Real-world outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma in Japanese patients: data with a minimum of 3 years of follow-up.

BACKGROUND: Long-term follow-up data regarding treatment outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma as a first-line therapy are limited in real-world Japanese populations. METHODS: We retrospectively evaluated data of 56 advanced renal cell carcinoma patients treated with nivolumab plus ipilimumab, with a follow-up of at least 3 years. Survival, tumour response and adverse event profiles were assessed. RESULTS: A total of 41 patients (73%) were histopathologically diagnosed with clear-cell renal cell carcinoma, and 34 (61%) were categorized into the International Metastatic renal cell carcinoma Database Consortium intermediate-risk group. The median follow-up period was 34.4 months. Regarding an effectiveness profile, median progression-free survival, time to treatment failure and overall survival were 9.01, 12.5 and 49.0 months, respectively. Objective response was observed in 27 patients (48%), including eight patients with complete response (14%), and the median duration of response was 30.8 months. Multivariate analyses showed that clear-cell histology was an independent factor of longer overall survival (hazard ratio: 0.23, P = 0.0013). Regarding safety profiles, adverse events of any grade and those with grade ≥3 developed in 40 (71%) and 25 patients (45%), respectively. Median time to adverse event development was 1.68 months. Treatment was interrupted in 28 patients (50%), and corticosteroid administration was needed in 25 (45%). CONCLUSION: The 3-year follow-up data showed that nivolumab plus ipilimumab combination therapy exhibited a feasible effectiveness in real-world Japanese patients with advanced renal cell carcinoma. Accordingly, the high risk of adverse event development, which often requires treatment withdrawal and corticosteroid administration, should be considered.

First-line dual immune checkpoint inhibitor therapies versus combination therapies comprising immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced renal cell carcinoma: a comparative analysis of the effectiveness using real-world data.

BACKGROUND: There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) for advanced renal cell carcinoma (RCC), especially in real-world settings. METHODS: We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups. RESULTS: Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3 months; p = 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0 months; p = 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%; p = 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%; p < 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%; p = 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%; p = 0.001). CONCLUSION: IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids.

Impact of sex on prognosis in patients with advanced renal cell carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Prognostic impact of sex in patients with malignancies treated with immune checkpoint inhibitors has been intensively discussed but remains unclear, especially in advanced renal cell carcinoma. METHODS: We retrospectively evaluated a total of 184 patients with advanced renal cell carcinoma treated with either nivolumab plus ipilimumab combined treatment as first-line therapy (n = 73) or nivolumab as later-line therapy (n = 111) at our affiliated institutions. Progression-free survival, overall survival and objective response rate as well as adverse event profile were compared between sexes. RESULTS: Of the total 184 patients, 48 (26%) were female. Female patients had a significantly shorter progression-free survival than male patients (median: 3.8 vs. 8.3 months, P = 0.0005), but overall survival (median: 39.2 vs. 45.1 months, P = 0.283) and objective response rate (29% vs. 42%, P = 0.119) were not different between them. Similar findings were observed when analyzing within each treatment; in both patient groups treated with nivolumab plus ipilimumab combined therapy and nivolumab monotherapy, progression-free survival was significantly shorter in female than in male patients (P = 0.007, P = 0.017), but overall survival (P = 0.914, P = 0.117) and objective response rate (P = 0.109, P = 0.465) were comparable between them. Moreover, in a more restricted cohort consisting of patients with clear-cell renal cell carcinoma, a shorter progression-free survival in female patients was also observed (3.8 vs. 11.0 months, P < 0.0001). CONCLUSIONS: This retrospective study showed that immune checkpoint inhibitors-based treatment for renal cell carcinoma exhibited less marked effects in female than in male patients. Thus, sex may be an important factor for decision-making on systemic therapy as renal cell carcinoma treatment, although further studies are required to validate the present findings.

