Published papers

筋層浸潤性膀胱癌に対する術前化学療法は各種ガイドラインにおいて高い推奨グレードで支持されているにもかかわらず、実臨床において実際に施行されている割合は低い。また、Gemcitabine+Cisplatinによる術前化学療法の長期成績に関する報告も限られている。本投稿では、Gemcitabine+Cisplatin術前化学療法の有用性、副作用発現など治療成績に関して当院のデータを交えつつ解説するとともに、独自にClinical Questionを設け、Gemcitabine+Cisplatin術前化学療法の実際、問題点、今後の展望を考えてみたい。(著者抄録)

患者は56歳の男性。会陰部から陰嚢にかけての瘻孔を主訴に当科を受診した。滲出液よりMycobacterium avium(以下,M.avium)を認めた。2011年1月12日よりclarithromycin(CAM)/rifampicin(RFP)/ethambutol hydrochloride(EB)による3剤併用療法を行ったが改善がみられず,2011年4月26日に会陰部瘻孔を外科的に切除した。M.aviumによる皮膚感染症は近年24時間風呂での感染例の報告が散見されており,家族内発生例もみられる。本患者では詳細な問診を行ったが,感染経路は不明であった。本例のように会陰部に生じた例は稀であり,若干の文献的考察を含め報告する。(著者抄録)

INTRODUCTION: Sarcopenia is a novel concept representing skeletal muscle wasting and has been identified as a prognostic factor for several cancers. The aims of this study were to evaluate the prognostic significance of sarcopenia and the relationship between sarcopenia and poor pathological findings in upper tract urothelial carcinoma (UTUC) patients who underwent radical nephroureterectomy (RNU). METHODS: We identified 123 UTUC patients who underwent RNU between 2003 and 2014. We assessed sarcopenia by measuring the area of skeletal muscle at the third lumber vertebra on preoperative computed tomography scans. Sarcopenia was classified based on a sex-specific consensus definition. We investigated whether sarcopenia predicts clinical outcomes, such as cancer death and poor pathological findings at RNU. RESULTS: A total of 50 (40.7%) patients had sarcopenia. In a multivariate Cox regression analysis, sarcopenia was not associated with cancer-specific survival (CSS), and lymphovascular invasion (LVI) (hazard ratio 5.88; p=0.002) was the only independent risk factor for CSS. A multivariate logistic regression analysis showed that sarcopenia independently correlated with the LVI status (odds ratio 2.36; p=0.025). LVI was positive in 27 of 50 (54%) and 25 of 73 (34%) patients with and without sarcopenia, respectively (p=0.029). CONCLUSIONS: Preoperative sarcopenia predicted the LVI status, which was a strong prognostic factor for UTUC patients after RNU.

We report a female patient diagnosed with retrocaval ureter (RCU) after ureteral reimplantation for vesicoureteral reflux (VUR). She was diagnosed as right grade IV VUR with breakthrough urinary tract infections, and underwent ureteral reimplantation with Cohen cross-trigonal technique. Thereafter, she developed severe right hydronephrosis associated with RCU, which was presumably due to caudal traction of right ureter at ureteral reimplantation. Sheunderwent uretero-ureterostomy anterior to the inferior vena cava, and recovered well. Detailed evaluation for upper urinary tract is mandatory for high grade VUR, and Cohen technique should be avoided for VUR associated with RCU.

