Extracellular vesicles secreted from bone metastatic renal cell carcinoma promote angiogenesis and endothelial gap formation in bone marrow in a time-dependent manner in a preclinical mouse model.

Introduction: Bone is a major metastatic site of renal cell carcinoma (RCC). Recently, it is well recognized that bone metastatic tumor cells remodel bone marrow vasculature. However, the precise mechanism underlying cell-cell communication between bone metastatic RCC and the cells in bone marrow remains unknown. Extracellular vesicles (EVs) reportedly play crucial roles in intercellular communication between metastatic tumor cells and bone marrow. Therefore, we conducted the current study to clarify the histological alteration in vascular endothelium in bone marrow induced by EVs secreted from bone metastatic RCC cells as well as association between angiogenesis in bone marrow and bone metastasis formation. Materials and methods: We established a bone metastatic RCC cell line (786-O BM) by in vivo selection and observed phenotypic changes in tissues when EVs were intravenously injected into immunodeficient mice. Proteomic analysis was performed to identify the protein cargo of EVs that could contribute to histological changes in bone. Tissue exudative EVs (Te-EVs) from cancer tissues of patients with bone metastatic RCC (BM-EV) and those with locally advanced disease (LA-EV) were compared for in vitro function and protein cargo. Results: Treatment of mice with EVs from 786-O BM promoted angiogenesis in the bone marrow in a time-dependent manner and increased the gaps of capillary endothelium. 786-O BM EVs also promoted tube formation in vitro. Proteomic analysis of EVs identified aminopeptidase N (APN) as a candidate protein that enhances angiogenesis. APN knockdown in 786-O BM resulted in reduced angiogenesis in vitro and in vivo. When parental 786-O cells were intracardially injected 12 weeks after treatment with786-O BM EVs, more bone metastasis developed compared to those treated with EVs from parental 786-O cells. In patient samples, BM-EVs contained higher APN compared to LA-EV. In addition, BM-EVs promoted tube formation in vitro compared to LA-EVs. Conclusion: EVs from bone metastatic RCC promote angiogenesis and gap formation in capillary endothelium in bone marrow in a time-dependent manner.

[A Case of Malacoplakia of the Prostate which was Difficult to Distinguish from Prostate Cancer].

A 70-year-old-man was referred with urination pain and pyuria. Prostate specific antigen was 10.6 ng/ml, and urine culture was Escherichia coli. The abdominal ultrasonography showed irregular low echo at the right lobe of prostate. Prostate magnetic resonance imaging (MRI) showed an extracapsular infiltrated prostate tumor in the right lobe. Levofloxacin was administered and prostate biopsy was performed. The pathological examination revealed that the prostate tissue was filled with inflammatory cells and had lost its glandular duct structure. The patient was diagnosed with malacoplakia of the prostate. Four months after prostate biopsy, prostate MRI imaging showed disappearance of the extracapsular infiltration in right peripheral zone.

Squamous cell and urothelial carcinomas in an ileal neobladder.

Introduction: In cases of ileal neobladder following radical cystectomy for the treatment of bladder cancer, tumor development in the isolated gut segment is extremely rare. Herein, we report a case of squamous cell and urothelial carcinomas in the ileal neobladder 23 years after radical cystectomy. Case presentation: A 71-year-old man was referred to our hospital for further examination of a solitary tumor in an ileal neobladder. At the age of 48 years, he underwent radical cystectomy with ileal neobladder reconstruction. Transurethral resection of the bladder tumor was performed, and histopathological findings showed squamous cell carcinoma with high-grade urothelial carcinoma. Conclusion: To our knowledge, this is the first report of squamous cell and urothelial carcinomas in an ileal neobladder. While secondary tumor development in an ileal neobladder is rare, it is a cause for concern as a late postoperative adverse event. Therefore, long-term follow-ups are recommended.

Detection of von Hippel-Lindau gene mutation in circulating cell-free DNA for clear cell renal cell carcinoma.

The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel-Lindau gene (VHL) using a combination of digital PCR and multiplex PCR-based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell-free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%-4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%-2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.

[A Case of Prostatic Cancer that Had Bilateral Ureteral Metastases at Initial Diagnosis].

