Effect of Antacids on the Survival of Patients With Metastatic Urothelial Carcinoma Treated With Pembrolizumab.

INTRODUCTION: Concomitant medications can affect the efficacy of immune checkpoint inhibitors. The association between histamine-2 receptor antagonists (H2RAs), major antacids similar to proton pump inhibitors (PPIs), and the efficacy of pembrolizumab for metastatic urothelial carcinoma (mUC) treatment has been poorly evaluated. We evaluated the impact of PPIs and H2RAs on oncological outcomes in mUC patients treated with pembrolizumab. PATIENTS AND METHODS: This retrospective multicenter study included patients with mUC treated with pembrolizumab. Patients prescribed PPIs or H2RAs within 30 days before and after the initial administration were extracted. The overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and objective response rates (ORR) were assessed. Kaplan-Meier survival curve analysis and multivariable Cox proportional hazard models were employed to assess the association between PPIs or H2RAs and survival outcomes. RESULTS: Overall, 404 patients were eligible for this study; 121 patients (29.9%) used PPIs, and 34 (8.4%) used H2RAs. Kaplan-Meier analysis showed significantly worse OS, CSS, and PFS in patients using PPIs compared to no PPIs (P = .010, .018, and .012, respectively). In multivariable analyses, the use of PPIs was a significant prognostic factor for worse OS (HR = 1.42, 95% CI 1.08-1.87, P = .011), CSS (HR = 1.45, 95% CI 1.09-1.93, P = .011), and PFS (HR = 1.35, 95% CI 1.05-1.73, P = .020). PPIs were not associated with ORRs. The use of H2RAs was not associated with survival or ORRs. CONCLUSION: PPIs were significantly associated with worse survival of patients with mUC treated with pembrolizumab, and H2RAs could be an alternative during administration. Both the oncological and gastrointestinal implications should be carefully considered when switching these antacids.

Prognostic impact of radiological tumor burden in patients with metastatic urothelial carcinoma treated with pembrolizumab.

PURPOSE: Radiological tumor burden has been reported to be prognostic in many malignancies in the immunotherapy era, yet whether it is prognostic in patients with metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains uninvestigated. We sought to assess the predictive and prognostic value of radiological tumor burden in patients with mUC. METHODS: We performed a retrospective analysis of 308 patients with mUC treated with pembrolizumab. Radiological tumor burden was represented by baseline tumor size (BTS) and baseline tumor number (BTN). Optimal cut-off value of BTS was determined as 50 mm using the Youden index (small BTS: n = 194, large BTS: n = 114). Overall (OS), cancer-specific (CSS), progression-free survival (PFS), and objective response rate (ORR) were compared. Non-linear associations between BTS and OS and CSS were evaluated using restricted cubic splines. RESULTS: Patients with large BTS were less likely to have undergone the surgical resection of the primary tumor (P = 0.01), and more likely to have liver metastasis (P < 0.001) and more metastatic lesions (P < 0.001). On multivariable analyses controlling for the effects of confounders (resection of primary tumor, metastatic site, number of metastases and lactate dehydrogenase level), large BTS and high BTN were independently associated with worse OS (HR 1.52; P = 0.015, and HR 1.69; P = 0.018, respectively) and CSS (HR 1.59; P = 0.01, and HR 1.66; P = 0.031, respectively), but not PFS. Restricted cubic splines revealed BTS was correlated with OS and CSS in linear relationships. Additionally, large BTS was significantly predictive of lower ORR and complete response rate on univariable analyses (P = 0.041 and P = 0.032, respectively), but its association disappeared on multivariable analyses. CONCLUSION: Radiological tumor burden has independent prognostic value with a linear relationship in pembrolizumab-treated patients with mUC and might help drive the earlier introduction of second-line pembrolizumab and/or switching to subsequent therapies.

Geriatric nutritional risk index as a prognostic marker of first-line immune checkpoint inhibitor combination therapy in patients with renal cell carcinoma: a retrospective multi-center study.