Although the clinical utility of a frozen section analysis (FSA) at the time of radical cystectomy (RC) has already been established, its significance and utility in bladder cancer patients receiving neoadjuvant chemotherapy (NAC) have not yet been fully evaluated. We identified 458 patients (937 ureters) who underwent open RC for bladder cancer at our 7 Japanese institutions between 2004 and 2015. Among these patients, 139 (284 ureters) received NAC before RC (NAC group), while 319 (653 ureters) underwent RC alone (non-NAC group). FSA was performed on 356 out of 937 (38.0%) ureters and 179 out of 458 (39.1%) patients. FSA was positive in 30 out of 356 (8.4%) ureters and its sensitivity, specificity, and accuracy were 89.3, 98.5, and 97.8%, respectively. In the NAC group, FSA was performed on 138 out of 284 (48.6%) ureters and 68 out of 139 (48.9%) patients. FSA was positive in 8 out of 138 ureters (5.8%), and its sensitivity, specificity, and accuracy were 77.8, 99.2, and 97.8%, respectively. In the non-NAC group, FSA was performed on 218 out of 653 (33.4%) ureters and 111 out of 319 (34.8%) patients. FSA was positive in 22 out of 218 (10.1%) ureters, and its sensitivity, specificity, and accuracy were 94.7, 98.0, and 97.7%, respectively. No correlation was observed between preoperative clinical factors and FSA positivity in the NAC group; however, in the non-NAC group, the incidence of FSA positivity in the ureters of patients with concomitant CIS in TUR-BT specimens was 8/41 (19.5%), which was significantly higher than that in their counterpart (14/177, 7.9%, p = 0.033). Even in the era of NAC in the management of bladder cancer patients, the performance of FSA does not change and FSA at the time of RC may provide useful diagnostic information.

BACKGROUND: Recently, laparoendoscopic single-site adrenalectomy (LESS-A) has been developed as an alternative treatment for adrenal tumors. Although LESS-A is more technically complex than conventional laparoscopic adrenalectomy, its learning curve and the factors associated with poor surgical outcomes are poorly understood. We analyzed the learning curve of LESS-A and attempted to identify risk factors associated with worse surgical outcomes. METHODS: We identified 103 patients who underwent LESS-A [performed by the same surgeon (A.M.)] from 2009 to 2015. The learning curve was analyzed using the moving average method (the 10-case moving average), and we assessed potential risk factors for a prolonged pneumoperitoneum time. RESULTS: The learning curve stabilized at 30 cases. The cases were divided into two groups, the learning stage (LS) (cases 1-29) and master stage (MS) (cases 30-103) groups. The percentage of females and the frequency of previous abdominal surgery were higher in the LS group (p = 0.022 and 0.001, respectively). In the LS group, the mean pneumoperitoneum time was 92 +/- 35 min, which was significantly longer than the equivalent value for the MS group (55 +/- 18 min, p < 0.001). In the LS group, univariate analysis revealed that tumor size (>/=50 mm) and the visceral fat area (VFA)/total fat area (TFA) ratio (>/=0.49) were significantly associated with a prolonged pneumoperitoneum time (p = 0.046 and 0.046, respectively). In the multivariate analysis, tumor size and the VFA/TFA ratio were confirmed to be associated with a prolonged pneumoperitoneum time (p = 0.029 and 0.029, odds ratio 20.83 and 20.83, respectively). On the other hand, none of the examined factors were found to be associated with a prolonged pneumoperitoneum time in the MS group. CONCLUSIONS: LESS-A was performed safely in most cases. However, surgeons who are learning the LESS-A procedure need to pay attention to tumor size and visceral obesity.

AIMS: The role of PD-1 (programmed cell death 1) expression on the clinical outcome of upper tract urothelial carcinoma has not yet been elucidated in detail. MATERIALS AND METHODS: PD-1 expression was immunohistochemically examined in 181 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy. A part of PD-1 protein expression in the tumour periphery and tumour nest was evaluated separately. The PD-1-positive cells were counted in the area showing the highest density of PD-1 expression at a magnification of 400x. RESULTS: PD-1 staining in the tumour nest was low in 137 (75.7%) and high in 44 (24.3%) patients. PD-1 staining in the tumour periphery was low in 78 (43.1%) and high in 103 (56.9%) patients. The 5 year progression-free survival rates in patients with the high PD-1 expression in the tumour nest and in the tumour periphery were 54.6% and 67.7%, respectively, which were significantly lower than those in their counterparts (79.4%, P < 0.001; 80.0%, P = 0.04). The 5 year cancer-specific survival rates in patients with the high PD-1 expression in the tumour nest and the tumour periphery were 69.1% and 75.7%, respectively, which were significantly lower than those in their counterparts (84.7%, P = 0.007; 87.8%, P = 0.01). A multivariate Cox regression analysis identified the high PD-1 expression in the tumour nest (hazard ratio 3.07, P < 0.001; hazard ratio 2.44, P = 0.011) and positive lymphovascular invasion (hazard ratio 4.86, P < 0.001; hazard ratio 4.03, P < 0.001) as independent predictors of disease progression and of cancer death, respectively. CONCLUSIONS: PD-1 positivity in the tumour nest could be a strong predictor for a worse clinical outcome and may be a useful indicator for selecting appropriate candidates for adjuvant therapy such as chemotherapy in upper tract urothelial carcinoma patients treated with radical nephroureterectomy.

