Impact of chronic kidney disease stages on surgical and functional outcomes in robot-assisted partial nephrectomy for localized renal tumors.

The influence of chronic kidney disease stage on robot-assisted partial nephrectomy outcomes remains underexplored. This study aimed to assess the impact of chronic kidney disease stage on functional and surgical outcomes of robot-assisted partial nephrectomy and identify preoperative predictors of significant postoperative 1-year renal-function loss (RFL). Clinical data of 408 patients who underwent robot-assisted partial nephrectomy at Yokohama City University Hospital between 2016 and 2023 were retrospectively reviewed. The da Vinci Surgical System was applied in all patients, and outcomes assessed included surgical parameters, postoperative estimated glomerular filtration rate, trifecta and pentafecta achievements, and complications. Significant RFL was defined as estimated glomerular filtration rate reduction ≥ 25% from baseline. Higher chronic kidney disease stages correlated with older age, hypertension, diabetes, and solitary kidneys. Postoperative estimated glomerular filtration rate decline was most pronounced in patients with chronic kidney disease stages 4-5. Although the chronic kidney disease stage did not significantly affect most surgical parameters, pentafecta achievement was higher in patients with chronic kidney disease stage 3 than in those with stages 4-5. Two patients required hemodialysis after robot-assisted partial nephrectomy. Multivariable logistic regression analysis showed that preoperative hemoglobin level and maximum tumor diameter were significant predictive factors for significant RFL. In conclusion, preoperative CKD stage did not influence on surgical outcome except for pentafecta achievement. RAPN may be feasible for patients with CKD stages 4-5 because of no rapid progression to hemodialysis induction and no procedure-related mortality. Preoperative hemoglobin levels and tumor diameter emerged as predictors of significant RFL.

Enfortumab vedotin prolongs overall survival in metastatic urothelial carcinoma following pembrolizumab therapy in real-world data.

OBJECTIVE: In December 2021, enfortumab vedotin (EV), an antibody-drug conjugate directed against nectin-4, was approved in Japan as a new treatment after platinum-containing chemotherapy and PD-1/PD-L1 inhibitors. This study evaluated, using real-world data, the efficacy and safety of EV therapy in patients with metastatic urothelial carcinoma (mUC). MATERIALS AND METHODS: Fifty-five patients with mUC who discontinued pembrolizumab therapy due to disease progression between June 2018 and April 2023 at Yokohama City University Hospital were evaluated retrospectively. Of the 55 patients, 25 received EV therapy (EV group) and 30 did not (non-EV group). All patients who underwent EV therapy were diagnosed with disease progression after the approval of EV in Japan. RESULTS: The median (range) follow-up period after pembrolizumab discontinuation was 6.3 (0.7-31.1) months. There were eight (32.0%) deaths due to cancer in the EV group and 27 (90.0%) in the non-EV group. The overall survival (OS) after pembrolizumab discontinuation was not reached in the EV group versus 2.6 months in the non-EV group (p < 0.001). A multivariate analysis revealed that EV therapy (EV vs. non-EV group; hazard ratio 0.26; 95% confidence interval 0.16-0.41; p < 0.001) was an independent prognostic factor for OS. CONCLUSION: EV prolonged OS in mUC following pembrolizumab therapy in real-world data.

Surgical proficiency in laparoscopic radical cystectomy with extracorporeal urinary diversion and its adequacy for the execution of robot-assisted radical cystectomy with intracorporeal urinary diversion.

