Microdissection testicular sperm extraction and intracytoplasmic sperm injection have made it possible for men with non-obstructive azoospermia (NOA) to conceive a child. A majority of men cannot ...produce sperm because spermatogenesis per se is believed to be “irreversibly” disturbed. For these men, it has been thought that any hormonal therapy will be ineffective. Further understandings of endocrinological regulation of spermatogenesis are needed and LH or FSH receptor knock out (KO) mice have revealed the roles of gonadotropin separately. Spermatogenesis has been shown to shift during evolution from FSH to LH dominance because LH receptor KO causes infertility while FSH receptor KO does not. High concentrations of intratesticular testosterone secreted from Leydig cells, ranging from 100- to 1,000-fold higher than in the systemic circulation, has pivotal roles during spermatogenesis. This is especially important during spermiogenesis, a post-meiotic step for progression from round to elongating spermatids. Sertoli cells are the target of FSH and have numerous androgen receptors, indicating that Sertoli cells are regulated by FSH and the paracrine functions of testosterone. In combination with Leydig cell-derived growth factors, particularly epidermal growth factor-like growth factors, Sertoli cells support spermatogenesis, especially at proximal levels of spermatogenesis (e.g., spermatogonial proliferation). Taken together, the current knowledge from human studies indicating that testosterone optimization by clomiphene, hCG and/or aromatase inhibitors and high dose hCG/FSH treatment can, at least in part, improve spermatogenesis in NOA. Accordingly hormonal therapy may open a therapeutic window for sperm production in selected patients.
Varicocele is the most common and treatable cause of male infertility. Studies of a rat experimental left varicocele model and human testicular biopsy samples have shown the involvement of various ...factors in its pathophysiology. Among them, oxidative stress plays a major role in impairing spermatogenesis and sperm function. Therefore, in addition to palpation, scrotal ultrasonography and color Doppler ultrasound, evaluation of testicular oxidative stress (e.g. scrotal temperature is a surrogate parameter) is recommended to enable diagnosis and suitable treatment of varicocele. Varicocelectomy increases the fertilization, pregnancy and live birth rates, indicating improved sperm function; it is therefore important even in couples undergoing intracytoplasmic sperm injection. Routine sperm‐function tests are warranted to monitor the sperm quality after varicocelectomy and consequent improvement in the outcomes of assisted reproductive technology. Furthermore, the indications of varicocelectomy in assisted reproductive technology should be widened.
Objectives
Despite just a 4‐year interval from the last version (2015) of the Clinical Practice Guidelines for Bladder Cancer, several dramatic paradigm shifts have occurred in the latest clinical ...practice regarding both the diagnosis and treatment of bladder cancer. Herein, we updated the 2019 version of the Clinical Practice Guidelines for Bladder Cancer under the instruction of the Japanese Urological Association.
Methods
We previously reported in a revision working position paper for Clinical Practice Guidelines for Bladder Cancer 2019 edition and described the methods of revision detail.
Results
The major points of change in the 2019 version are presented and explanations are given as follows: (i) introduction of the new reference assessment system; (ii) modification of the risk classification for non‐muscle‐invasive bladder cancer; (iii) addition of clinical questions for the new tumor‐visible techniques in non‐muscle‐invasive bladder cancer; (iv) inclusion of minimally invasive surgeries for muscle‐invasive bladder cancer and immune checkpoint inhibitors for locally advanced/metastatic muscle‐invasive bladder cancer; (v) overview chapter of the histological variant of urothelial cancer and rare cancers of the bladder; and (vi) recommendation of follow up in non‐muscle‐invasive bladder cancer and muscle‐invasive bladder cancer.
Conclusions
Guidelines should be updated based on the current evidence and updates carried out without delay. The hope is that this guidelines will be assessed by many urologists and will be the cornerstone for the next revision.
Background
Klinefelter syndrome (KS) is one of the major causes of nonobstructive azoospermia (NOA). Microdissection testicular sperm extraction (micro‐TESE) is often performed to retrieve sperm. ...Infertility specialists have to care for KS patients on a lifelong basis.
Methods
Based on a literature review and our own experience, male infertility treatment and KS pathophysiology were considered on a lifelong basis.
Main findings
Patients diagnosed early often have an increased number of aberrant X chromosomes. Cryptorchidism and hypospadias are often found, and surgical correction is required. Cryopreservation of testicular sperm during adolescence is an issue of debate because the sperm retrieval rate (SRR) in KS patients decreases with age. The SRR in adult KS patients is higher than that in other patients with NOA; however, low testosterone levels after micro‐TESE will lower the general health and quality of life. KS men face a number of comorbidities, such as malignancies, metabolic syndrome, diabetes, cardiovascular disease, bone disease, and immune diseases, which ultimately results in increased mortality rates.