A single-center retrospective comparative analysis of urinary continence in robotic prostatectomy with a combination of umbilical ligament preservation and Hood technique.

OBJECTIVES: Data available on the effect of the recently developed Hood technique and its modified iterations in robot-assisted radical prostatectomy on postoperative urinary continence are insufficient. We evaluated the time to achieve urinary continence with the modified Hood technique compared with the standard or umbilical ligament preservation robot-assisted radical prostatectomy. METHODS: This retrospective analysis examines patient records for those who underwent robot-assisted radical prostatectomy at the Jyoban Hospital of Tokiwa Foundation in Fukushima, Japan, from 2017 to 2021. The main outcome was to determine significant differences in the time taken to achieve urinary continence among the three procedure types. We employed the Kaplan-Meier survival analysis to estimate the time to achieve urinary continence in the three procedure types of robot-assisted radical prostatectomy. Additionally, we used a Cox regression hazard model to evaluate the association between the time to achieve urinary continence and the procedure types. RESULTS: We considered 196 patients in this study. The estimated rates of achieving urinary continence at 6 months following standard, umbilical ligament preservation, and modified Hood technique robot-assisted radical prostatectomy were 77.6%, 89.5%, and 100%, respectively. The multivariable Cox hazard regression model showed that patients who underwent the modified Hood technique were significantly more likely to achieve urinary continence than those who underwent the standard robot-assisted radical prostatectomy. CONCLUSIONS: The modified Hood technique achieved better urinary continence outcomes, with all patients with the procedure achieving urinary continence at 6 months. Further randomized controlled trials are required to validate this finding.

Telepathology in intraoperative frozen section consultation of breast cancer sentinel node biopsy in Fukushima, Japan following the 2011 triple disaster: diagnostic accuracy and required time during the early implementation phase.

In breast cancer surgery, some medical facilities lack the necessary resources to conduct sentinel lymph node biopsy and its intraoperative frozen section consultation. In the coastal rural area of Fukushima, Japan, which has suffered from physician undersupply following the 2011 triple disaster of earthquake, tsunami and nuclear disaster, we explored the feasibility of telepathology by evaluating the diagnostic accuracy in remote intraoperative frozen section consultation of sentinel lymph node biopsy and its required time. Although examination time has room for improvement, telepathology can be one possible solution in resource-limited areas.

Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

OBJECTIVES: To explore the therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. PATIENTS AND METHODS: Forty-one patients with synchronous metastatic renal cell carcinoma who received nivolumab plus ipilimumab as first-line systemic therapy at our affiliated institutions were retrospectively evaluated. We focused on the prognosis, including tumor responses in primary kidney and metastatic lesions in patients treated with deferred cytoreductive nephrectomy. In addition, the overall survival according to nephrectomy status (i.e. deferred cytoreductive nephrectomy vs. upfront cytoreductive nephrectomy vs. without cytoreductive nephrectomy) was compared. RESULTS: During a median follow-up period of 12.0 months, seven (30%) patients received deferred cytoreductive nephrectomy at a median time of 10.4 months after nivolumab plus ipilimumab initiation. All the patients showed tumor shrinkage in their primary kidney lesions, including six (86%) patients with ≥30% of shrinkage. Metastatic lesions were also shrunk by ≥30% in six (86%) patients, including two (29%) obtaining complete response. At the last time of follow-up, three (43%) patients were disease-free. The overall survival rate after nivolumab plus ipilimumab initiation tended to be higher in patients with deferred cytoreductive nephrectomy compared with those with upfront cytoreductive nephrectomy (1-year survival rate: 100% vs. 72.4%, P = 0.0587) and those without cytoreductive nephrectomy (vs. 58.2%, P = 0.0613). CONCLUSIONS: The present retrospective data showed that deferred cytoreductive nephrectomy had the potential to exert a therapeutic effect in a subset of patients who obtained favorable tumor responses to nivolumab plus ipilimumab for a certain period. Prospective randomized clinical trials are needed to confirm the prognostic impact of deferred cytoreductive nephrectomy after frontline immunotherapy in synchronous metastatic renal cell carcinoma.