INTRODUCTION: The number of facilities adopting intracorporeal urinary diversion (ICUD) using robots instead of extracorporeal urinary diversion (ECUD) is increasing. However, guidance on how to introduce robot-assisted radical cystectomy (RARC) + ICUD in each urological institute remains unclear. This study aimed to verify the feasibility of the transition from laparoscopic radical cystectomy (LRC) + ECUD to RARC + ICUD. METHODS: We retrospectively analyzed 26 consecutive patients who underwent ICUD with an ileal conduit after RARC between 2018 and 2020 (RARC + ICUD early group). We then compared these patients with 26 consecutive patients who underwent ECUD with an ileal conduit after LRC between 2012 and 2019 (LRC + ECUD late group) at Yokohama City University Hospital. RESULTS: In the RARC + ICUD early group compared with the LRC + ECUD late group, the median total operation time was 516 versus 532.5 min (P = .217); time to cystectomy, 191 versus 206.5 min (P = .234); time of urinary diversion with an ileal conduit, 198 versus 220 min (P = .016); postoperative maximum C-reactive protein levels, 6.98 versus 12.46 mg/L (P = .001); number of days to oral intake, 3 versus 5 days (P = .003); length of hospital stay, 17 versus 32 days (P < .001). The postoperative complication rates (within 90 days) were 23.1% and 42.3% in the RARC + ICUD early and LRC + ECUD late groups, respectively (P = .237). Clavien-Dindo classification ≥3 was noted in 1 and 4 patients in the RARC + ICUD early and LRC + ECUD late groups, respectively (P = .350). CONCLUSION: Regarding perioperative outcomes, the RARC + ICUD early group was not inferior to the LRC + ECUD late group. This study suggests the feasibility of a transition from LRC + ECUD to RARC + ICUD.

Impacts of Complete Endophytic Renal Tumors on Surgical, Functional, and Oncological Outcomes of Robot-Assisted Partial Nephrectomy.

Objective: Complete endophytic renal tumors (CERTs) are the most challenging for robot-assisted partial nephrectomy (RAPN). This study aimed to determine the impact of CERT on outcomes of RAPN. Methods: All RAPN cases for localized renal tumor undertaken at Yokohama City University Hospital between 2016 and 2023 were enrolled. Tumor characteristics and surgical, functional, and oncologic outcomes of RAPN were compared between CERT and non-CERT groups. Results: Consecutive 666 patients were enrolled, and 76 (11.4%) were identified as CERT (3 points of "E" score). CERT showed smaller tumor diameters (p < 0.001), more predominant hilar tumor (p = 0.029), higher "N" scores (p < 0.001) and "L" scores (p = 0.006) than non-CERT. The CERT group showed longer warm ischemia times (p < 0.001), more frequent positive surgical margins (p = 0.028), and relatively lower trifecta achievement rates (p = 0.101) than the non-CERT group. In multivariable analysis, the CERT was an independent predictor for trifecta achievement but not for pentafecta achievement. Conclusions: CERT was associated with longer warm ischemia time, positive surgical margin, and lower trifecta achievement, but not with surgical complication and pentafecta achievement in RAPN. This study suggested that CERT had limited influence on long-term renal functional preservation; however, it had strong impacts on short-term surgical outcome.

Correlation between Higher Aging Males' Symptoms Scores and a Higher Risk of Lower Urinary Tract Symptoms.

BACKGROUND: Late-onset hypogonadism (LOH) is a condition caused by the decline of testosterone levels with aging and is associated with various symptoms, including lower urinary tract symptoms (LUTSs). Although some reports have shown that testosterone replacement treatment for LOH improves LUTSs, no large study has revealed a correlation between LUTSs and LOH. This study investigated the correlation between the severity of LOH and LUTSs in Japanese males >40 years of age using a web-based questionnaire with the Aging Males' Symptoms (AMS) scale. METHODS: We asked 2000 Japanese males to answer both the AMS and IPSS/QOL questionnaires using a web-based survey. Among these 2000 individuals, 500 individuals were assigned to each age group. RESULTS: The IPSS total score was positively correlated with the severity of AMS (shown as median [mean ± SD]): no/little group, 2 (3.67 ± 5.36); mild group, 6 (7.98 ± 6.91); moderate group, 11 (12.49 ± 8.63); and severe group, 16 (14.83 ± 9.24) (p < 0.0001). CONCLUSIONS: Individuals with higher AMS values, representing cases with severe LOH symptoms, had a higher risk of experiencing nocturia and LUTSs than those with lower AMS values.

Mitochondrial DNA Variants at Low-Level Heteroplasmy and Decreased Copy Numbers in Chronic Kidney Disease (CKD) Tissues with Kidney Cancer.