PURPOSE: This study aimed to investigate the effectiveness of the Geriatric Nutritional Risk Index (GNRI) in predicting the efficacy of first-line immune checkpoint inhibitor (ICI) combination therapy for metastatic or unresectable renal cell carcinoma (RCC) and associated patient prognosis. METHODS: A retrospective study was conducted using data from 19 institutions. The GNRI was calculated using body mass index and serum albumin level, and patients were classified into two groups using the GNRI values, with 98 set as the cutoff point. RESULTS: In all, 119 patients with clear cell RCC who received first-line drug therapy with ICIs were analyzed. Patients with GNRI ≥ 98 had significantly better overall survival (OS) (p = 0.008) and cancer-specific survival (CSS) (p = 0.001) rates than those with GNRI < 98; however, progression-free survival (PFS) did not differ significantly. Inverse probability of treatment weighting analysis showed that low GNRI scores were significantly associated with poor OS (p = 0.004) and CSS (p = 0.015). Multivariate analysis showed that the Karnofsky performance status (KPS) score was a better predictor of prognosis (OS; HR 5.17, p < 0.001, CSS; HR 4.82, p = 0.003) than GNRI (OS; HR 0.36, p = 0.066, CSS; HR 0.35, p = 0.072). In a subgroup analysis of patients with a good KPS and GNRI ≥ 98 vs < 98, the 2-year OS rates were 91.4% vs 66.9% (p = 0.068), 2-year CSS rates were 91.4% vs 70.1% (p = 0.073), and PFS rates were 39.7% vs 21.4 (p = 0.27), respectively. CONCLUSION: The prognostic efficiency of GNRI was inferior to that of the KPS score at the initiation of the first-line ICI combination therapy for clear cell RCC.

Efficacy of urine loss ratio for prognosis of urinary continence after radical prostatectomy: A retrospective cohort study in a single Japanese institution.

PURPOSE: The usefulness of the urine loss ratio in the early postoperative period for prognosis of long-term urinary continence after radical prostatectomy has not been fully determined. MATERIALS AND METHODS: All patients who underwent radical prostatectomy for prostate cancer at our institution between November 2015 and March 2021 were retrospectively included. We investigated the rate of continence achievement 1 year after surgery, as well as the associated risk factors for reduced continence achievement, classified by every 10% of the urine loss ratio. RESULTS: Of the 100 patients with available urine loss ratio data, 66 achieved urinary continence. Ninety-three percent of patients with urine loss ratios of ≤10%, 40%-75% of patients with urine loss ratios of 11%-80%, and 20%-36% of patients with urine loss ratios of >80%, achieved continence. The logistic regression analysis showed that the urine loss ratio severity, body mass index (BMI) of >25 kg/m², and smoking history were unfavorable to achieve urinary continence. A BMI of ≤25 kg/m² was favorable for urinary continence achievement, but only up to an 80% urine loss ratio. Nonsmokers achieved continence well, even with a urine loss ratio of >80%. CONCLUSIONS: Classifying patients into three groups based on their urine loss ratios is potentially useful for urinary continence prognosis. Smoking and obesity were risk factors for continued urinary incontinence, although the prognostic accuracy was expected to improve when considering the severity of the urine loss ratio.

[DIAGNOSIS OF GENETIC VARIANT CARRIERS IN A PATIENT WITH ASYMPTOMATIC BIRT-HOGG-DUBÉ SYNDROME: A CASE REPORT].

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). It is characterized by skin tumors, multiple lung cysts, and renal tumors. Active genetic testing and appropriate periodic examinations of family lines of patients with BHD syndrome have not been widely performed. In this report, we present our experience regarding the diagnosis of asymptomatic family members with BHD syndrome. The proband was a 65-year-old female with a family history of colorectal cancer and spontaneous pneumothorax that affected her father. Computed tomography revealed an approximately 10 cm-sized tumor protruding from the upper pole of the left kidney, a buried tumor approximately 1.5 cm in length in the right kidney, and multiple pulmonary cysts. The patient underwent laparoscopic radical left nephrectomy. Pathological examination indicated that the resected tumor was a chromophobe renal cell carcinoma. After the surgery, there was no evidence of local recurrence or metastasis. The size of the tumor in the right kidney was monitored, but it did not increase. On FLCN genetic examination, targeted next generation sequencing revealed a partial deletion of exon 14, thus confirming the diagnosis of the patient to be BHD syndrome that caused the previously unreported pathogenic variant. Three years after the surgery, we conducted genetic counseling for the proposita and her three children. Genetic examination, performed at the request of the second daughter, confirmed that she carried the same genetic variant as her mother. This diagnosis prompted the second daughter to begin managing her health via periodic imaging tests.

