Since the 2000s, there have been dramatic advances in the treatment of metastatic renal cell carcinoma (mRCC), including drugs targeting vascular endothelial growth factor (VEGF) and mammalian target ...of rapamycin (mTOR) pathways. The first VEGF inhibitors approved for mRCC were sorafenib and sunitinib. Subsequently, two mTOR inhibitors (everolimus and temsirolimus) and other VEGF inhibitors (pazopanib and axitinib) were approved. Overall survival (OS) of mRCC patients has significantly increased during this period. Two novel VEGF inhibitors have recently been approved overseas, including cabozantinib and lenvatinib. Additionally, the recent advent of immunotherapy with checkpoint inhibitors has led to significant changes in the treatment of mRCC. The PD-1 inhibitor nivolumab improved the OS rate of patients with mRCC following VEGF inhibitors. Moreover, the CheckMate 214 trial demonstrated the benefit of nivolumab plus ipilimumab combination therapy in OS and objective response rate in treatment-naive intermediate- and poor-risk mRCC. In this review, current evidence related to the clinical use of targeted therapies and checkpoint inhibitors for the treatment of patients with mRCC is discussed. In addition, we review ongoing trials investigating combinations of checkpoint inhibitors with targeted agents and the identification of biomarkers to guide patient selection and enable individualization of therapy.
Objective
Pheochromocytomas and paragangliomas (PPGLs) are rare tumors arising from the neural crest cells that form the sympathetic and parasympathetic nervous systems. Radiotherapy with
131
...Imetaiodobenzylguanidine (MIBG) is recommended for unresectable PPGLs. We investigated the usefulness of the metabolic tumor volume (MTV) and total lesion glycolysis (TLG) derived from
18
Ffluorodeoxyglucose-positron emission tomography (FDG-PET) for predicting the prognosis of patients with unresectable PPGL(s) before receiving
131
IMIBG therapy.
Patients and methods
We retrospectively analyzed the cases of 25 patients with unresectable PPGLs treated with
131
IMIBG at our hospital between 2001 and 2020. The MTV and TLG were measured in reference to liver accumulation. We divided the patients into two groups based on median values for the maximum standardized uptake value (SUVmax), MTV, and TLG, and evaluated between-group differences using log-rank tests. Cox proportional hazards models were used to determine whether there were significant differences in prognosis with respect to tumor type (pheochromocytoma vs. paraganglioma), site of metastasis, age, past treatment (chemotherapy, external radiation or
131
IMIBG treatment before the current
131
IMIBG treatment), urinary catecholamine, SUVmax, MTV, and TLG.
Results
The median follow-up time was 42 months (range 2–136 months). The median overall survival was 63 months. The overall survival (OS) was significantly shorter in the high-MTV group (log-rank test,
p
= 0.049) and the high-TLG group (
p
= 0.049), with no significant difference between the high- and low-SUVmax groups (
p
= 0.19). Likewise, there was no significant difference in prognosis according to pheochromocytoma or paraganglioma, metastasis location, age, or prior chemotherapy. A history of external radiation before
131
IMIBG treatment was associated with a significantly worse prognosis (hazard ration HR = 7.95,
p
= 0.0018). Urinary adrenaline and noradrenaline were not significant prognostic factors (
p
= 0.70,
p
= 0.25, respectively), but urinary dopamine did predict a worse outcome (
p
= 0.022). There was no increased risk of death for higher SUVmax or TLG (
p
= 0.63 and 0.057, respectively), but higher MTV did predict a worse outcome (HR = 7.27,
p
= 0.029).
Conclusion
High MTV and high TLG were significantly associated with a poor prognosis after
131
IMIBG therapy for PPGLs. Other treatment strategies for such patients may need to be explored.
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
Our aim was to characterize the motions of multiple laparoscopic surgical instruments among participants with different levels of surgical experience in a series of wet-lab training ...drills, in which participants need to perform a range of surgical procedures including grasping tissue, tissue traction and dissection, applying a Hem-o-lok clip, and suturing/knotting, and digitize the level of surgical competency.