The human mitochondrial genome (mtDNA) is a circular DNA molecule with a length of 16.6 kb, which contains a total of 37 genes. Somatic mtDNA mutations accumulate with age and environmental exposure, and some types of mtDNA variants may play a role in carcinogenesis. Recent studies observed mtDNA variants not only in kidney tumors but also in adjacent kidney tissues, and mtDNA dysfunction results in kidney injury, including chronic kidney disease (CKD). To investigate whether a relationship exists between heteroplasmic mtDNA variants and kidney function, we performed ultra-deep sequencing (30,000×) based on long-range PCR of DNA from 77 non-tumor kidney tissues of kidney cancer patients with CKD (stages G1 to G5). In total, this analysis detected 697 single-nucleotide variants (SNVs) and 504 indels as heteroplasmic (0.5% ≤ variant allele frequency (VAF) < 95%), and the total number of detected SNVs/indels did not differ between CKD stages. However, the number of deleterious low-level heteroplasmic variants (pathogenic missense, nonsense, frameshift and tRNA) significantly increased with CKD progression (p < 0.01). In addition, mtDNA copy numbers (mtDNA-CNs) decreased with CKD progression (p < 0.001). This study demonstrates that mtDNA damage, which affects mitochondrial genes, may be involved in reductions in mitochondrial mass and associated with CKD progression and kidney dysfunction.

Real-World Data on the Effectiveness of Microporous Polysaccharide Hemospheres for Allowing Even Novice Surgeons to Perform Robot-Assisted Radical Prostatectomy Safely.

OBJECTIVE: Radical prostatectomy can be performed more safely and with fewer com- plications since the advent of robot-assisted surgery. However, increased bleeding is a concern when robot-assisted radical prostatectomy includes lymph node dissection and nerve sparing. In real-world clinical practice, inexperienced surgeons sometimes perform robot-assisted radical prostatectomy. In this study, we investigated the effec- tiveness of microporous polysaccharide hemospheres as a local hemostatic agent in robot-assisted radical prostatectomy. METHODS: We retrospectively evaluated 301 patients who underwent robot-assisted radical prostatectomy at our institution between December 2017 and November 2020. The patients were divided into 2 groups according to whether their surgery was per- formed after the introduction of microporous polysaccharide hemospheres as a local hemostatic agent (group A, n = 140) or before it (group B, n = 161: historical control). RESULTS: Preoperative androgen deprivation therapy was significantly more common in group A than in group B (23 vs. 11, P = .009). Furthermore, surgeons were significantly less experienced (P < .001) and the operation time was significantly longer (260 min- utes vs. 229 minutes; P < .001) in group A than in group B. There was no significant difference in any other patient background characteristics or in the surgical outcomes between the groups. CONCLUSION: The use of microporous polysaccharide hemospheres allowed even inex- perienced surgeons to perform robot-assisted radical prostatectomy without compro- mising surgical outcomes.

Administration of Enfortumab Vedotin after Immune-Checkpoint Inhibitor and the Prognosis in Japanese Metastatic Urothelial Carcinoma: A Large Database Study on Enfortumab Vedotin in Metastatic Urothelial Carcinoma.

BACKGROUND: Enfortumab vedotin shows promise as a targeted therapy for advanced urothelial carcinoma, particularly in patients who have previously received platinum-based chemotherapy and an immune-checkpoint inhibitor. The EV-301 phase III trial demonstrated significantly improved overall survival and response rates compared to standard chemotherapy. However, more data, especially from larger real-world studies, are needed to further assess its effectiveness in Japanese patients. METHODS: A total of 6007 urothelial cancer patients inducted with pembrolizumab as a second-line treatment were analyzed. Among them, 563 patients received enfortumab vedotin after pembrolizumab, while 443 patients received docetaxel or paclitaxel after pembrolizumab, and all were included in the study for efficacy as a life prolonging agent. RESULTS: The enfortumab vedotin group showed a longer overall survival than the paclitaxel/docetaxel group (p = 0.013, HR: 0.71). In multivariate analysis, enfortumab vedotin induction was the independent risk factor for overall survival (p = 0.013, HR: 0.70). There were no significant differences in cancer-specific survival. CONCLUSIONS: Enfortumab vedotin prolonged the overall survival for Japanese advanced or metastatic urothelial carcinoma patients compared to paclitaxel or docetaxel after pembrolizumab treatment.

