Since 1989, when we performed the first ABO-incompatible living-related kidney transplantation (ABO-ILKT) in Japan, many Japanese institutions have started their own ABO-ILKT programs. By the end of ...2005, 851 ABO-ILKTs had been performed in Japan at 82 institutions. In the present study, we review the surveillance data of the Japanese ABO-Incompatible Transplantation Committee and our own, recent experience of ABO-ILKT. One-, 3-, 5-, and 10-year patient survival has been 95%, 92%, 90%, and 85%, respectively, whereas 1-, 3-, 5-, and 10-year graft survival has been 89%, 85%, 79%, and 61%, respectively. Between 1989 and 1999, a triplicate immunosuppressive regimen consisting of tacrolimus or cyclosporine A plus azathioprine or mizoribine plus methylprednisolone was administered at most institutions. Between 2000 and 2004, tacrolimus, mycophenolate mofetil, and methylprednisolone were used at most of the institutions. Splenectomy was performed in most recipients between 1989 and 2004. Recently, many institutions started to use anti-CD20 antibody (rituximab) as an alternative to splenectomy. In most cases, ABO-ILKT recipients underwent 3 or 4 sessions of plasmapheresis or double-filtration plasmapheresis before transplantation. A greater incidence of acute rejection was observed during the cyclosporine A era, but the incidence of rejection was markedly reduced in the tacrolimus era. Anti-CD20 antibody induction markedly reduced the incidence of antibody-mediated rejection and greatly improved the results. In conclusion, there were significant differences in graft survival and the incidence of rejection before and after the introduction of tacrolimus/mycophenolate mofetil. In addition, rituximab as an alternative to splenectomy is definitely an effective regimen for successful ABO-ILKT.
Locally advanced and metastatic invasive bladder cancer (BC) has a poor prognosis, and no advanced therapies beyond cisplatin‐based combination chemotherapy have been developed. Therefore, it is an ...urgent issue to elucidate the underlying mechanisms of tumor progression and metastasis of invasive BC for the development of new therapeutic strategies. Here, we clarified a novel role of exosomes containing ErbB2 and CRK in a formation of premetastatic niches and subsequent metastases. CRK adaptors were overexpressed in invasive UM‐UC‐3 BC cells. In an orthotopic xenograft model, metastases to lung, liver, and bone of UM‐UC‐3 cells were completely abolished by CRK elimination. Mass spectrometry analysis identified that ErbB2 was contained in UM‐UC‐3‐derived exosomes in a CRK‐dependent manner; the exosomes significantly increased proliferation and invasion properties of low‐grade 5637 BC cells and HUVECs through FAK and PI3K/AKT signaling pathways. In athymic mice educated with UM‐UC‐3‐derived exosomes, i.v. implanted UM‐UC‐3 cells were trapped with surrounding PKH67‐labeled exosomes in lung and led to development of lung metastasis with disordered vascular proliferation. In contrast, exosomes derived from CRK‐depleted BC cells failed to induce these malignant features. Taken together, we showed that CRK adaptors elevated the expression of ErbB2/3 in BC cells, and these tyrosine kinase/adaptor units were transferred from host BC cells to metastatic recipient cells by exosomes, leading to vascular leakiness and proliferation and contributing to the formation of distant metastasis. Thus, CRK intervention with ErbB2/3 blockade might be a potent therapeutic strategy for patients with ErbB2 overexpressing advanced and metastatic BC.
CRK adaptors elevate the expression of ErbB2/3 in bladder cancer (BC) cells, and these tyrosine kinase/adaptor units are transferred from host BC cells to metastatic recipient cells by exosomes, leading to vascular leakiness and proliferation and contributing to the formation of distant metastasis. Thus, CRK intervention with ErbB2/3 blockade might be a potent therapeutic strategy for patients with ErbB2 overexpressing advanced and metastatic BC.
The role of lymphadenectomy has been controversial in urological malignancies. Urothelial carcinoma of the bladder and upper urinary tract has a high potential to spread through the lymphatic network ...compared with other malignancies, including renal cell carcinoma or prostate cancer. In urothelial carcinoma of the bladder, lymphadenectomy of pelvic nodes had been considered as the standard procedure when radical cystectomy was carried out. Recently, many investigators have examined the influence of its extent, and the majority of the studies have supported the beneficial role of extended lymphadenectomy in accurate staging or in improving patient survival. Although randomized controlled trials are required to establish a greater level of evidence, more urological surgeons have already noticed the necessity for extended lymphadenectomy in bladder cancer. In contrast to bladder cancer, there have been far fewer studies on urothelial carcinoma of the upper urinary tract. This might be because of the smaller number of the patients with urothelial carcinoma of the upper urinary tract and the lack of understanding of regional nodes. However, studies of lymph node mapping and the retrospective analyses with respect to the benefit of lymphadenectomy have been carried out in urothelial carcinoma of the upper urinary tract by some investigators, although the results are still controversial. However, the results from multi‐institutional studies by high volume centers have supported the beneficial role of lymphadenectomy in urothelial carcinoma of the upper urinary tract, as it has been proposed in bladder cancer. Thus, lymphadenectomy for urothelial carcinoma of the bladder and the upper urinary tract might have a potential role in staging and improving the oncological outcomes.