Methods
Participants performed tissue dissection around the aorta, dividing encountered vessels after applying a Hem-o-lok (Task 1), and renal parenchymal closure (Task 2: suturing, Task 3: suturing and knot-tying), using swine cadaveric organs placed in a box trainer under a motion capture (Mocap) system. Motion-related metrics were compared according to participants’ level of surgical experience (experts: 50 ≤ laparoscopic surgeries, intermediates: 10–49, novices: 0–9), using the Kruskal–Wallis test, and significant metrics were subjected to principal component analysis (PCA).
Results
A total of 15 experts, 12 intermediates, and 18 novices participated in the training. In Task 1, a shorter path length and faster velocity/acceleration/jerk were observed using both scissors and a Hem-o-lok applier in the experts, and Hem-o-lok-related metrics markedly contributed to the 1st principal component on PCA analysis, followed by scissors-related metrics. Higher-level skills including a shorter path length and faster velocity were observed in both hands of the experts also in tasks 2 and 3. Sub-analysis showed that, in experts with 100 ≤ cases, scissors moved more frequently in the “close zone (0 ≤ to < 2.0 cm from aorta)” than those with 50–99 cases.
Conclusion
Our novel Mocap system recognized significant differences in several metrics in multiple instruments according to the level of surgical experience. “Applying a Hem-o-lok clip on a pedicle” strongly reflected the level of surgical experience, and zone-metrics may be a promising tool to assess surgical expertise. Our next challenge is to give completely objective feedback to trainees on-site in the wet-lab.
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.
The quality of transurethral resection of bladder tumor (TURBT) markedly varies among surgeons and may have a considerable impact on treatment outcomes. The importance of a surgical checklist for ...TURBT has been suggested in order to standardize the procedure and improve surgical and oncological outcomes. In the present study, we verified the usefulness of a checklist for managing patients with non-muscle-invasive bladder cancer (NMIBC). This retrospective study included 201 NMIBC patients diagnosed with Ta, T1, or Tis between October 2011 and February 2021. After September 2016, TURBT was performed with a checklist. We analyzed the intravesical recurrence-free survival (RFS) rate and the presence or absence of the detrusor muscle in resected specimens before and after the introduction of the checklist. Survival rates were compared using the Log-rank test. A multivariate analysis with Cox proportional hazards modeling was performed to verify risk factors for intravesical recurrence. Ninety-nine patients who underwent TURBT with the checklist (checklist group) were compared with 102 patients who underwent TURBT without the checklist (non-checklist group). When the analysis was narrowed down to 9 critical items, we observed a mean number of 9 documented items per operative report (98.0% completion) after implementation of the checklist. Two-year intravesical RFS rates in the checklist and non-checklist groups were 76.7 and 69.5%, respectively (p = 0.1059). The Cox proportional multivariate analysis showed that the rate of intravesical recurrence was slightly lower in the checklist group (hazard ratio 0.7376, 95% CI 0.4064-1.3388, P = 0.3170). The introduction of a checklist is recommended for the standardization of TURBT and increasing the quality of operative reporting, and it may also improve oncological outcomes.
Efficacy and safety results of CheckMate 025 were consistent between the global and the Japanese populations, with a notably higher OS and ORR in Japanese patients treated with nivolumab.
Abstract
...Background
Nivolumab treatment resulted in superior efficacy and safety versus everolimus treatment in the 2-year follow-up of the CheckMate 025 Phase III study, with consistent results in the global population and the Japanese population. Here, we report the 3-year follow-up in both groups.
Methods
Patients were randomized 1:1 to nivolumab 3 mg/kg intravenously every 2 weeks or everolimus 10 mg orally once daily until progression/intolerable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included objective response rate, progression-free survival, safety and patient-reported quality of life.