Ureteral metastases from prostate cancer are uncommon. We report a case of prostate cancer with bilateral ureteral metastases. A 76-year-old man visited our hospital because of serum prostate specific antigen (PSA) level of 40.7 ng/ml. Contrast-enhanced computed tomography revealed bilateral ureteral tumors causing bilateral hydronephrosis. Magnetic resonance imaging and prostate biopsy showed prostate cancer involving the bladder neck with bone metastases. Voided urine cytology suggested urothelial carcinoma. Retrograde pyelography demonstrated left ureteral filling defect and right lower ureteral stenosis. Left ureteral tumor and concomitant prostate cancer were suspected ; thus, combined androgen blockade therapy was initiated, and left nephroureterectomy was subsequently performed. Pathological and immunohistochemical examination of the left ureteral tumor revealed PSA-positive adenocarcinoma. The contralateral ureteral lesion was presumed to be metastasis from the same origin ; hence, prostate cancer with bilateral ureteral metastases was diagnosed. Although the mechanism is unknown, ureteral metastasis should be considered in the differential diagnosis of prostate cancer patients with ureteral tumor.

[Complete Transurethral Resection of Large Non-Muscle-Invasive Bladder Cancer Preoperatively Suspected to Be Muscle-Invasive Disease : A Case Report and Literature Review].

A 69-year-old man presented with gross hematuria. Cystoscopy revealed a large papillary tumor occupying the bladder. Magnetic resonance imaging showed a large bladder tumor more than 8cm in maximum diameter,suspected to be muscle-invasive disease. We performed the 1st transurethral resection of bladder tumor (TURBT) for the main purpose of pathological confirmation. Histopathological findings of the resected specimens showed urothelial carcinoma,low grade pTa. We performed subsequent treatments with TURBT twice,resulting in complete resection. The histopathological findings showed the same results as those of the 1st TURBT conclusively,which was consistent with non-muscle-invasive bladder cancer. He received intravesical instillation of pirarubicin eight times in total and has remained free from recurrence for more than 26 months after the final TURBT.

Functional and genomic characterization of patient-derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma.

Resistance to the mechanistic target of rapamycin (mTOR) inhibitors, which are a standard treatment for advanced clear cell renal cell carcinoma (ccRCC), eventually develops in most cases. In this study, we established a patient-derived xenograft (PDX) model which acquired resistance to the mTOR inhibitor temsirolimus, and explored the underlying mechanisms of resistance acquisition. Temsirolimus was administered to PDX model mice, and one cohort of PDX models acquired resistance after repeated passages. PDX tumors were genetically analyzed by whole-exome sequencing and detected several genetic alterations specific to resistant tumors. Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a potential candidate for developing the resistant phenotype. While DNMT1 expression in temsirolimus-resistant tumors was comparable with the control tumors, DNMT enzyme activity was decreased in resistant tumors compared with controls. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated heterozygous knockdown of DNMT1 in the temsirolimus-sensitive ccRCC (786-O) cell line was shown to result in a temsirolimus-resistant phenotype in vitro and in vivo. Integrated gene profiles using methylation and microarray analyses of PDX tumors suggested a global shift for the hypomethylation status including promotor regions, and showed the upregulation of several molecules that regulate the mTOR pathway in temsirolimus-resistant tumors. Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.

Spontaneous remission of rectal ulcer associated with SpaceOAR® hydrogel insertion in radiotherapy for prostate cancer.

INTRODUCTION: The SpaceOAR® hydrogel system separates the prostate and rectum to reduce rectal irradiation during prostate radiotherapy. However, it could induce rectal toxicity. CASE PRESENTATION: A 75-year-old man with localized prostate cancer underwent external beam radiotherapy with the use of SpaceOAR® System. However, postimplant magnetic resonance imaging showed hydrogel infiltration to the rectum. Three months after implantation, he complained of bowel symptoms, including bloody stool. Colonofiberscopy and computed tomography revealed a rectal ulcer associated with SpaceOAR® hydrogel insertion. He was treated with fasting, fluid replacement, and blood transfusion. One year after implantation, complete healing was confirmed during outpatient follow-up. CONCLUSION: To our knowledge, this is the first report of a rectal ulcer associated with SpaceOAR® hydrogel insertion assessed by magnetic resonance imaging beforehand. Postimplant magnetic resonance imaging evaluation might be a useful follow-up tool in such cases.

[A Case of Primary Ewing Sarcoma of the Kidney Treated with Multidisciplinary Approach].