Detection rate and variables associated with incidental prostate cancer by holmium laser enucleation of the prostate.

OBJECTIVES: Holmium laser enucleation of the prostate is well-established and effective for bladder outlet obstruction due to benign prostatic hyperplasia. The objective of this study was to examine the detection rate of incidental prostate cancer by holmium laser enucleation of the prostate and variables associated with them. METHODS: A total of 612 patients were enrolled. We retrospectively examined the detection rate of incidental prostate cancer and perioperative variables associated with them. RESULTS: Forty-nine of 612 patients were diagnosed with incidental prostate cancer. Univariate logistic regression analysis showed that higher prostate-specific antigen density (odds ratio 3.34, 95% confidence interval 1.02-10.94, P = 0.05), higher prostate-specific antigen density of the transition zone (odds ratio 2.28, 95% confidence interval 1.02-5.09, P = 0.04), and findings of the prostate cancer on magnetic resonance imaging (peripheral zone: odds ratio 4.71, 95% confidence interval 1.70-13.1, P = 0.003; transition zone: odds ratio 3.46, 95% confidence interval 1.74-6.86, P < 0.001; peripheral and transition zones: odds ratio 6.00, 95% confidence interval 1.51-23.8, P = 0.01) were significantly associated with incidental prostate cancer. Multivariate logistic regression analysis showed that findings of the prostate cancer on magnetic resonance imaging (peripheral zone: odds ratio 4.36, 95% confidence interval 1.49-12.8, P = 0.001; transition zone: odds ratio 3.54, 95% confidence interval 1.75-7.16, P < 0.001; peripheral and transition zones: odds ratio 6.14, 95% confidence interval 1.53-24.5, P = 0.01) was an independent risk factor for incidental prostate cancer. CONCLUSION: The detection rate of incidental prostate cancer was 8.0%, and findings of the prostate cancer on magnetic resonance imaging were an independent predictive factor for incidental prostate cancer.

Association of tumor burden with outcome in first-line therapy with nivolumab plus ipilimumab for previously untreated metastatic renal cell carcinoma.

OBJECTIVES: To investigate the prognostic impact of tumor burden in patients receiving nivolumab plus ipilimumab as first-line therapy for previously untreated metastatic renal cell carcinoma (mRCC). METHODS: We retrospectively evaluated 62 patients with IMDC intermediate- or poor-risk mRCC, treated with nivolumab plus ipilimumab as first-line therapy at five affiliated institutions. Tumor burden was defined as the sum of diameters of baseline targeted lesions according to the RECIST version.1.1. We categorized the patients into two groups based on the median value of tumor burden (i.e., high vs. low). The association of tumor burden with progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) with nivolumab plus ipilimumab treatment was analyzed. RESULTS: The median tumor burden was 63.0 cm (interquartile range: 34.2-125.8). PFS was significantly shorter in patients with high tumor burden (n = 31) than in those with low tumor burden (n = 31) (median: 6.08 [95% CI: 2.73-9.70] vs. 12.5 [4.77-24.0] months, P = 0.0134). In addition, OS tended to be shorter in patients with high tumor burden; however, there was no statistically significant difference (1-year rate: 77.3 vs. 96.7%, P = 0.166). ORR was not significantly different between patients with high and low tumor burden (35 vs. 55%, P = 0.202). Multivariate analysis of PFS further showed that tumor burden was an independent factor (HR: 2.22 [95% CI: 1.11-4.45], P = 0.0242). CONCLUSIONS: Tumor burden might be a useful factor for outcome prediction, at least for PFS prediction, in patients receiving nivolumab plus ipilimumab for mRCC. Further prospective studies are warranted to confirm our findings.