Results
Of 410 and 411 patients randomized to nivolumab and everolimus, 37 and 26 were Japanese, respectively. The median OS for the global population was 25.8 months with nivolumab and 19.7 months with everolimus (hazard ratio 0.74; 95.5% confidence interval CI: 0.63–0.88; P = 0.0005); in the Japanese population, median OS was 45.9 months and not reached (hazard ratio 1.08; 95% CI: 0.50–2.34; P = 0.85), respectively. The investigator-assessed objective response rate was 26% versus 5% with nivolumab versus everolimus (odds ratio OR 6.19; 95% CI: 3.82–10.06) in the global population and 43% versus 8% in the Japanese population (OR 6.80; 95% CI: 1.60–28.91; P = 0.0035), respectively. The incidence of any-grade treatment-related adverse events was lower with nivolumab versus everolimus in both the global patient population (80% versus 89%) and the Japanese population (81% versus 100%).
Conclusions
At the 3-year follow-up, the efficacy and safety results of CheckMate 025 are generally consistent in the global and the Japanese populations.
Parkinson's disease (PD) is a neurodegenerative condition caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. As activation of dopaminergic receptors is fundamentally ...involved in the micturition reflex in PD, the objective of this study was to determine the effect of a single dose of rotigotine (-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin) on intercontraction interval (ICI) and voiding pressure (VP) in a rat model of PD. We used 27 female rats, PD was induced by injecting 6-hydroxydopamine (6-OHDA; 8 μg in 2 μL of 0.9% saline containing 0.3% ascorbic acid), and rotigotine was administrated at doses of 0.125, 0.25, or 0.5 mg/kg, either intravenous or subcutaneous injection. In rats with 6-OHDA-induced PD, intravenous injection of 0.25 or 0.5 mg/kg rotigotine led to a significantly lower ICI than after vehicle injection (p < 0.05). Additionally, VP was significantly lower in animals administered rotigotine compared to those injected with vehicle (p < 0.05). Compared to vehicle-injected animals, subcutaneous administration of rotigotine (0.125, 0.25, or 0.5 mg/kg) led to a significantly higher ICI at 2 h after injection (p < 0.05); however, there was no change in ICI after injection with (+)-SCH23390 hydrochloride. Dermal administration of rotigotine in a rat model of PD could suppress an overactive bladder.
Background
Patients with favorable-risk prostate cancer on active surveillance (AS) are strictly followed for safer execution. Repeat protocol biopsy is essential for evaluating cancer ...aggressiveness. However, the acceptance rate of repeat biopsy is not high enough because of the burdens of biopsy. We assessed the impact of complications after the initial biopsy on repeat protocol biopsy at 1 year using data from the Prostate Cancer Research International: Active Surveillance (PRIAS)-JAPAN study.
Methods
We performed a retrospective analysis using a prospective cohort in the PRIAS-JAPAN study. Patients with favorable-risk prostate cancer (
n
= 856) who consented to participate in the PRIAS-JAPAN study from 2010 to 2018 were enrolled. Follow-up evaluations included regular prostate-specific antigen, digital rectal examination and biopsy. Rates of complications after biopsies and repeat protocol biopsy non-acceptance rate at 1 year were reported. Logistic regression analysis explored the association between the complications after the initial biopsy and repeat protocol biopsy non-acceptance.
Results
Altogether, 759 patients (88.7%) actually proceeded to protocol at 1 year. Repeat protocol biopsy non-acceptance rate at 1 year was 14.9%. Regarding complications after the initial biopsy, hematuria (
p
= 0.028) and pain (
p
< 0.001) rates were significantly higher in the repeat biopsy non-acceptance group, but infection (
p
= 0.056) and hematospermia (
p
= 0.337) rates were not different. On multivariate logistic regression analysis, pain was a significant predictor for repeat protocol biopsy non-acceptance (odds ratio 4.68, 95% confidence interval 1.864–11.75;
p
= 0.001).
Conclusions
Pain at the initial biopsy negatively impacts patients’ compliance with further protocol biopsies during AS.
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