Objective
The objective of this study was to evaluate the early surgical outcomes of robot-assisted partial nephrectomy (RAPN) for small renal masses in a large Japanese multicenter series.
Methods
A ...total of 804 consecutive cases of RAPN were examined at 42 institutes between 2011 and 2016. Medical records for clinical, pathological characteristics and perioperative outcomes were retrospectively reviewed. Univariable and multivariable analyses were performed to determine factors predicting Trifecta achievement.
Results
The median tumor size was 2.6 cm. The median RENAL score was 7. The median warm ischemia time was 21 min. The median estimated blood loss was 30 mL. Eight patients (1.0%) were converted to radical nephrectomy. The overall and Clavien–Dindo grade ≥ 3 complication rates were 13.0% and 5.8%, respectively. Pathologically, 91.4% of tumors were malignant and the positive surgical margin (PSM) rate was 1.1%. During the median 27.1-month observation period, the recurrence rate was 1.6%. Postoperative preservation rates of eGFR at 1, 6, 12 and 24 months were 90.3, 89.8, 89.4 and 89.2%, respectively. Trifecta was achieved in 62.1%. Multivariable analysis demonstrated that tumor diameter, estimated blood loss and hilar location of the tumor were significant negative factors predicting Trifecta achievement. The rate of Trifecta achievement for T1b tumors and hilar tumors was significantly lower (48.4% and 50.0%, respectively).
Conclusions
RAPN was safely performed with acceptable oncological and functional outcomes, but the rate of Trifecta accomplishment for T1b or hilar tumors was significantly lower than that for T1a or non-hilar tumors, respectively.
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.
Objective
Identifying the predictive factors for tumor recurrence after partial nephrectomy (PN) is useful to determine patients who require careful observation after surgery. Therefore, we ...investigated recurrence after partial nephrectomy (PN) in patients with clinical T1 renal cell carcinoma (RCC) and analyzed predictive factors for recurrence-free survival (RFS).
Methods
This study included 1227 patients who underwent PN for clinical T1 RCC and retrospectively investigated patients’ characteristics and tumor factors that are associated with tumor recurrence.
Results
The median patient age was 59 years, and the median tumor size was 30 mm. Although 970 (74%) and 319 (26%) patients had clinical T1a and T1b RCCs, respectively, 20 patients (1.6%) were upstaged to pathological T3a. A positive surgical margin was found in 19 (1.5%) patients. The distribution of surgical approaches was open surgery in 428 (35%) patients and minimally invasive surgery in 799 (65%) patients. With a median follow-up of 35 months (Interquartile range 19–55 months), 39 (3.2%) patients, including ten with local recurrence, five with recurrence in the ipsilateral kidney, and 28 with other organs or lymph-nude, developed recurrence. The 3-year RFS was 99%, and the median recurrence time from PN was 19 months (interquartile range: 11–37 months). Multivariate analysis identified high grade tumor and upstaging to pT3a as significant predictors for worse RFS.
Conclusion
Patients with high grade tumors and tumors upstaged to pT3 had a high risk of worse RFS, which suggested that careful monitoring is required for such patients after PN, even if a good prognosis is achieved in patients with clinical T1 RCC.
To investigate the detection of peritumoral pseudocapsule (PC) using multi-detector row computed tomography (MDCT) for tumors resected by robot-assisted laparoscopic partial nephrectomy (RAPN) for T1 ...renal cell carcinoma (RCC). Study participants included 206 patients with clinical T1 RCC who underwent RAPN between October 2017 and February 2018. Two radiologists who were blinded to the pathological findings evaluated the computed tomography (CT) images. Radiological diagnosis of a PC was defined by a combination of observations, including a low-attenuation rim between the tumor and renal cortex in the cortico-medullary phase and a high-attenuation rim at the edge of the tumor in the nephrogenic or excretory phase. A PC was detected on CT in 156/206 tumors (76%) and identified by pathology in 182/206 (88%) tumors including 153/166 (92%) clear cell RCC, 13/14 (93%) papillary RCC, and 7/16 (44%) chromophobe RCC. In the whole cohort, CT findings showed a sensitivity of 81.3% (148/182), specificity of 66.7% (16/24), and positive predictive value of 94.9% (148/156). When the data were stratified according to pathological subtypes, MDCT was observed to have a sensitivity of 86.9% (133/153) and specificity of 61.5% (8/13) in clear cell RCC, sensitivity of 38.5% (5/13) and specificity of 100% (1/1) in papillary RCC, and sensitivity of 44.4% (4/7) and specificity of 66.7% (6/9) in chromophobe RCC. A low or high-attenuation rim around the tumor in the cortico-medullary or nephrographic-to-excretory phase indicates a PC of RCC, though the accuracy is not satisfactory even with 64- or 320-detector MDCT.