Predictive factors for pentafecta achievement in robot-assisted partial nephrectomy for intermediate highly complex RENAL tumors (RENAL score ≥ 7).

OBJECTIVES: To investigate the predictive factors for pentafecta achievement of robot-assisted partial nephrectomy (RAPN) for intermediate highly complex renal tumors (RENAL score ≥ 7). METHODS: We retrospectively analyzed the data of 247 patients with renal tumors with a RENAL score ≥ 7 who underwent RAPN. Baseline characteristics and perioperative outcomes were compared between the pentafecta achieved group and the unachieved group. A multivariable logistic regression model was used to identify the predictive factors for pentafecta achievement for cT1 renal tumors with a RENAL score ≥ 7. RESULTS: Of the 247 patients, 75 (30.3%) patients were in the achieved group and 172 (69.7%) patients were in the unachieved group. The median warm ischemia time and total operation time were 18 min versus 23 min (p < 0.001) and 179 min versus 201 min (p < 0.001) in the achieved and unachieved groups, respectively. In the unachieved group, six patients (3.4%) had major perioperative complications (Clavien-Dindo classification system ≥3). The median preservation rates of estimated GFR at the 1-year postoperative period were 96.5% versus 83.0% (p < 0.001) in the achieved and unachieved groups. Multivariable logistic regression models revealed that age and tumor size were independent predictive factors for pentafecta achievement for cT1 renal tumors with a RENAL score ≥ 7. There were no significant differences in cancer-free survival between the two groups (p = 0.456). CONCLUSION: Age and tumor size were independent predictive factors for pentafecta achievement, although there was no difference in oncological outcomes between the pentafecta achieved group and the unachieved group in RAPN for cT1 renal tumors with a RENAL score ≥ 7.

Comparative analyses define differences between BHD-associated renal tumour and sporadic chromophobe renal cell carcinoma.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. METHODS: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. FINDINGS: RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. INTERPRETATION: These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. FUNDING: This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research.

[COMPARING LAPAROSCOPIC AND ROBOT-ASSISTED PYELOPLASTY FOR URETERO-PELVIC JUNCTION OBSTRUCTION: INITIAL EXPERIENCE FROM A SINGLE CENTER].

(Objective) To compare the initial results of robot-assisted laparoscopic pyeloplasty (RALP) and laparoscopic pyeloplasty (LP) for uretero-pelvic junction obstruction (UPJO). (Methods) Between April 2008 to October 2021, we identified 104 cases of UPJO where LP was performed and 18 cases where RALP was performed at our hospital. We retrospectively analyzed their perioperative outcomes. Furthermore, we recorded the operative times for each cases of LP and RALP. (Results) The median operative time for RALP was 141 minutes, which was significantly shorter than that for LP (204 minutes). No patient in the RALP group demonstrated any Clavien-Dindo complications (≥grade 3). During the observation period, improvement of symptoms was observed in all cases. The median suturing time in RALP was 38 minutes. Compared with the last 20 cases of LP, the time to expose the uretero-pelvic junction, the time of renal pelvis incision, and suturing time were significantly shorter in RALP. In addition, the console and suturing times were stable since the initial stage. In cases with a high grade of hydronephrosis, there was a large variation in the time to expose the uretero-pelvic junction and suture the renal pelvis and ureter in LP; however, this variation was smaller in RALP. (Conclusion) At our hospital, RALP for UPJO is considered to be a safe procedure. In the future, it is necessary to consider the long-term results and effectiveness of RALP.

Administration of radium-223 and the prognosis in Japanese bone metastatic castration-resistant prostate cancer patients: A large database study.

