Expressions of PD-L1 and Nectin-4 in urothelial cancer patients treated with pembrolizumab.

OBJECTIVES: Recently, the standard of care for advanced urothelial cancer (UC) has been changed by developing immune-checkpoint inhibitors (ICIs). However, its response rate is limited to 20-30%. The identification of biomarkers to predict the therapeutic effects of ICIs is urgently needed. The present study explored the association between immunohistochemical biomarkers and clinical outcomes in UC patients treated with pembrolizumab. PATIENTS AND METHODS: A total of 85 patients with UC who received pembrolizumab after chemotherapy from January 2018 to May 2020 were retrospectively reviewed. Tumor tissues were obtained for immunohistochemical study from 47 out of 85 patients. The protein expressions of PD-L1, WT1, Nectin-4, CD4, CD8, Foxp3, and CD68 in tumor cells and/or tumor infiltrating lymphocytes were immunohistochemically examined. The associations between protein expressions and overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) were statistically analyzed. RESULTS: Patients with positive PD-L1 in tumor cells showed significantly worse OS (Log-rank test: HR 5.146, p = 0.001, Cox regression analysis: HR 4.331, p = 0.014) and PFS (Log-rank test: HR 3.31. p = 0.022), along with significantly lower DCR (14.3%) compared to the PD-L1 negative patients (67.5%). In addition, patients with strong expression of Nectin-4 in tumor cells showed significantly higher DCR (100%) than the other patients (50%). CONCLUSION: PD-L1 expression in tumor cells was associated with poor prognosis (OS and PFS) and low DCR. Interestingly, the strong expression of Nectin-4 was correlated with high DCR. PD-L1 and Nectin-4 expression in tumor cells could be prognostic biomarkers useful for pembrolizumab in patients with advanced UC.

Enhanced sensitivity to androgen withdrawal due to overexpression of interleukin-6 in androgen-dependent human prostate cancer LNCaP cells.

BACKGROUND: The objective of this study was to investigate the effects of interleukin-6 (IL-6) overexpression in androgen-dependent prostate cancer LNCaP cells on their phenotype under an androgen-deprived condition. METHODS: We established IL-6-overexpressing LNCaP (LNCaP/IL-6) by introducing the expression vector containing IL-6 cDNA. Changes in the phenotype in LNCaP/IL-6 were compared with that in LNCaP transfected with control vector alone (LNCaP/Co). RESULTS: In vitro, the growth of LNCaP/IL-6 was significantly inferior to that of LNCaP/Co under an androgen-deprived condition. Similarly, LNCaP/IL-6 tumour in nude mice rapidly regressed after castration; however, LNCaP/Co tumour growth was transiently inhibited after castration and then continuously accelerated. After androgen withdrawal, expression levels of phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and Akt in LNCaP/IL-6 were markedly upregulated compared with those in LNCaP/Co; however, additional treatment with specific inhibitor of the MAPK or Akt signalling pathway significantly inhibited the growth of LNCaP/IL-6 compared with that of LNCaP/Co. Furthermore, gene microarray analyses showed that androgen deprivation resulted in differential expression of genes involved in growth, apoptotsis and tumorigenesis between LNCaP/Co and LNCaP/IL-6. CONCLUSION: Excessive secretion of IL-6 by LNCaP cells in an autocrine manner may have a suppressive function in their growth and acquisition of androgen-independent phenotype under an androgen-deprived condition.

Expressions of PD-L1 and Nectin-4 in urothelial cancer patients treated with pembrolizumab

ObjectivesRecently, the standard of care for advanced urothelial cancer (UC) has been changed by developing immune-checkpoint inhibitors (ICIs). However, its response rate is limited to 20–30%. The identification of biomarkers to predict the therapeutic effects of ICIs is urgently needed. The present study explored the association between immunohistochemical biomarkers and clinical outcomes in UC patients treated with pembrolizumab.Patients and methodsA total of 85 patients with UC who received pembrolizumab after chemotherapy from January 2018 to May 2020 were retrospectively reviewed. Tumor tissues were obtained for immunohistochemical study from 47 out of 85 patients. The protein expressions of PD-L1, WT1, Nectin-4, CD4, CD8, Foxp3, and CD68 in tumor cells and/or tumor infiltrating lymphocytes were immunohistochemically examined. The associations between protein expressions and overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) were statistically analyzed.ResultsPatients with positive PD-L1 in tumor cells showed significantly worse OS (Log-rank test: HR 5.146, p = 0.001, Cox regression analysis: HR 4.331, p = 0.014) and PFS (Log-rank test: HR 3.31. p = 0.022), along with significantly lower DCR (14.3%) compared to the PD-L1 negative patients (67.5%). In addition, patients with strong expression of Nectin-4 in tumor cells showed significantly higher DCR (100%) than the other patients (50%).ConclusionPD-L1 expression in tumor cells was associated with poor prognosis (OS and PFS) and low DCR. Interestingly, the strong expression of Nectin-4 was correlated with high DCR. PD-L1 and Nectin-4 expression in tumor cells could be prognostic biomarkers useful for pembrolizumab in patients with advanced UC.