Microscopy analysis of tumour samples is commonly performed on fixed, thinly sectioned and protein-labelled tissues. However, these examinations do not reveal the intricate three-dimensional structures of tumours, nor enable the detection of aberrant transcripts. Here, we report a method, which we name DIIFCO (for diagnosing in situ immunofluorescence-labelled cleared oncosamples), for the multimodal volumetric imaging of RNAs and proteins in intact tumour volumes and organoids. We used DIIFCO to spatially profile the expression of diverse coding RNAs and non-coding RNAs at the single-cell resolution in a variety of cancer tissues. Quantitative single-cell analysis revealed spatial niches of cancer stem-like cells, and showed that the niches were present at a higher density in triple-negative breast cancer tissue. The improved molecular phenotyping and histopathological diagnosis of cancers may lead to new insights into the biology of tumours of patients.

Tumor budding has been defined as an isolated single cancer cell or a cluster composed of fewer than five cancer cells scattered in the stroma. It is a strong predictor for lymph node metastasis in T1 colorectal cancer. We introduced this concept to T1 non-muscle invasive bladder cancer and evaluated whether tumor budding could have a prognostic impact on the clinical outcome. We identified 121 consecutive patients with newly diagnosed T1 bladder cancer between 1994 and 2014 at Keio University Hospital. All slides were re-reviewed by a dedicated uropathologist. Budding foci were counted under x200 magnification. When the number of budding foci was 10 or more, tumor budding was defined as positive. The relationship between tumor budding and clinical outcomes was assessed using a multivariate analysis. The median follow-up was 52 months. Tumor budding was positive in 21 patients (17.4%). Tumor budding was significantly associated with T1 substaging, tumor architecture and lymphovascular invasion. The 5-year progression-free survival rate in T1 bladder cancer patients with tumor budding was 53.8%, which was significantly lower than that in patients without tumor budding (88.4%, P = 0.001). A multivariate Cox regression analysis revealed that tumor budding was independently associated with stage progression (P = 0.002, hazard ratio = 4.90). In a subgroup of patients treated with bacillus Calmette-Guerin instillation (n = 88), tumor budding was also independently associated with stage progression (P = 0.003, hazard ratio = 5.65). Tumor budding may be a novel indicator for predicting stage progression in T1 bladder cancer, and would likely be easily introduced in clinical practice.

OBJECTIVES: To evaluate postoperative pain and esthetic outcomes in patients undergoing transumbilical laparoscopic adrenalectomy with wound closure using 2-octyl cyanoacrylate. METHODS: A total of 26 patients who underwent laparoscopic adrenalectomy with the transumbilical approach and agreed to participate in this study were included. Patients were randomly divided into two groups: the 2-octyl cyanoacrylate group (Glue group) or the non-use group (non-Glue group). A single surgeon (AM) carried out all procedures between 2014 and 2017. RESULTS: There were no significant differences in the clinical background of the Glue and non-Glue groups. The number of patients with moderate or high levels of pain in the resting/moving period on postoperative days 1, 2 and 3 was 6/10 (46%/77%), 6/9 (46%/69%) and 3/5 (23%/38%) in the non-Glue group, and 5/7 (38%/54%), 2/7 (15%/54%) and 1/3 (8%/23%) in the Glue group. These differences were not significant. In the subgroup analysis of patients aged <50 years, the numbers were 4/6 (57%/86%), 5/7 (71%/100%) and 3/5 (43%/71%) in the non-Glue group, and 3/4 (33%/44%), 1/4 (11%/44%) and 0/1 (0%/11%) in the Glue group in the resting/moving period. On postoperative days 2 and 3, these differences were significant (P = 0.035 and 0.037 in the resting period, and P = 0.017 and 0.013 in the moving period). CONCLUSIONS: 2-octyl cyanoacrylate can be used safely for laparoscopic adrenalectomy with the transumbilical approach, and might be useful for reducing postoperative pain in patients aged <50 years.