An autopsy case of autoimmune meningoencephalitis caused by pembrolizumab.

A 91-year-old man was on his seventh course of pembrolizumab for recurrence of right renal pelvic cancer. On the 8th day of treatment, he was admitted to the hospital with idiopathic fever and malaise. On the 12th day, the patient experienced tonic convulsions and exhibited an impaired consciousness. Based on cerebrospinal fluid examination and the course of the disease, we diagnosed him with autoimmune meningoencephalitis as an immune-related adverse event triggered by pembrolizumab. We administered steroids, which restored the patient's consciousness. When he died of debility two months later, a pathological specimen was obtained, confirming the diagnosis of autoimmune meningoencephalitis.

Retroperitoneal myofibroblastoma in an 88-year-old male.

Introduction: Extramammary myofibroblastomas are extremely rare. Case presentation: The patient was an 88-year-old male. He presented for evaluation of frequent urination and a "pushing up" sensation from the groin during defecation. Thorough physical and radiographic examinations revealed a retroperitoneal tumor on the right side of the rectum. The pathologic examination of the biopsy tissue showed that the tumor was unlikely to be malignant. Nevertheless, the patient was symptomatic and thus underwent a laparoscopic tumor resection through a transperitoneal approach. The tumor was circumscribed with a solid capsule. Based on the pathologic findings, which included immunostaining, the tumor was diagnosed as a myofibroblastoma. There was no evidence of a recurrence 6 months postoperatively. Conclusion: We present this case with the clinical course and surgical findings, and discuss the possibility of establishing a preoperative pathologic diagnosis of a myofibroblastoma.

A Clinical Trial Evaluating the Usefulness of Tailored Antimicrobial Prophylaxis Using Rectal-culture Screening Media Prior to Transrectal Prostate Biopsy: A Multicenter, Randomized Controlled Trial.

The aim of this report is to introduce an on-going, multicenter, randomized controlled trial to evaluate whether tailored antimicrobial prophylaxis guided by rectal culture screening prevents acute bacterial prostatitis following transrectal prostate biopsy (TRPB). Patients will be randomized into an intervention or non-intervention group; tazobactam-piperacillin or levofloxacin will be prophylactically administered according to the results of rectal culture prior to TRPB in the intervention group whereas levofloxacin will be routinely given in the non-intervention group. The primary endpoint is the occurrence rate of acute bacterial prostatitis after TRPB. Recruitment begins in April, 2021 and the target total sample size is 5,100 participants.

[Usefulness of screening for prostate cancer with prostate specific antigen (PSA) in the medical checkup ("human dock") at Onomichi Municipal Hospital: clinical significance of the cases diagnosed as prostate cancer].

PURPOSE: The usefulness of the screening for prostate cancer with prostate specific antigen (PSA) in the medical checkup ("Human Dock") at Onomichi Municipal Hospital was evaluated. METHODS: From April 1997 to December 2007, serum PSA of 1,234 male (median age: 59) was measured in the medical checkup and each parameter of screening was evaluated. In addition, for the cases with prostate cancer, results of treatment and clinical significance were assessed. RESULTS: PSA was elevated in 82 cases (6.6%), aged 42-87 (median 64), in which PSA varied 3.1-66.5 ng/ml (median 5.4). Trans-rectal biopsy was performed in 35 cases and prostate cancer was detected in 15 (42.9% of biopsied cases and 1.2% of whole group), aged 58-81 (median 70), with PSA value 4.2-66.5 ng/ml (median 10.3). Clinical stage of these cases was cT1cN0M0 in 12 and cT2aN0M0 or more in 3, Gleason score was 3 + 3 in 4 and 3 + 4 or more in 11. Initial treatment was radical prostatectomy in 12, androgen-deprivation therapy in 2 and external beam irradiation in 1. During the follow-up for 8-107 months (median 60), 14 were alive with good control and 1 was alive with relapse. Only one case was "clinically insignificant" cancer (impalpable and localized and tumor volume less than 0.5 ml and Gleason score 3 + 3 or less). CONCLUSIONS: Most of the prostate cancers detected in the medical checkup were clinically significant, therefore, PSA screening doesn't result in overtreatment and it is meaningful to perform PSA screening in the medical checkup.