A fungal chitinase gene fromRhizopus oligosporus confers antifungal activity to transgenic tobacco.

We have studied whether a chitinase involved in cell autolysis of a filamentous fungus,Rhizopus oligosporus, can operate as an antifungal defense system in tobacco. Thechi1 gene was introduced into tobacco by theAgrobacterium tumefaciens leaf disc system. Among 22 transgenic tobacco plants, 2 were selected and their individual homozygous progeny, Tch1-1 and Tch2-1, were studied. Chitinase activity in the extracts of young leaves from Tch1-1 or Tch2-1, in which thechi1 gene product was detected by Western blot analysis, was three- to four-fold higher than that from the control plants. A fungal infection assay on the leaves infected with the discomycete pathogensSclerotinia sclerotiorum andBotrytis cinerea revealed that the symptoms observed with these two were remarkably suppressed as compared with the control leaves.

Is hormonal therapy necessary in prepubertal boys with cryptorchidism?

Three hundred and twenty-eight prepubertal boys with cryptorchidism who had orchiopexy were reviewed in regard to the attachment of the gubernaculum. Normal attachment of the gubernaculum was found in only 19 out of 240 unilateral testes (8%), and in 12 out of 176 testes (7%) of 88 patients with bilateral cryptorchidism. Abnormal attachment of the gubernaculum was found in 307 out of 338 testes (91%). These data suggest that hormonal therapy for undescended testis may be effective in only 9% of the cases with cryptorchidism, and it cannot replace surgery.

Ultrasonographically demonstrated nutcracker phenomenon: alternative to angiography.

We report on a child with nutcracker phenomenon, which is a possible cause of intermittent gross haematuria of unknown origin. Early serial ultrasound examinations can demonstrate the lesions. The merits and demerits of conventional angiographic imaging are also discussed.

[A case of retroperitoneal fibrosis with special emphasis on diagnosis using the magnetic resonance imaging].

A case of idiopathic retroperitoneal fibrosis (RF) is reported. MRI showed a low signal intensity on T1 and heterogeneous signal intensity on T2-predominant image. Although this could be demonstrated either in malignant RF or early stage of non-malignant RF, differentiation from malignancy was made from the quick response to steroid therapy.

[Congenital arteriovenous malformation of the kidney: report of two cases--detection by digital subtraction angiography with carbon dioxide].

Two cases of arteriovenous malformation of the kidney were reported. The first case was a 19-year-old female, complaining of right flank pain and gross hematuria. Right selective renal arteriography revealed a 2 x 1.5 cm large cisoid type arteriovenous malformation at the most distal region of the lower branch of the renal artery. Transcatheter embolization, using Gelfoam and absolute ethanol, was successfully done, which was confirmed with repeated digital subtraction angiography with carbon dioxide (CO2-DSA). The second patient was a 55-year-old female with past history of right idiopathic renal bleeding, complaining of right flank colicky pain and gross hematuria. Right selective renal arteriography was done without any pathological findings, while CO2-DSA documented an arteriovenous malformation in the hilar region. Transcatheter embolization was not done, because the malformation seemed to be proximally located. Thus CO2-DSA was thought to be a reliable method in the diagnosis of arteriovenous fistula.

[XYY syndrome: report of three cases].

Three cases of XYY syndrome (YY syndrome) were experienced. Two cases had such rare associated anomalies as hypospadias and cryptorchism. Pathogenesis, incidence, clinical symptoms, gonadal function and fertility of the patients with XYY syndrome are briefly discussed.

[Metastatic renal tumor originating from esophageal carcinoma: a case report].