超音波ガイド下経直腸的前立腺針生検では予防抗菌薬としてニューキノロン系抗菌薬が推奨されることが多いが,耐性菌の増加も指摘されている。済生会横浜市東部病院泌尿器科(以下,当施設)では抗菌薬の組織移行性を考慮し予防抗菌薬としてスルファメトキサゾール・トリメトプリム合剤(ST合剤)単回投与を採用した。本研究では急性前立腺炎の予防に対するST合剤の有用性について検討した。対象は380例で急性前立腺炎を9例(2.6%)に認めた。過去の報告と比較しても急性前立腺炎発症率は同程度であった。(著者抄録)

39歳女性。左側腹部痛を主訴に近医を受診し、左腎中極に80mm大の腫瘍を指摘された。腫瘍内および腎周囲に出血を認め、腫瘍破裂が側腹部痛の原因と考えられた。精査加療目的に当院を受診した。ダイナミック造影CTで経時的に漸増する造影パターンを示し、腫瘍内外への出血が高度である点より類上皮型腎血管筋脂肪腫と診断し、左腎摘除術を施行した。類上皮型腎血管筋脂肪腫は腎細胞癌と術前診断されることが多く、術前診断が可能であった例は報告されていない。(著者抄録)

BACKGROUND: Analysis of long noncoding RNA (lncRNA) localisation at both the tissue and subcellular levels can provide important insights into the cell types that are important for their function. METHODS: By applying new fluorescent in situ hybridisation technique called hybridisation chain reaction (HCR), we achieved a high-throughput lncRNA visualisation and evaluation of clinical samples. RESULTS: Assessing 1728 pairs of 16 lncRNAs and clear-cell renal-cell carcinoma (ccRCC) specimens, three lncRNAs (TUG1, HOTAIR and CDKN2B-AS1) were associated with ccRCC prognosis. Furthermore, we derived a new lncRNA risk group of ccRCC prognosis by combining the expression levels of these three lncRNAs. Examining genomic alterations underlying this classification revealed prominent features of tumours that could serve as potential biomarkers for targeting lncRNAs. We then derived combination of HCR with expansion microscopy and visualised nanoscale-resolution HCR signals in cell nuclei, uncovering intracellular colocalization of three lncRNA (TUG1, HOTAIR and CDKN2B-AS1) signals such as those located intra- or out of the nucleus or nucleolus in cancer cells. CONCLUSION: LncRNAs are expected to be desirable noncoding targets for cancer diagnosis or treatments. HCR involves plural probes consisting of small DNA oligonucleotides, clinically enabling us to detect cancerous lncRNA signals simply and rapidly at a lower cost.

Despite the high sensitivity of renal cell carcinoma (RCC) to immunotherapy, RCC has been recognized as an unusual disease in which CD8(+) T-cell infiltration into the tumor beds is related to a poor prognosis. To approach the inner landscape of immunobiology of RCC, we performed multiplexed seven-color immunohistochemistry (CD8, CD39, PD-1, Foxp3, PD-L1, and pan-cytokeratin AE1/AE3 with DAPI), which revealed the automated single-cell counts and calculations of individual cell-to-cell distances. In total, 186 subjects were included, in which CD39 was used as a marker for distinguishing tumor-specific (CD39(+)) and bystander (CD39(-)) T-cells. Our clear cell RCC cohort also revealed a poor prognosis if the tumor showed increased CD8(+) T-cell infiltration. Intratumoral CD8(+)CD39(+) T-cells as well as their exhausted CD8(+)CD39(+)PD-1(+) T-cells in the central tumor areas enabled the subgrouping of patients according to malignancy. Analysis using specimens post-antiangiogenic treatment revealed a dramatic increase in proliferative Treg fraction Foxp3(+)PD-1(+) cells, suggesting a potential mechanism of hyperprogressive disease after uses of anti-PD-1 antibody. Our cell-by-cell study platform provided spatial information on tumors, where bystander CD8(+)CD39(-) T-cells were dominant in the invasive margin areas. We uncovered a potential interaction between CD8(+)CD39(+)PD-1(+) T-cells and Foxp3(+)PD-1(+) Treg cells due to cell-to-cell proximity, forming a spatial niche more specialized in immunosuppression under PD-1 blockade. A paradigm shift to the immunosuppressive environment was more obvious in metastatic lesions; rather the infiltration of Foxp3(+) and Foxp3(+)PD-1(+) Treg cells was more pronounced. With this multiplexed single-cell pathology technique, we revealed further insight into the immunobiological standing of RCC.