A woman in her 40s visited our hospital for further examination and treatment of a left renal tumor. Imaging studies showed that the patient had a large left renal tumor, 10.5 cm in diameter, which contained foci of necrosis. Open left radical nephrectomy was performed. In pathological examination, hematoxylin-eosin staining showed uniform small round cells with alveolar growth. Immunohistochemistry findings showed that CD99 and NKX2. 2 were positive, and synaptophysin was focally positive. Fluorescence in situ hybridization confirmed (11 ; 22) (q24 ; q12) chromosomal translocation which led to diagnosis of primary Ewing sarcoma of the kidney. Two months after the surgery, new tumors were found inside and outside of the left psoas muscles and in the left paracolic gutter. Six courses of chemotherapy were administered with VDC (vincristine/doxorubicin/cyclophosphamide) and IE (ifosfamide/etoposide). After completing the combined chemotherapy, the recurrent tumors disappeared completely on imaging. To prevent further recurrence, external radiation was administered to the left retroperitoneal region. About 16 months after the surgery, numerous new tumors appeared in the left retroperitoneal, left pleura, and erector spinae muscles. Chemotherapy was resumed following radiotherapy, and then trabectedin was administered. However, she eventually died of progressive disease at 26 months after the surgery.

[A Case of Metastatic Mucinous Adenocarcinoma Derived from the Right Ovary to the Ileal Ureter].

A 76-year-old woman presented with temporary right back pain and renal dysfunction. She had undergone ileal ureter interposition for right ureteral resection due to retroperitoneal liposarcoma about forty years ago. Abdominal computed tomographic (CT) scan showed right hydronephrosis and a stenosis in the middle of the ileal ureter. The symptoms were relieved, and the patient was followed. Six months later, however, a contrast enhanced lesion was newly observed at the stenosis of the ileal ureter, and nineteen months later, right ovarian tumor and peritoneal dissemination were subsequently observed. Aiming at diagnosis and cytoreduction, right nephroureterectomy and bilateral oophorectomy were performed. Histopathological findings of the resected tumors showed common characteristics of infiltrating and proliferating adenocarcinoma. Immunohistochemistry findings showed that Cytokeratin 7 and Cytokeratin 20 stained positive. On the other hand, Mucin 2 and Special AT-rich sequence-binding protein 2 were not found. The histopathological diagnosis was metastatic mucinous adenocarcinoma of the ovary with ileal ureter and a wide peritoneal dissemination. The patient rejected adjuvant chemotherapy and a new lesion was found in the pelvic fourmonths afterthe surgery.

[A Case of Malignant Lymphoma with an Elevated Serum IgG4].

A man in his 60s was referred to our hospital for further examination of left hydronephrosis and renal dysfunction. An enhanced abdominal computed tomographic scan showed that the patient had chronic abdominal aortic dissection and a non-enhancing retroperitoneal soft tissue occupying the front of the abdominal aorta as well as the bilateral common iliac arteries. The left ureter was compressed by the soft tissue at the fourth lumbar level. No tumor markers were significantly elevated and idiopathic retroperitoneal fibrosis was suspected to be the cause. Before starting treatment, however, right hydronephrosis was newly observed. We placed bilateral ureteral stents and reviewed our diagnosis. Elevated serum IgG4 and accumulation of 18F-fluorodeoxyglucose in the soft tissue were the points at issue. To determine the diagnosis, we performed open wedge biopsy. Histopathological findings showed mainly fibrous connective tissue with lymphocytic infiltration, which was positive for CD10, CD20, and bcl-2. These findings indicated follicular lymphoma. Induction chemotherapy was performed with 6 cycles of rituximab/cyclophosphamide/vincristine/prednisolone. The soft tissue tumor shrank markedly and the patient has been free from bilateral ureteral stents.

Downregulation of RalGTPase-activating protein promotes invasion of prostatic epithelial cells and progression from intraepithelial neoplasia to cancer during prostate carcinogenesis.