A 46-year-old woman with a past history of esophageal carcinoma was hospitalized with the chief complaint of right abdominal pain. Enhanced computed tomography (CT) and selective renal angiography suggested a metastatic renal tumor. Right nephrectomy was performed. Histological examination revealed a renal tumor originated from esophageal squamous cell carcinoma. Metastatic renal tumors are frequently observed at autopsy, but clinically they are extremely uncommon. Thirty-four clinical cases of metastatic renal tumors reported in the Japanese literature during these 20 years are discussed including the present case.

[A case of renal pseudotumor caused by pyelonephritis].

A case of renal pseudotumor due to pyelonephritis is reported. A 70-year-old female was admitted to our hospital for the evaluation of right renal mass in pyelogram. She had had episodes of pyelonephritis many times. Computed tomography (CT) revealed poorly marginated low density mass that exhibits inhomogenous enhancement with contrast medium. Angiography showed an avascular mass. On magnetic resonance imaging (MRI), the mass was isointensity or slightly low intensity on T1 weighted scan, while it showed low intensity on T2 weighted scan. The patient died from small cell carcinoma in the lung two years later. Autopsy was performed and no malignancy was found in the kidney. MRI was useful to differentiate such inflammatory change from renal tumor, which is mostly high intensity on T2 weighted scan.

[Clinical statistics on outpatients, inpatients and operations in 1986].

Statistical studies were made on 1,637 outpatients, 568 inpatients and 563 operative procedures at our department in 1986. The most frequent diseases among the outpatients were urogenital infections followed by anomalies, tumors and stones. The major diseases among the inpatients were hypospadias, vesicoureteral reflux, benign prostatic hypertrophy, bladder tumor and congenital urethral stenosis. A total of 563 operations were performed. The five major operations were hypospadia repair, optic internal urethrotomy, transurethral resection of prostate, ureterocystoneostomy and percutaneous nephrolithotripsy.

[Clinical statistics on outpatients, inpatients and operations in 1985].

Statistical studies were made on 1,795 outpatients, 528 inpatients and 518 operative procedures at our department in 1985. The most frequent diseases among the outpatients were urogenital infections followed by anomalies, stones and tumors. The major diseases among the inpatients were hypospadias, vesicoureteral reflux, congenital urethral stenosis, bladder tumor and benign prostatic hypertrophy. A total of 518 operations were performed. The five major operations were optic internal urethrotomy, hypospadias repair, ureterocystoneostomy, and transurethral resection of prostate and of bladder tumors.

[Clinical statistics on outpatients, inpatients and operations in 1988].

Statistical studies were made on 1,766 outpatients, 657 inpatients and 687 operative procedures at our department in 1988. The most frequent diseases among the outpatients were urogenital infections followed by anomalies, tumors and stones. The major diseases among the inpatients were congenital urethral stenosis, hypospadias, vesicoureteral reflux, benign prostatic hypertrophy and bladder tumor. A total of 687 operations were performed. The five major operations were optic internal urethrotomy, hypospadias repair, transurethral resection of prostate, ureterocystoneostomy and transurethral resection of bladder tumor.

[Clinical statistics on outpatients, inpatients and operations in 1987].

Statistical studies were made on 1,859 outpatients, 587 inpatients and 601 operative procedures at our department in 1987. The most frequent diseases among the outpatients were urogenital infections followed by anomalies, tumors and stones. The major diseases among the inpatients were hypospadias, vesicoureteral reflux, congenital urethral stenosis, benign prostatic hypertrophy and bladder tumor. A total of 601 operations were performed. The five major operations were hypospadias repair, optic internal urethrotomy, transurethral resection of prostate, ureterocystoneostomy and transurethral resection of bladder tumor.

[Transurethral ureterolithotripsy under hydraulic ureteral dilatation].

Transurethral ureterolithotripsy was performed in 32 patients with ureteral stones. A rigid ureteroscope was used and for the purpose of ureteral dilatation a hydraulic ureteral dilator (Ureteromat) was used. In total 39 stones were treated and of these 30 stones (77%) were successfully extracted or disintegrated. The success rate according to the location of the stone was as follows; 50% for the upper ureteral stone, 55% for middle ureteral stone and 96% for lower ureteral stone. As a complication of the procedure a lower ureteral stricture was noted in one patient. Hydraulic ureteral dilatation is a useful method of ureteral dilatation in transurethral ureterolithotripsy.