Objective
To evaluate the quality of recovery in patients who underwent robot‐assisted partial nephrectomy and to compare the outcomes of the transperitoneal or retroperitoneal approach.
Methods
This ...study included 121 patients who underwent robot‐assisted partial nephrectomy under general anesthesia from April 2019 to September 2019 at Tokyo Women’s Medical University, Tokyo, Japan. Quality of recovery was defined according to the QoR‐40 Japanese version. The participants responded to the QoR‐40 Japanese version on three designated days. The patients were assigned to two groups according to the surgical approach: transperitoneal or retroperitoneal. A multivariate logistic regression analysis was carried out to identify independent factors associated with better quality of recovery.
Results
Out of the 121 patients, 56 (46%) and 65 (54%) patients were included in the transperitoneal and retroperitoneal group, respectively. Although the QoR‐40 Japanese version scores were not different between the two groups at admission, a better quality of recovery was observed in the retroperitoneal group than in the transperitoneal group at discharge based on the total score: physical comfort, emotional state, physical independence and pain. A multivariate analysis showed that the retroperitoneal approach and male sex were associated with a better QoR‐40 Japanese version score at discharge.
Conclusions
A retroperitoneal approach offers better quality of recovery than a transperitoneal approach, and therefore it might represent the optimal approach in selected patients undergoing robot‐assisted partial nephrectomy.
New pathological subtypes of renal cell carcinoma (RCC) were designated in the 2016 World Health Organization (WHO) classification corresponding to the features commonly seen in patients with ...end‐stage renal disease (ESRD). To determine the clinicopathological findings of new subtypes, we reanalyzed all sections from 315 kidneys in 291 ESRD patients bearing RCC tumors surgically resected in three Japanese institutes by the central pathologist. Clear cell RCC was diagnosed in 144 kidneys (45.7%), acquired cystic disease (ACD)‐associated RCC in 100 (31.7%), papillary RCC in 41 (13.0%), and other minor subtypes in 30 (9.52%). Multivariate analysis showed that longer duration of dialysis, young age, and male sex were independent prognostic clinical factors for the occurrence of ACD‐associated RCC. ACD‐associated RCC included more WHO/International Society of Urologic Pathology (ISUP) grade 3/4 cases compared to other RCCs. In contrast, other unfavorable findings were less frequent in ACD‐associated RCC, including the presence of a sarcomatoid component, lymphovascular invasion, and necrosis. In conclusion, ACD‐associated RCC is a common histology in Japanese patients with ESRD. In addition, ACD‐associated RCC showed more cases with a higher WHO/ISUP grade, but fewer cases with other unfavorable pathological features, suggesting a favorable prognosis of ACD‐associated RCC.
Objectives
To determine the influence of the early unclamping technique on the risk of renal artery pseudoaneurysm during robot‐assisted laparoscopic partial nephrectomy.
Methods
From January 2013 to ...October 2014, 96 patients underwent robot‐assisted laparoscopic partial nephrectomy for renal masses at Tokyo Women's Medical University Hospital, Tokyo, Japan. Computed tomography angiography was carried out 3–4 days after surgery. Early in the series, renal hilum was left unclamped and renorrhaphy was subsequently carried out (conventional unclamping technique). An early unclamping technique has been used since November 2013.
Results
A total of 61 patients underwent robot‐assisted laparoscopic partial nephrectomy with early unclamping, and 35 patients underwent robot‐assisted laparoscopic partial nephrectomy with conventional unclamping. Ischemia time was significantly shorter in the early unclamping group (16.5 vs 23.1 min; P < 0.01). The early unclamping group showed a significantly lower incidence of asymptomatic renal artery pseudoaneurysm relative to the conventional unclamping group (11.4% vs 28.6%; P = 0.03). Multivariate analysis showed that the early unclamping technique was a significant independent factor in reducing the risk of renal artery pseudoaneurysm (hazard ratio 0.27; P = 0.01).
Conclusions
The present findings suggest that an early unclamping technique might reduce ischemic time and risk of renal artery pseudoaneurysm. The absence of arterial bleeding before renorrhaphy is likely to be a key step in preventing renal artery pseudoaneurysm during robot‐assisted laparoscopic partial nephrectomy.
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