Androgen-dependent and DNA-binding-independent association of androgen receptor with chromatic regions coding androgen-induced noncoding RNAs.

Androgen induces the binding of its receptor (AR) to androgen-responsive elements (AREs), while genome-wide studies showed that most androgen-induced AR binding sites on chromatin were unrelated to AREs. Enhancer RNAs (eRNAs), a class of noncoding RNAs (ncRNAs), are transcribed from superenhancers (SEs) and trigger the formation of large ribonucleoprotein condensates of transcription factors. By in silico search, an SE is found to be located on the locus of KLK3 that encodes prostate specific antigen. On the KLK3 SE, androgen-induced expression of ncRNAs was detected and designated as KLK3eRNAs in LNCaP cells, and androgen-induced association of AR and FOXA1 on the KLK3eRNA coding regions was detected. Such androgen-induced association of an AR mutant lacking DNA binding activity on the KLK3eRNA coding regions was undetectable on an exogenous ARE. Thus, the present findings suggest a molecular basis of androgen-induced association of AR with chromatin on ARE-unrelated sequences.

[Bone and calcium metabolism associated with malignancy. The function of sex hormone receptors in sex hormone-dependent cancers.]

Both Breast and prostate cancers are dependent on the actions of sex hormones mediated through their nuclear receptors in onset and development of the cancers. Nuclear estrogen and androgen receptors(ER and AR)are DNA-binding transcription factors and regulate expressions of the target mRNA genes by modulating chromatin structure and function. In this short review, the function of nuclear sex hormone receptors in sex hormone-depend cancers are overviewed in the chromatin reorganization for target gene regulations. Moreover, the role of enhancer RNA(eRNA), one of the non-coding RNAs, in chromatin reconfiguration is discussed for enhancer function in tumor development.

Whole-body counter surveys of over 2700 babies and small children in and around Fukushima Prefecture 33 to 49 months after the Fukushima Daiichi NPP accident.

BABYSCAN, a whole-body counter (WBC) for small children was developed in 2013, and units have been installed at three hospitals in Fukushima Prefecture. Between December, 2013 and March, 2015, 2707 children between the ages of 0 and 11 have been scanned, and none had detectable levels of radioactive cesium. The minimum detectable activities (MDAs) for (137)Cs were ≤ 3.5 Bq kg(-1) for ages 0-1, decreasing to ≤ 2 Bq kg(-1) for ages 10-11. Including the (134)Cs contribution, these translate to a maximum committed effective dose of ∼ 16 µSv y(-1) even for newborn babies, and therefore the internal exposure risks can be considered negligibly small.Analysis of the questionnaire filled out by the parents of the scanned children regarding their families' food and water consumption revealed that the majority of children residing in the town of Miharu regularly consume local or home-grown rice and vegetables, while in Minamisoma, a majority avoid tap water and produce from Fukushima. The data show, however, no correlation between consumption of locally produced food and water and the children's body burdens.

Association Between Kidney Function and Outcomes Following Immune Checkpoint Inhibitor-Based Combination Therapy in Patients With Advanced Renal Cell Carcinoma.

BACKGROUND: It remains unclear whether kidney function affects outcomes following immune checkpoint inhibitor (ICI)-based combination therapy for advanced renal cell carcinoma (RCC). METHODS: We retrospectively evaluated data of 167 patients with advanced RCC, including 98 who received ICI dual combination therapy (ie, immunotherapy [IO]-IO) and 69 who received ICI combined with tyrosine kinase inhibitor (TKI) (ie, IO-TKI). In each regimen, treatment profiles were assessed according to the grade of chronic kidney disease (CKD) as defined by the KDIGO 2012 criteria. RESULTS: Of the 98 patients who received IO-IO, 31 (32%), 30 (31%), 15 (15%), and 22 (22%) had CKD G1/2, G3a, G3b, and G4/5, respectively. Of the 69 patients who received IO-TKI, 18 (26%), 25 (36%), and 26 (38%) had G1/2, G3a, and G3b/4/5, respectively. Regarding efficacy, progression-free survival, overall survival, or objective response rate was not different according to the CKD grade in both treatment groups (P > .05). Regarding safety, the rate of adverse events, treatment interruption, or corticosteroid administration was not different according to the CKD grade in the IO-IO group (P > .05), whereas in the IO-TKI group, the incidence of grade ≥ 3 adverse events were significantly higher (P = .0292), and the rates of ICI interruption (P = .0353) and corticosteroid administration (P = .0685) increased, according to the CKD grade. CONCLUSION: There is a differential safety but comparable efficacy profile between the IO-IO and IO-TKI regimens in patients with CKD. Further prospective studies are required to confirm these findings.