Amphiphysin 1 is important for actin polymerization during phagocytosis.

Amphiphysin 1 is involved in clathrin-mediated endocytosis. In this study, we demonstrate that amphiphysin 1 is essential for cellular phagocytosis and that it is critical for actin polymerization. Phagocytosis in Sertoli cells was induced by stimulating phosphatidylserine receptors. This stimulation led to the formation of actin-rich structures, including ruffles, phagocytic cups, and phagosomes, all of which showed an accumulation of amphiphysin 1. Knocking out amphiphysin 1 by RNA interference in the cells resulted in the reduction of ruffle formation, actin polymerization, and phagocytosis. Phagocytosis was also drastically decreased in amph 1 (-/-) Sertoli cells. In addition, phosphatidylinositol-4,5-bisphosphate-induced actin polymerization was decreased in the knockout testis cytosol. The addition of recombinant amphiphysin 1 to the cytosol restored the polymerization process. Ruffle formation in small interfering RNA-treated cells was recovered by the expression of constitutively active Rac1, suggesting that amphiphysin 1 functions upstream of the protein. These findings support that amphiphysin 1 is important in the regulation of actin dynamics and that it is required for phagocytosis.

Implication of amphiphysin 1 and dynamin 2 in tubulobulbar complex formation and spermatid release.

Tubulobulbar complexes (TBCs) are composed of several tubular invaginations formed at the plasma membrane of testicular Sertoli cells. TBCs are transiently formed at the contact region with spermatids at spermatogenic stage VII in rat and mouse, and such TBC formation is prerequisite for spermatid release. Since the characteristic structure of TBCs suggests that the molecules implicated in endocytosis could be involved in TBC formation, we here investigated the localization and physiological roles of endocytic proteins, amphiphysin 1 and dynamin 2, at TBCs. We demonstrated by immunofluorescence that the endocytic proteins were concentrated at TBCs, where they colocalized with cytoskeletal proteins, such as actin and vinculin. Immunoelectron microscopy disclosed that both amphiphysin 1 and dynamin 2 were localized on TBC membrane. Next, we histologically examined the testis from amphiphysin 1 deficient {Amph(-/-)} mice. Morphometric analysis revealed that the number of TBCs was significantly reduced in Amph(-/-). The ratio of stage VIII seminiferous tubules was increased, and the ratio of stage IX was conversely decreased in Amph(-/-). Moreover, unreleased spermatids in stage VIII seminiferous tubules were increased in Amph(-/-), indicating that spermatid release and the following transition from stage VIII to IX was prolonged in Amph(-/-) mice. These results suggest that amphiphysin 1 and dynamin 2 are involved in TBC formation and spermatid release at Sertoli cells.

Minimal invasiveness and effectivity of subinguinal microscopic varicocelectomy: a comparative study with retroperitoneal high and laparoscopic approaches.