Bacillus Calmette-Guérin induction with or without maintenance is the gold standard therapy for intermediate-/high-risk non-muscle-invasive bladder cancer; however, one-third of patients treated with adequate bacillus Calmette-Guérin therapy do not achieve sufficient responses, and this is referred to as "bacillus Calmette-Guérin failure." The term, bacillus Calmette-Guérin failure, is ambiguous and includes a very heterogeneous population of patients. By strictly focusing on patients who are unlikely to benefit from additional bacillus Calmette-Guérin therapy and who need to be treated with radical cystectomy, the new concept of "bacillus Calmette-Guérin unresponsive" was recently proposed, and might accelerate the development of novel therapeutic options for bacillus Calmette-Guérin-unresponsive disease. A promising therapeutic strategy for bacillus Calmette-Guérin-unresponsive disease is the blockade of the programmed cell death-1/programmed cell death-ligand 1 pathway, which is considered to be activated by bacillus Calmette-Guérin therapy. Several large clinical trials have been carried out to assess the potential of programmed cell death-1/programmed cell death-ligand 1 blockade in bacillus Calmette-Guérin-naïve high-risk non-muscle-invasive bladder cancer and bacillus Calmette-Guérin-unresponsive disease. Furthermore, clinical trials that are targeting bacillus Calmette-Guérin-unresponsive disease with other strategies, such as vaccines, gene therapy, and targeted and cytotoxic therapies, are ongoing. The findings of these trials are awaited in order to establish appropriate bladder-sparing approaches for patients with bacillus Calmette-Guérin-unresponsive disease.

BACKGROUND: The programmed cell death-1 (PD-1) pathway has been suggested to play an important role in tumor immune escape. We evaluated changes in PD-1 expression before and after Bacillus Calmette-Guerin (BCG) therapy and its prognostic significance in non-muscle-invasive bladder cancer (NMIBC) patients. METHODS: We examined 78 paired tissue samples of NMIBC in tumors just before BCG therapy and BCG-relapsing tumors, defined as recurrence after achieving disease-free status by initial BCG instillations for 6 months. We counted PD-1-positive cells, and PD-1 expression was defined as high when the number of PD-1-positive cells was more than 18 under x200 magnification. RESULTS: The median number of PD-1-positive cells in tumors just before BCG therapy was 3.5, significantly lower than that in BCG-relapsing tumors (17.0, p < 0.001). High PD-1 expression was observed in 20 tumors just before BCG therapy (25.6%) and 36 BCG-relapsing tumors (46.2%). Fifty-two cases (66.6%) showed an increase in the number of PD-1-positive cells in BCG-relapsing tumors. High PD-1 expression in BCG-relapsing tumors was independently associated with subsequent tumor recurrence (p = 0.011) and stage progression (p = 0.033). The 5-year recurrence-free and progression-free survival rates were 40.7 and 74.1% in patients with high PD-1 expression in BCG-relapsing tumors, significantly lower than those in their counterparts (72.9 and 94.1%, respectively). CONCLUSIONS: PD-1 was induced by BCG therapy, and its expression in BCG-relapsing tumors may be an important indicator for predicting worse clinical outcomes in NMIBC patients treated with BCG therapy.