BACKGROUND: The ALSYMPCA trial revealed radium-223 (Ra-223) to be a life-prolonging agent for bone metastatic castration-resistant prostate cancer (CRPC). However, only 2.8% of enrolled patients in that clinical trial were Asian, and no Japanese patients were enrolled. Several retrospective studies have been published concerning Japanese bone metastatic CRPC patients receiving Ra-223. However, no study has yet reported the correlation between Ra-223 induction and the survival in Japanese bone metastatic CRPC patients. This study investigated the effect of Ra-223 as a life-prolonging agent in a large Japanese healthcare fee database. METHODS: A total of around 410 000 prostate cancer patients were extracted from this database, and 25 934 were diagnosed with CRPC. In these patients, the age, date of the CRPC diagnosis, date of Ra-223 induction, and prognosis were analyzed. RESULTS: A total of 1628 patients received Ra-223, and 6693 patients were diagnosed with bone metastasis CRPC, with the remaining 17 613 patients diagnosed with CRPC without bone metastasis. The patients who completed six courses of Ra-223 showed a significantly more favorable overall and cancer-specific survival than those who received ≤5 courses (p < 0.0001 and p < 0.0001, respectively). For time from CRPC diagnosis date to death, the Ra-223 induction group showed a significantly more favorable prognosis with regard to both the overall and cancer-specific survival than the bone metastatic CRPC patients without Ra-223 (p < 0.0001 and p < 0.0001, respectively). CONCLUSIONS: Bone metastatic CRPC patients who received Ra-223 showed a significantly better prognosis than bone metastatic CPRC patients who did not receive Ra-223.

Single-cell transcriptomes underscore genetically distinct tumor characteristics and microenvironment for hereditary kidney cancers.

Our understanding of how each hereditary kidney cancer adapts to its tissue microenvironment is incomplete. Here, we present single-cell transcriptomes of 108,342 cells from patient specimens including from six hereditary kidney cancers. The transcriptomes displayed distinct characteristics of the cell of origin and unique tissue microenvironment for each hereditary kidney cancer. Of note, hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated kidney cancer retained some characteristics of proximal tubules, which were completely lost in lymph node metastases and present as an avascular tumor with suppressed T cells and TREM2-high macrophages, leading to immune tolerance. Birt-Hogg-Dubé (BHD)-associated kidney cancer exhibited transcriptomic intratumor heterogeneity (tITH) with increased characteristics of intercalated cells of the collecting duct and upregulation of FOXI1-driven genes, a critical transcription factor for collecting duct differentiation. These findings facilitate our understanding of how hereditary kidney cancers adapt to their tissue microenvironment.

Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide-chlorambucil conjugate.

Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3-dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient-derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC.

Roughness of the renal tumor surface could predict the surgical difficulty of robot-assisted partial nephrectomy.

INTRODUCTION: Preoperative prediction of surgical difficulty of partial nephrectomy (PN) is essential to minimize the perioperative complications and to achieve a good surgical outcome. Recently, various scoring systems have been used to evaluate the difficulty of PN including R.E.N.A.L (Radius, Exophytic/Endophytic, Nearness, Anterior/Posterior, Location) nephrometry score. There were no scoring systems evaluating the roughness of the renal tumor surface and we hypothesized that the roughness of the renal tumor surface might affect the surgical difficulty of robot-assisted partial nephrectomy (RAPN). This study aimed to evaluate the impact of roughness of the renal tumor surface on the surgical outcome of RAPN. METHODS: Overall, 161 patients underwent RAPN performed by the same surgeon between May 2016 and April 2019. We divided those tumors into two groups, like "roughness positive (tumor with roughness of tumor surface)" and "roughness negative (tumor without roughness of tumor surface)" according to the roughness of the endophytic region on preoperative computed tomography images. Clinical and pathological outcomes were compared between the two groups. RESULTS: Eighty-five and 78 tumors were identified roughness negative and positive, respectively. Cases with roughness positive showed a significantly longer operative time, console time, and ischemia time and had greater blood loss than those with roughness negative. Significant and independent predictors of ischemia time and estimated glomerular filtration rate (eGFR) decrease were roughness of tumor surface, tumor size (not for eGFR decrease), and N score of the R.E.N.A.L nephrometry score. CONCLUSION: Roughness of renal tumor surface was significantly and positively associated with ischemia time and the eGFR decrease rate.

Correlation of urinary loss rate after catheter removal and long-term urinary continence after robot-assisted laparoscopic radical prostatectomy.