Survival Impact of Glucocorticoid Administration for Adverse Events During Immune Checkpoint Inhibitor Combination Therapy in Patients with Previously Untreated Advanced Renal Cell Carcinoma.

BACKGROUND: The impact of glucocorticoid administration for adverse events (AEs), including immune-related AEs, on the effectiveness of immune checkpoint inhibitor (ICI) combination therapy for advanced renal cell carcinoma (RCC) remains unknown. OBJECTIVES: To clarify the prognostic impact of glucocorticoid use for AEs during first-line ICI combination therapy for advanced RCC. PATIENTS AND METHODS: We retrospectively evaluated data from 194 patients who received dual ICI combination therapy [i.e., immunotherapy (IO)-IO] or combinations of ICIs with tyrosine kinase inhibitors (TKIs) as first-line therapy. The patients were divided into two groups according to the history of glucocorticoid administration in each treatment group. Survival based on glucocorticoid administration was assessed. RESULTS: A total of 101 (52.0%) and 93 (48.0%) patients received IO-IO and IO-TKI combination therapy, respectively. Glucocorticoids were administered to 46 (46%) and 22 (24%) patients in the IO-IO and IO-TKI groups, respectively. In the IO-IO group, progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with glucocorticoid administration than in those without administration (median PFS: 14.4 versus 3.45 months, p = 0.0005; median OS: 77.6 versus 33.9 months, p = 0.0025). Multivariable analysis showed that glucocorticoid administration was an independent predictor of longer PFS (hazard ratio: 0.43, p = 0.0005) and OS (hazard ratio: 0.35, p = 0.0067) after adjustment for covariates. In the IO-TKI group, neither PFS nor OS significantly differed between patients treated with and without glucocorticoid administration (PFS: p = 0.0872, OS: p = 0.216). CONCLUSIONS: Glucocorticoid administration did not negatively impact the effectiveness of ICI combination therapy for RCC, prompting glucocorticoid treatment use when AEs develop.

Long-term Experience on Breast Cancer-related Lymphedema in the Coastal Area of Fukushima, Japan After the 2011 Triple Disaster.

BACKGROUND/AIM: Disasters can jeopardize breast cancer care and Japan's triple disaster in 2011 (earthquake, tsunami, and nuclear accident) is no exception. However, detailed information is lacking regarding the care of breast cancer related lymphedema (BCRL) following the disaster. We aimed to explore the process by which local patients become aware of BCRL, the problems faced, and the support they require. We also aimed to clarify the effects of the 2011 disaster on experiences related to lymphedema in the target population. PATIENTS AND METHODS: Patients who developed BCRL after breast cancer treatment were recruited from Iwaki city, a municipality located in the southern coastal region of Fukushima (N=16). In-depth, semi-structured, face-to-face interviews were conducted, and the obtained data were appraised using thematic analysis. RESULTS: Five themes related to BCRL were identified: 1) the process of becoming aware of BCRL, 2) troubles or worries/concerns due to BCRL, 3) information sources regarding BCRL management, 4) strategies to cope with BCRL, and 5) the adverse impacts of the 2011 disaster on BCRL management. CONCLUSION: Except for the disaster context, the themes are in line with those of previous studies conducted in the non-disaster context. Nonetheless, there were limited but non-negligible adverse effects of the 2011 disaster on long-term local BCRL management. The findings of this study demonstrate the necessity for individualizing coping strategies against BCRL among healthcare professionals in the Fukushima coastal area and beyond.