AIM: The standard management of varicocele repair is the subject of ongoing controversy. We retrospectively evaluated three surgical methods of varicocele treatment to determine the minimally invasive and most effective procedure. METHODS: We performed 144 varicocelectomies on infertile patients with left clinical varicocele. Of the patients, 50 were treated with retroperitoneal high ligation under lumbar anesthesia, 33 with laparoscopic ligation under general anesthesia, and 61 with subinguinal microscopic ligation under local anesthesia. Operative time, hospital days, and clinical outcomes were compared between these techniques. RESULTS: The operating time and hospitalization period required for subinguinal microscopic ligation was signi fi cantly shorter compared to those for the other procedures. All patients treated with subinguinal microscopic ligation could achieve normal activity as soon as they returned to their rooms. Postoperative complications were observed in fi ve (10.0%) cases treated with high ligation and three (9.1%) laparoscopic cases, but were not observed after the subinguinal procedure. There were six cases (12.0%) of recurrence in the high ligation group and six (6.1%) in the laparoscopic group, but none in the subinguinal group. Sperm density was signi fi cantly improved in all procedures postoperatively, but sperm motility was not improved. The two-year pregnancy rate calculated by the Kaplan-Meier method was 35.8% for high ligation, 40.4% for laparoscopic ligation and 50.9% for subinguinal microscopic ligation, although there were no statistical differences between the three groups. CONCLUSION: We concluded that subinguinal microscopic varicocelectomy could be a minimally invasive procedure compared to the other two techniques and a worthy method for treating male infertility due to clinical varicocele.

Clinical results of one-stage urethroplasty with parameatal foreskin flap for hypospadias.

We investigated the usefulness of one-stage urethroplasty by the parameatal foreskin flap method (OUPF procedure), which is useful for repairing all types of hypospadias. Between June 1992 and March 2001, the OUPF procedure was performed on 18 patients with hypospadias: 10 patients with distal and 8 with proximal hypospadias. The follow-up periods ranged from 33-75 months, with an average of 52 months. The duration of surgery, the catheter indwelling period, and the postoperative complications of each patient were analyzed. The median age of the patients at the time of surgery was 3 years and 8 months. The length of surgery for OUPF II ranged from 150-230 min (average 186 min), and from 190-365 min (average 267 min) for OUPF IV. Postoperative complications were confirmed in 3 of the 18 patients (16.6%). Two patients had fistulas, and one had a meatal regression. The fistulas were successfully closed by the simple multilayered closure method. After adopting DuoDerm dressings instead of elastic bandages for protection of the wound, no fistulization occurred. DuoDerm dressings are useful in the healing of wounds without complications. To date, the longest follow-up period has been 75 months, and during that time there have been no late complications such as urethral stenosis or penile curvature. OUPF is a useful method in the treatment of hypospadias with a low incidence of early and late complications.

Adeno-associated virus 2-mediated intratumoral prostate cancer gene therapy: long-term maspin expression efficiently suppresses tumor growth.

Maspin is a member of the serine protease inhibitors and the maspin gene, a tumor suppressor gene, is down-regulated in a large fraction of prostate cancers. We evaluated the use of adeno-associated virus (AAV, serotype 2) vector encoding maspin as a means for in vivo gene therapy for human prostate cancer. TUNEL assay of subcutaneously formed LNCaP or DU145 tumors in nude mice showed that intratumoral AAV-mediated maspin expression significantly upregulated the number of apoptotic cells compared with AAV-LacZ treatment. Immunofluorescence double staining for maspin protein and apoptosis in LNCaP tumors showed that the percentage of apoptotic cells in AAV-maspin-mediated maspin-expressing cells was significantly high compared with that in AAV-GFP-mediated GFP-expressing cells. Moreover, significantly fewer CD31-positive microvessels were observed in AAV-maspin-treated tumors compared with the control tumors. These therapeutic responses were highly correlated to persistent maspin expression in tumors, confirmed by Western blot analysis until at least day 56 after treatment. Finally, intratumoral delivery of AAV-maspin significantly suppressed growth of LNCaP and DU145 tumors and improved survival of mice. We conclude that AAV-mediated prolonged maspin expression efficiently suppresses human prostate tumor growth in vivo by apoptosis induction and inhibition of angiogenesis.

Varicocele rupture due to sexual intercourse.

Varicocele rupture was diagnosed in a 23-year-old man who presented with swelling and pain in the left scrotum after sexual intercourse. Color Doppler ultrasonography revealed blood flowing into the space surrounding the left testis, a hematoma and reflux of blood in the left spermatic vein. Varicocele rupture is a very rare condition and there have been only five reported cases.