OBJECTIVES: To assess the correlation of urine loss rate after catheter removal with long-term continence after robot-assisted radical prostatectomy. METHODS: We enrolled 163 patients on whom robot-assisted radical prostatectomy was carried out and whose urine loss rate we were able to evaluate after catheter removal. Urinary incontinence was evaluated from immediately after removal of the catheter to the date of discharge, and at 1, 3, 6 and 12 months after surgery. Urine loss rate was defined as the urine loss volume divided by the total urine volume. RESULTS: The continence rates of patients with ≤1% urine loss rate on the day of catheter removal were 100% at 6 and 12 months after surgery. A multivariate analysis proved that ≤10% urine loss rate on the day of catheter removal was a significant predictor of continence at 3 months after surgery. Furthermore, the continence rate at 12 months of patients who did not achieve ≤10% urine loss rate on the day of catheter removal was 79.5%. Among them, the continence rate at 12 months of patients who achieved ≥15% urine loss rate improvement from the day of catheter removal to the next day was 95.2%; the factor differed significantly between the continence and incontinence groups at 12 months after surgery. CONCLUSIONS: The urine loss rate on the day of catheter removal is significantly related to the acquisition of urinary continence. Furthermore, our findings suggest that long-term urinary continence can be expected, even in the event of poor urine loss rate on the day of catheter removal, if it improves on the next day.

A lower psoas muscle index predicts a poorer prognosis in metastatic hormone-naïve prostate cancer.

Introduction: A recent investigation revealed that sarcopenia was associated with a poorer prognosis in some solid malignancies, including prostate cancer. In most reports, sarcopenia was defined as a low psoas volume on CT. This study investigated the association of sarcopenia, determined according to the psoas muscle volume and density on CT, with the prognosis in patients with metastatic hormone-naïve prostate cancer (mHNPC). Methods: A total of 66 patients initially diagnosed with mHNPC were enrolled in this study. Skeletal muscle was evaluated according to the psoas muscle index density (PMID) on computed tomography scans. The psoas muscle volume was calculated at the level of L3 and CT density was evaluated as the mean CT density at the psoas muscle area. We divided the patients into higher and lower PMID groups. Results: The lower PMID group (on both sides) showed a poorer overall survival than the higher PMID group (Right: 32.5 vs 99.0 months in Rt PMID, P = .014; Left: 36.0 vs 100.0 months in Lt PMID, P = .029). The lower PMID group (on both sides) showed a shorter time to CRPC (Right: 9.0 vs 42.0 months in Rt PMID, P = .006; Left: 9.0 vs 31.0 months in Lt PMID, P = .005). A multivariate analysis showed that lower Rt PMID and Lt PMID were independent risk factors for poorer OS (HR:2.02, 95%CI: 1.04-3.90, P = .037, HR:2.29, 95%CI: 1.18-4.47, P = .015, respectively). For CRPC, both Rt and Lt lower PMID also showed independent risk factors for shorter time to CRPC (HR:2.39, 95%CI: 1.23-4.62, P = .010, HR:2.43, 95%CI: 1.23-4.78, P = .010, respectively). Conclusions: Among mHNPC patients, both lower PMID groups showed a poorer overall survival and shorter time to CRPC than the higher PMID groups.

Complete response of hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated renal cell carcinoma to nivolumab and ipilimumab combination immunotherapy by: a case report.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant disorder that results from a germline mutation in the fumarate hydratase gene (FH). Individuals with FH mutations are at risk of developing renal cell carcinoma (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is as yet no standardized therapy for advanced HLRCC-RCC. We report an aggressive RCC case in a 49-year-old man. Nine weeks after undergoing a total nephroureterectomy of the right kidney, he had a metastasectomy at port site. Within 14 weeks of the initial surgery, multiple recurrent tumors developed in the right retroperitoneal space. The pathological diagnosis was FH-deficient RCC. Genetic testing identified a heterozygous germline mutation of FH (c.641_642delTA), which confirmed the diagnosis of HLRCC-RCC. He received combination therapy with the immune checkpoint inhibitors (ICIs) nivolumab and ipilimumab as the first-line therapy. After 31 weeks of ICI treatment, a complete response was achieved. The disease-free condition has been prolonged for 24 months since the initial surgical treatment. This is the first case report of successful treatment of HLRCC-RCC with nivolumab plus ipilimumab. This combination immunotherapy is expected to be an effective approach to treat patients with advanced-stage HLRCC-RCC.