A Propensity Score-Matched Analysis of Perioperative Outcomes of Holmium Laser Enucleation of the Prostate Between Lumenis Pulse 120H and VersaPulse Select 80W.

Objectives: Holmium laser enucleation of the prostate (HoLEP) is a valid and safe procedure for the treatment of benign prostatic hyperplasia. This study aimed to examine the perioperative outcomes of HoLEP using a new laser platform, Lumenis Pulse™ 120H, and a previous laser platform, VersaPulse Select 80W. Methods: A total of 612 patients who underwent holmium laser enucleation were enrolled, including 188 and 424 patients who underwent enucleation using Lumenis Pulse 120H and VersaPulse Select 80W, respectively. They were matched using propensity scores with preoperative patient characteristics, and the differences between the two groups, including operative time, enucleated specimen, transfusion rate, and complication rate, were examined. Results: Propensity score-matched cohort comprised 364 patients with 182 in the Lumenis Pulse 120H group (50.0%) and 182 in the VersaPulse Select 80W group (50.0%). Operative time was significantly shorter with Lumenis Pulse 120H (55.2 ± 34.4 vs 101.4 ± 54.3 minutes, p < 0.001). In contrast, no significant differences were seen in resected specimen weight (43.8 ± 29.8 vs 39.6 ± 22.6 g, p = 0.36), rate of incidental prostate cancer (7.7% vs 10.4%, p = 0.36), transfusion rate (0.6% vs 1.1%, p = 0.56), and perioperative complication rates, including urinary tract infection, hematuria, urinary retention, and capsular perforation (5.0% vs 5.0%, 4.4% vs 2.7%, 0.5% vs 4.4%, 0.5% vs 0%, respectively, p = 0.13). Conclusions: Lumenis Pulse 120H improved the operative time significantly, which is regarded as one of the disadvantages of HoLEP.

An examination of the relationship between satisfaction with overactive bladder (OAB) treatment and the doctor-patient gender: A questionnaire-based single-institution study.

Overactive bladder (OAB) significantly reduces quality of life. The primary goal of this study was to determine whether the gender combination of patient and physician may be associated with satisfaction with OAB treatment. This questionnaire survey was conducted at Jyoban Hospital. We considered the adult patients aged 18 years or older who attended the outpatient office of the urology department of the hospital, were diagnosed with OAB and had been taking anticholinergics or ß3-receptor stimulants, or both, for at least 3 months. In addition to the OAB treatment satisfaction, the questionnaire covered OABSS, IPSS, oral medications, effectiveness of OAB treatment, response to OAB symptoms, and the medium and extent of information collection. A total of 147 patients participated in the study. In summary, 91 (61.9%) were male, and the mean age was 73.5 years. Compared to when the gender of doctor and patient was not the same, female patients tended to be significantly more satisfied when they were treated by female doctors (OR 10.79, 95% CI 1.27-92.05). On the other hand, no similar trend was observed when male patients were treated by male doctors (OR 1.26, 95% CI 0.25-6.34). In the present study, which examined doctor-patient gender combinations in satisfaction with OAB treatment, as hypothesized, satisfaction was higher for female doctor-female patient combinations compared to different doctor-patient genders. A notable fact was that similar associations were not observed among the male doctor-patient combination. This means that an embarrassment of female patients could be stronger than male patients particularly in disclosing urinary symptoms to healthcare providers. The percentage of female urologists in Japan is only 8.2%, and it will be necessary to further promote the recruitment of female doctors in urology fields in order to encourage female patients with OAB to more actively visit doctors.