Analysis of human ejaculation using color Doppler ultrasonography: a comparison between antegrade and retrograde ejaculation.

OBJECTIVES: To observe the phenomenon of human ejaculation dynamically using color Doppler ultrasonography. METHODS: Human ejaculation was observed using transrectal color Doppler ultrasonography in a healthy man and a patient with retrograde ejaculation. Ejaculation was induced manually with audiovisual sexual stimulation. The ejaculatory phenomenon was analyzed and compared with that of retrograde ejaculation. RESULTS: In the healthy man, the prostatic urethra flattened slightly and the bladder neck contracted just before expulsion. The ejaculatory stream spurted from the seminal vesicles to the bulbous urethra through the ejaculatory duct. In the patient with retrograde ejaculation, the ejaculatory stream from the seminal vesicles and inframontanal and distal prostatic urethras distended into a globular-shaped sac filled with semen. No seminal flow toward the bulbous urethra occurred. The semen remaining in the prostatic urethra began flowing slowly into the bladder. CONCLUSIONS: Differences between antegrade and retrograde ejaculation can be clearly detected by color Doppler ultrasonography, providing a noninvasive method to diagnose ejaculatory disorders.

Intracavernous injection of prostaglandin E1 is effective in patients with erectile dysfunction not responding to phosphodiseterase 5 inhibitors.

We report on 64 patients who did not achieve erections adequate for satisfactory sexual intercourse from among a total of 243 patients who were prescribed PDE5 inhibitors for erectile dysfunction (ED). Intracavernous injection (ICI) of PGE was performed in this non-responder group. An ICI of 20 or 40 mcg of PGE1 in 1 ml saline was performed and the responses evaluated. Forty-nine out of 64 (77 percent ) cases responded to 20 mcg of PGE1. Forty mcg of PGE was injected into the 15 non-responding cases, and 9 patients responded favorably. The overall effective rate was 58/64 (91 percent ). No major adverse effects were observed.

Dynamin-2 regulates oxidized low-density lipoprotein-induced apoptosis of vascular smooth muscle cell.

BACKGROUND: On exposure to oxidized low-density lipoprotein (oxLDL), vascular cells generally undergo apoptosis, which is one of the major pathogenic factors of atherosclerosis. In this study, we examined the role of dynamin (a crucial GTPase protein in endocytosis) in oxLDL-induced apoptosis of vascular smooth muscle cells (VSMC). METHODS AND RESULTS: After oxLDL stimulation, dynamin-2 colocalized with LOX-1 around the cell surface, as well as oxLDL in the cytoplasm, suggesting that dynamin-2 was involved in scavenger receptor-mediated oxLDL endocytosis. Downregulation of dynamin-2 induced by dynamin-2 dominant negative plasmid (K44A) resulted in a decrease of oxLDL uptake and thereby in a reduction of apoptosis. These data demonstrated that dynamin-2 was involved in oxLDL-induced apoptosis via the oxLDL endocytotic pathway. On the other hand, dynamin-2 wild-type plasmid transfection promoted oxLDL-induced apoptosis without increasing oxLDL uptake. Interestingly, the p53 inhibitor pifithrin-alpha (PFT) significantly reduced apoptosis promoted by wild-type dynamin-2 (78% reduction compared with the PFT[-] condition). These results indicated that dynamin-2 enhanced oxLDL-induced apoptosis of VSMC by participating in the p53 pathway, probably as a signal transducer. Moreover, we demonstrated that, in advanced plaques of apolipoprotein E-/- mice, dynamin-2 expression was often enhanced in apoptotic VSMC, suggesting that dynamin-2 might participate in apoptosis of VSMC even in vivo. CONCLUSIONS: Our data demonstrated that dynamin-2 at least partially regulated oxLDL-induced apoptosis of VSMC by participating in 2 independent pathways: the oxLDL endocytotic pathway and the p53 pathway. These findings suggest that dynamin-2 may serve as a new research or therapeutic target in vascular disease.