Conclusion
A deeper understanding of the pathophysiology of KS and the histories of KS patients before they seek infertility treatment, during which discussions with multidisciplinary teams are sometimes needed, will help to properly treat these patients.
Male hypogonadotropic hypogonadism (MHH) is effectively treated by gonadotropins with a high rate of ejaculate sperm and paternity; however, there is no information regarding the appropriate ...management, including patient-reported outcomes (PROs), of men with MHH who have finished infertility treatment. To compare health-related quality of life, erectile function and biochemical alterations in men with MHH who were treated with testosterone replacement therapy (TRT) or human chorionic gonadotropin (hCG). Twenty-six MHH patients (mean age: 34 years) who needed to improve their androgen deficiency symptoms underwent either hCG therapy (n = 16, started with self-injection of 2,000–7,500 IU per week) or TRT (n = 10, testosterone enanthate 250 mg every 3 weeks). The 36-item Short Form Health Survey (SF-36) questionnaire, five-item International Index of Erectile Function (IIEF-5) and hormonal and biochemical analyses were assessed every 3 months. Changes and comparison of each treatment regarding these parameters were analyzed. Both hCG and TRT significantly improved all domains of the SF-36, except for bodily pain and social functioning. hCG significantly improved the general and mental health domains compared with TRT. Significant improvements in IIEF-5 were observed with both treatments, showing significant improvement with hCG compared to TRT. TRT caused progressive testicular atrophy. There were significant decreases in waist circumference and triglycerides in both treatment groups and significant elevations in prostate-specific antigen and hematocrit. Both hCG and TRT are effective and safe, with preferable PROs by hCG, for treating androgen deficiency in men with MHH who do not need infertility treatment.
Objectives
Vasoepididymostomy is an ideal surgical approach for epididymal obstructive azoospermia. The aim of the present study was to compare reproductive outcomes of vasoepididymostomy with ...several anastomotic techniques, including end‐to‐side and longitudinal intussusception vasoepididymostomy, and partial intussusception and endo‐to‐side vasoepididymostomy.
Methods
A case–control study including 110 infertile men with epididymal obstructive azoospermia with mean age of 35 years was carried out. Univariate and multivariate analyses using clinical factors were carried out to predict patency and non‐assisted reproductive technology pregnancy. Johnsen score count and proliferating cell nuclear antigen expression were used as surrogates for spermatogenic function. Operative time, number of 10‐0 sutures and late failure rates were also compared.
Results
The overall patency and non‐assisted reproductive technology pregnancy rates were 70% and 32%, respectively. Multivariate analyses showed that the presence of motile sperm in the epididymis and a higher spermatogenic function (P < 0.05) were independent predictors for patency, and that a higher spermatogenic function and anastomosis at the caput/corpus (P < 0.001) were predictors for non‐assisted reproductive technology pregnancy. The operative time was significantly shorter with partial intussusception and endo‐to‐side than with the other techniques (P < 0.001), and the number of 10‐0 sutures was significantly less with partial intussusception and endo‐to‐side than with longitudinal intussusception vasoepididymostomy (P < 0.01).
Conclusions
Partial intussusception and endo‐to‐side as well as end‐to‐side and longitudinal intussusception vasoepididymostomy are feasible vasoepididymostomy techniques for epididymal obstruction. Spermatogenic function plays important roles in patency and non‐assisted reproductive technology pregnancy after vasoepididymostomy. Depending on the surgeon’s expertise, partial intussusception and endo‐to‐side provides similar functional outcomes to those of more established vasoepididymostomy techniques, such as end‐to‐side and longitudinal intussusception vasoepididymostomy, and it could therefore be considered an effective technique for seminal reconstruction in patients with epididymal obstructive azoospermia.