[Complete testicular feminization syndrome associated with thermolabile androgen receptor].

Radioreceptor assay and thermostability test for the androgen receptor in two cases with complete testicular feminization syndrome were performed in regard to the fibroblasts cultured from genital skin on the basis of dispersed whole cell binding assay (Eil et al., 1980). No [3H]dihydrotestosterone binding to the androgen receptor was observed in case 1 (receptor negative), while maximum binding capacity and dissociation constant of androgen receptor for [3H]dihydrotestosterone in case 2 were 21000 sites per cell and 1.67 x 10(-10) M (receptor positive). The specific binding of [3H]dihydrotestosterone to the androgen receptor in case 2 decreased remarkably to 6.6% after high temperature (42 degrees C) incubation in comparison with that at 22 degrees C incubation. The specific binding of [3H]dihydrotestosterone to the androgen receptor in normal controls decreased down to 81.6% at high temperature incubation. Thermostability test was useful to demonstrate qualitative abnormality of androgen receptor in receptor positive testicular feminization syndrome.

[Treatment of congenital urethral stenosis (urethral ring) in children. Optic internal urethrotomy in the congenital bulbar urethral stenosis in boys].

Congenital urethral stenosis in boys occurs at the junction of the entodermal primary urethra and ectodermal secondary urethra. Endoscopically this lesion is recognized as a ring-form stenosis just distal to the external urethral sphincter. It has been considered as rare congenital anomaly in American literature. But in our experience congenital urethral stenosis is an important cause of recurrent urinary tract infections, enuresis, pollakisuria or hematuria in pediatric urological practice. It also disturbs spontaneous healing of vesicoureteral reflux. The most effective treatment of this lesion is optic internal urethrotomy under direct vision. We would like to report our experience of optic internal urethrotomy for congenital urethral stenosis in boys. From 1974 to 1986, 226 boys with congenital bulbar urethral stenosis were treated in our clinic. Optic internal urethrotomy was performed using a Sachse urethrotome with a 10 or 13 Fr. sheath. Of the 176 ureters with vesicoureteral reflux, spontaneous disappearance of reflux after optic internal urethrotomy was noted in 62.5% of Grade I-II, 65.0% of Grade III, 28.9% of Grade IV and 16.7% of Grade V ureters. These spontaneous disappearance rates were significantly higher than those of primary vesicoureteral reflux in Grade III, IV and V ureters. Of the drug-resistant enuretic boys with a congenital bulbar urethral stenosis, enuresis disappeared or ameliorated in 69.4% after optic internal urethrotomy. Furthermore, urinary tract infections were mostly prevented by optic internal urethrotomy, irrespective of the presence or absence of vesicoureteral reflux. Our results support the view that congenital urethral stenosis (urethral ring) is an important clinical entity in pediatric urology.

Prognostic significance of tumor extension into venous system in patients undergoing surgical treatment for renal cell carcinoma with venous tumor thrombus.

AIMS: The objective of this study was to evaluate the prognostic significance of the extent of a tumor thrombus in renal cell carcinoma (RCC) involving the venous system. METHODS: This study included 135 consecutive RCC patients with a venous tumor thrombus undergoing radical nephrectomy and tumor thrombectomy between 1985 and 2009. These patients were classified based on the maximal level of the tumor thrombus extending into the venous system, as follows: group 1, renal vein; group 2, infradiaphragmatic; and group 3, supradiaphragmatic. RESULTS: Of the 135 patients, 65, 49 and 21 were classified into groups 1, 2 and 3, respectively. The 1, 3 and 5-year cancer-specific survival (CSS) rates in these 135 patients were 89.2, 56.9 and 49.2%, respectively. Among several factors examined, tumor size, tumor grade, perirenal fat invasion and presence of metastasis, but not extent of tumor thrombus, were significantly associated with CSS on univariate analysis. Of these significant factors, only tumor size and presence of metastasis appeared to be independently related to CSS on multivariate analysis. When the patients without metastasis were analyzed separately, CSS in groups 2 and 3 was significantly poorer than that in group 1. CONCLUSIONS: These findings suggest the absence of a significant prognostic impact of the level of the tumor thrombus in a complete cohort of RCC patients with a venous tumor thrombus; however, it is warranted to determine whether the level of the tumor thrombus has different effects on the prognosis according to the presence of metastatic diseases.