed in high-grade urothelial carcinoma (UC) and pathological T1 cancers. High expression of PAR-2 was significantly associated with a worse recurrence rate in NMIBC. In subgroup analysis, the expression of PAR-2 was also correlated with high recurrence rate in low-grade UC. In addition, expression of matriptase tended to correlate with worse recurrence rate in high-grade UC.Conclusion: Increased expression of PAR-2 was significantly correlated with worse recurrence rate in patients with NMIBC. In addition, expression of matriptase also indicated a tendency toward recurrence in high-grade UC, suggesting an important role of matriptase-induced PAR-2 activation in NMIBC.Keywords: PAR-2, matriptase, MET, NMIBC

The association of concurrent proton pump inhibitor (PPI) use with treatment outcome of metastatic urothelial carcinoma (UC) remains controversial.We retrospectively analyzed the records of 227 patients with platinum-treated metastatic UC treated with pembrolizumab. The primary outcome was overall survival (OS). Immune progression-free survival (iPFS) and objective response per immune response evaluation criteria in solid tumors were also compared. Inverse probability of treatment weighting (IPTW)-adjusted multivariable Cox regression models and an IPTW-adjusted multivariable logistic regression model were used to evaluate the oncological outcomes. Furthermore, the heterogeneity of the treatment effect on OS was examined using interaction terms within the IPTW-adjusted univariate Cox regression models.Overall, 86 patients (37.9%) used PPIs. After weighting, no significant differences in patient characteristics were observed between PPI users and non-users. PPI use was significantly associated with a shorter OS (hazard ratio [HR]: 2.02, 95% confidence interval [CI]: 1.28-3.18, P = 0.003) and iPFS (HR: 1.70, 95% CI: 1.23-2.35, P = 0.001). Although not statistically significant, PPI use was associated with objective response as well (OR: 0.61, 95% CI: 0.36-1.02, P = 0.06). The interaction analyses showed that the effect of PPI significantly decreased with age (HR: 0.97, 95% CI: 0.93-1.00, P[interaction] = 0.048) and was increased in males (HR: 2.97, 95% CI: 1.10-8.05, P[interaction] = 0.032).PPI use was significantly associated with worse survival of patients with metastatic UC treated with pembrolizumab. Furthermore, the results suggested that its effects decreased with age and was increased in males.