Objective: It is considered that laparoscopic single-site surgery should be performed by specially trained surgeons because of the technical difficulty in using special instruments through limited access. We investigated suitable patients for single-port laparoscopic radical nephrectomy, focusing on the anatomy and distribution of the renal artery and vein. Methods: This retrospective study was conducted in 52 consecutive patients who underwent single-port radical nephrectomy by the transperitoneal approach. In patients undergoing right nephrectomy, a 2-mm port was added for liver retraction. We retrospectively re-evaluated all of the recorded surgical videos and preoperative computed tomography images. The pneumoperitoneum time (PT) was used as an objective index of surgical difficulty. Results: The PT was significantly shorter for right nephrectomy than left nephrectomy (94 vs. 123 min, P = 0.004). With left nephrectomy, dissection of the spleno-renal ligament to mobilize the spleen medially required additional time. Also, the left renal vein could only be divided after securing the adrenal, gonadal and lumbar veins. In patients whose renal artery was located cranial to the renal vein, PT tended to be longer than in the other patients (131 vs. 108 min, P = 0.070). In patients with a superior renal artery, the inferior renal vein invariably covered the artery and made it difficult to ligate the renal artery via the umbilical approach at the first procedure. Conclusions: These findings indicate that patients undergoing right nephrectomy in whom the renal artery is not located cranial to the renal vein are suitable for single-port laparoscopic radical nephrectomy.

PURPOSE: To investigate whether a history of non-muscle-invasive bladder cancer (NMIBC) plays a prognostic role in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy in the era when neoadjuvant chemotherapy was established as standard therapy for MIBC. PATIENTS AND METHODS: A total of 282 patients who were diagnosed with cT2-T4aN0M0 bladder cancer treated with open radical cystectomy at our institutions were included. Initially diagnosed MIBC without a history of NMIBC was defined as primary MIBC group (n = 231), and MIBC that progressed from NMIBC was defined as progressive MIBC (n = 51). RESULTS: The rate of cT3/4a tumors was significantly higher in the primary MIBC group than in the progressive MIBC group (P = .004). Five-year recurrence-free survival and cancer-specific survival (CSS) rates for the primary MIBC group versus progressive MIBC group were 68.2% versus 55.9% (P = .039) and 76.1% versus 61.6% (P = .005), respectively. Progressive MIBC (hazard ratio, 2.170; P = .008) was independently associated with cancer death. In the primary MIBC group, the 5-year CSS rate in patients treated with neoadjuvant chemotherapy was 85.4%, which was significantly higher than that in patients without (71.5%, P = .023). In the progressive MIBC group, no significant differences were observed in CSS between patients treated with and without neoadjuvant chemotherapy. CONCLUSION: MIBC that progressed from NMIBC had a significantly worse clinical outcome than MIBC without a history of NMIBC and may not respond as well to neoadjuvant chemotherapy. These results are informative, even for NMIBC patients treated with conservative intravesical therapy.

BACKGROUND: Lymphovascular invasion (LVI) is an important step in the process of tumor dissemination and metastasis outside the primary organ, but the relationship between LVI and the prognosis of T1 non-muscle invasive bladder cancer (NMIBC) has not been fully evaluated. Accordingly, the present study was performed to evaluate whether LVI had an impact on the clinical outcome in patients with T1 NMIBC. METHODS: A total of 116 consecutive patients were diagnosed with T1 NMIBC from 1994 to 2013 at Keio University Hospital. All cases were reviewed by a single uro-pathologist. The prognostic significance of LVI was assessed in relation to recurrence and stage progression. RESULTS: The median follow-up period was 53 months. LVI was histologically confirmed in 30 patients (25.9%). There were no significant differences of clinical features between the patients with and without LVI. In T1 patients, univariate analysis demonstrated that LVI positivity was associated with stage progression (p = 0.003), but not with tumor recurrence (p = 0.192). Multivariate analysis confirmed that LVI was independently associated with stage progression (p = 0.006, hazard ratio = 4.00). In 85 patients who received BCG instillation, LVI was independently associated with both tumor recurrence and stage progression (p = 0.036 and 0.024, hazard ratio = 2.19 and 3.76). CONCLUSIONS: LVI is a strong indicator of an increased risk of recurrence and progression in BCG-treated patients with T1 NMIBC. This information might assist clinicians to develop appropriate management and counseling strategies for these patients.