Blood and lymphatic systems are segregated by the FLCN tumor suppressor.

Blood and lymphatic vessels structurally bear a strong resemblance but never share a lumen, thus maintaining their distinct functions. Although lymphatic vessels initially arise from embryonic veins, the molecular mechanism that maintains separation of these two systems has not been elucidated. Here, we show that genetic deficiency of Folliculin, a tumor suppressor, leads to misconnection of blood and lymphatic vessels in mice and humans. Absence of Folliculin results in the appearance of lymphatic-biased venous endothelial cells caused by ectopic expression of Prox1, a master transcription factor for lymphatic specification. Mechanistically, this phenotype is ascribed to nuclear translocation of the basic helix-loop-helix transcription factor Transcription Factor E3 (TFE3), binding to a regulatory element of Prox1, thereby enhancing its venous expression. Overall, these data demonstrate that Folliculin acts as a gatekeeper that maintains separation of blood and lymphatic vessels by limiting the plasticity of committed endothelial cells.

C-reactive protein at 1 month after treatment of nivolumab as a predictive marker of efficacy in advanced renal cell carcinoma.

PURPOSE: Nivolumab is part of the standard therapy for mRCC. Although deep and long-lasting responses are seen in some patients, the benefit of treatment is limited to some patients and the majority of patients will experience disease progression. PD-L1 is still under evaluation as a predictive biomarker and there is an urgent need to establish biomarkers for the treatment of nivolumab. Here, we investigate C-reactive protein (CRP) at 1 month after treatment of nivolumab as a target to predict the response of patients with metastatic renal cell carcinoma (mRCC) to nivolumab. METHODS: After approval of the study by our institutional review board, 64 patients with mRCC who underwent nivolumab treatment at Kanagawa Cancer Center and Yokohama City University Hospital were enrolled. The patient characteristics, blood examination data at start of nivolumab treatment and 1 month after treatment, response to treatment and progression-free survival (PFS) were evaluated. Tumour responses were assessed according to both the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the immune RECIST (iRECIST) criteria. Moreover, in 12 patients who agreed to an additional blood examination, several serum inflammatory factors were investigated and their correlation with CRP level was examined. RESULTS: The median follow-up was 8.3 months (range 0.2-29.8 months). The median PFS period was 4.5 months and the median immune-PFS (iPFS) period was 5.3 months. RECIST 1.1 criteria underestimated the benefits of nivolumab in four (6.4%) cases. Multivariate analyses showed that an Eastern Cooperative Oncology Group performance status (≥ 2) at start of treatment and CRP level at 1 month after treatment (≥ 1.5 mg/dL) were independent risk factors for a poor iPFS of nivolumab. The CRP level at baseline was not an independent prognostic factor for iPFS. When compared with the responder group (iCR + iPR + iSD), the non-responder group (iPD) had a significantly higher CRP levels at 1 month after treatment (p < 0.001). In the responder group, there was significant decrease in the CRP level after nivolumab treatment when compared with the baseline (p = 0.002), whereas there was a significant increase in the non-responder group (p = 0.019). Even patients with high baseline CRP (≥ 1.5 mg/dL) obtained good iPFS if CRP was decreased (< 1.5 mg/dL) 1 month after treatment. In addition, the classification of Glasgow prognostic score (GPS), which is a cumulative prognostic score based on CRP and albumin, was a significant predictor for iPFS. A strong correlation (|r| > 0.7) with CRP level at 1 month after treatment was seen for sCD163, IL-34, MMP-1, MMP-2, osteopontin, sTNF-R1 and sTNF-R2. Of these, MMP-1 and MMP-2 were not correlated at baseline. CONCLUSION: Our results indicated that the CRP level at 1 month after treatment with nivolumab appears to be a promising predictive biomarker for response to nivolumab treatment in patients with mRCC. It is clinically useful to be able to predict the effect within a short period. Further prospective trials are needed to prove these preliminary findings.