Recently, immunotherapy based on blocking immune checkpoints with programmed death‐1 (PD‐1) or PD‐ligand 1 (PD‐L1) Abs has been introduced for the treatment of advanced clear cell renal cell ...carcinoma (ccRCC), especially tumors resistant to vascular endothelial growth factor‐tyrosine kinase inhibitors (VEGF‐TKIs), but the significance of their expression in the tumor microenvironment is unclear. We investigated these immune checkpoint markers in tumor cells and tumor‐infiltrating immune cells (TIIC) in the tumor microenvironment of 100 untreated and 25 VEGF‐TKI‐treated primary ccRCC tissues. Upregulated expression of PD‐1 and PD‐L1 by TIIC, and PD‐L1 by tumor cells was associated with the histological grade and unfavorable prognosis of RCC patients. High PD‐1 and PD‐L1 expression by TIIC was associated with a poorer response to VEGF‐TKI, whereas PD‐L1 expression by tumor cells did not affect the efficacy of the treatment. Furthermore, increased PD‐1‐positive TIIC and PD‐L1‐positive TIIC were observed in tumors treated with VEGF‐TKIs compared with those in untreated tumors. Our data suggest that PD‐1 and PD‐L1 expression by TIIC in the tumor microenvironment is involved in treatment resistance, and that sequential therapy with immune checkpoint inhibitors could be a promising therapeutic strategy for ccRCC resistant to VEGF‐TKI treatment.
In the present study, we showed that PD‐1 and PD‐L1 expression by tumor‐infiltrating immune cells (TIIC) is associated with malignant potential and poor response to vascular endothelial growth factor‐tyrosine kinase inhibitor (VEGF‐TKI) treatment in renal cell carcinoma (RCC) patients. Moreover, RCC patients treated with VEGF‐TKI had significantly more PD‐1‐ and PD‐L1‐positive TIIC compared with untreated tumors. These results suggested that upregulated PD‐1 and PD‐L1 expression by TIIC in the tumor microenvironment is associated with resistance to VEGF‐TKI treatment, and that blocking the PD‐1/PD‐L1 pathway could be an effective sequential therapy for RCC resistant to VEGF‐TKI treatment.
Objective
To confirm the reproducibility of the effectiveness and safety in photodynamic diagnosis of non‐muscle‐invasive bladder cancer using 5‐aminolevulinic acid in a prospective multicenter ...non‐randomized phase III trial.
Methods
A total of 61 patients with primary or recurrent non‐muscle‐invasive bladder cancer were prospectively enrolled from five hospitals between May 2015 and March 2016. 5‐Aminolevulinic acid (20 mg/kg) was orally administered 3 h before transurethral resection of bladder tumors using white light or fluorescent light. Of 60 evaluable patients, 511 specimens were obtained from tumor‐suspicious lesions and normal‐looking mucosa. The primary end‐point was sensitivity. The secondary end‐points were specificity, positive and negative predictive values, and safety.
Results
The sensitivity of the fluorescent light source (79.6%) was significantly higher (P < 0.001) than that of the white light source (54.1%). In total, 25.4% (46/181) of tumor specimens were diagnosed as positive with only the fluorescent light source. In nine (15%) of 60 patients, the risk classification and recommended treatment after transurethral resection of bladder tumors were changed depending on the additional types of tumor diagnosed by the fluorescent light source. The specificity of the fluorescent light versus white light source was 80.6% versus 95.5%. No grade 4–5 adverse event was noted. Hypotension and urticaria were severe adverse events whose relationship to oral 5‐aminolevulinic acid could not be excluded.
Conclusions
These findings confirm the diagnostic efficacy and safety of photodynamic diagnosis with 20 mg/kg of oral 5‐aminolevulinic acid, and show that transurethral resection of bladder tumors with a fluorescent light source using oral 5‐aminolevulinic acid is well tolerated.
The intravesical administration of bacillus Calmette–Guérin (BCG) is widely used to control the intravesical recurrence of non-muscle-invasive bladder cancer (NMIBC). This study aimed to reveal the ...effects of zygosity on human leukocyte antigen (HLA) genes and individual HLA genotypes on intravesical recurrence after intravesical BCG therapy for NMIBC. This study included Japanese patients who had received intravesical BCG for NMIBC. HLA genotyping of HLA-A, B, C, and DRB1 was performed. The effect of HLA zygosity and HLA genotype on intravesical recurrence was evaluated. Among 195 patients, those homozygous for the HLA-B supertype were more likely than those heterozygous for the HLA-B supertype to experience intravesical recurrence by univariate analysis (hazard ratio HR, 95% confidence interval CI; 1.87, 1.14–3.05,
P
= 0.012) and multivariate analysis (HR, 95% CI; 2.26, 1.02–5.01,
P
= 0.045). Patients with B07 or B44 had a decreased risk of intravesical recurrence by univariate analysis (HR, 95% CI; 0.43, 0.24–0.78,
P
= 0.0056) and multivariate analysis (HR, 95% CI; 0.36, 0.16–0.82,
P
= 0.016). This study suggests the importance of the diversity and specificity of HLA-B loci in the antitumor effect of BCG immunotherapy for NMIBC. These findings may contribute to the delineation of risk strata for BCG therapy and improve the medical management of NMIBC.
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