RalGTPase-activating protein (RalGAP) is an important negative regulator of small GTPases RalA/B that mediates various oncogenic signaling pathways in various cancers. Although the Ral pathway has been implicated in prostate cancer (PCa) development and progression, the significance of RalGAP in PCa has been largely unknown. We examined RalGAPα2 expression using immunohistochemistry on two independent tissue microarray sets. Both datasets demonstrated that the expression of RalGAPα2 was significantly downregulated in PCa tissues compared to adjacent benign prostatic epithelia. Silencing of RalGAPα2 by short hairpin RNA enhanced migration and invasion abilities of benign and malignant prostate epithelial cell lines without affecting cell proliferation. Exogenous expression of wild-type RalGAP, but not the GTPase-activating protein activity-deficient mutant of RalGAP, suppressed migration and invasion of multiple PCa cell lines and was phenocopied by pharmacological inhibition of RalA/B. Loss of Ralgapa2 promoted local microscopic invasion of prostatic intraepithelial neoplasia without affecting tumor growth in a Pten-deficient mouse model for prostate tumorigenesis. Our findings demonstrate the functional significance of RalGAP downregulation to promote invasion ability, which is a property necessary for prostate carcinogenesis. Thus, loss of RalGAP function has a distinct role in promoting progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma.

A family case with germline TSC1 and mtDNA mutations developing bilateral eosinophilic chromophobe renal cell carcinomas without other typical phenotype of tuberous sclerosis.

AIM: We examined the genetic alterations in a mother and son with multiple eosinophilic chromophobe renal cell carcinomas (chRCCs) showing no other features. METHODS: Germline DNA and bilateral renal cell carcinoma DNA were genetically analysed by whole-exome sequencing. Candidate gene alterations in the first patient's germline were investigated in her child's germline and the chRCCs. RESULTS: We detected several germline gene alterations in the mother. Among the identified alterations, TSC1 and mitochondrial DNA mutations were also confirmed in her son. Regarding somatic alterations in bilateral chRCCs, no common candidate gene alteration was found. CONCLUSION: To the best of our knowledge, this is the first report of whole-exome sequencing revealing bilateral eosinophilic chRCCs associated with tuberous sclerosis complex in a family case without classical phenotype. These results suggest that germline TSC1 and mitochondrial DNA gene mutations may be involved in the development of chRCCs in some cases.

Dysregulated HAI-2 Plays an Important Role in Renal Cell Carcinoma Bone Metastasis through Ligand-Dependent MET Phosphorylation.

MET, a c-met proto-oncogene product and hepatocyte growth factor (HGF) receptor, is known to play an important role in cancer progression, including bone metastasis. In a previous study, we reported increased expression of MET and matriptase, a novel activator of HGF, in bone metastasis. In this study, we employed a mouse model of renal cell carcinoma (RCC) bone metastasis to clarify the significance of the HGF/MET signaling axis and the regulator of HGF activator inhibitor type-2 (HAI-2). Luciferase-transfected 786-O cells were injected into the left cardiac ventricle of mice to prepare the mouse model of bone metastasis. The formation of bone metastasis was confirmed by whole-body bioluminescent imaging, and specimens were extracted. Expression of HGF/MET-related molecules was analyzed. Based on the results, we produced HAI-2 stable knockdown 786-O cells, and analyzed invasiveness and motility. Expression of HGF and matriptase was increased in bone metastasis compared with the control, while that of HAI-2 was decreased. Furthermore, we confirmed increased phosphorylation of MET in bone metastasis. The expression of matriptase was upregulated, and both invasiveness and motility were increased significantly by knockdown of HAI-2. The significance of ligand-dependent MET activation in RCC bone metastasis is considered, and HAI-2 may be an important regulator in this system.

[A Case Report : Metastatic Carcinoma of the Collecting Ducts of Bellini in a Hemodialysis Patient Treated with Temsirolimus].

Carcinoma of the collecting ductsof Bellini isa rare histological subtype of renal cell carcinoma and mostly has unfavorable prognosis. Radical nephrectomy is generally chosen for the 1st line treatment but therapeutic approaches for the metastasis/recurrence have not been established. We report a case of carcinoma of collecting ducts of Bellini in a patient receiving hemodialysis treated with temsirolimus. A 62- year-old man receiving hemodialysis was admitted to our hospital with drug-resistant anemia and high-grade cyclic fever. Computed tomography revealed the right renal tumor and multiple metastatic lung tumors. Open radical nephrectomy wasperformed. Pathological findingswere compatible with carcinoma of the collecting ducts of Bellini. He was given weekly temsirolimus treatment. The disease progressed modestly but kept the stable disease (SD) status for six months. He died of the cancer 11 months after the initial diagnosis.

[The Efficacy of a Released Ultrasonic Lithotripsy in Percutaneous Nephrolithotomy : Randomized Trial Comparing Swiss LithoClast® Master Versus Swiss LithoClast®].

We prospectively randomized total 29 patients with renal stones into two groups between Aug 2014 and March 2016. The US group was treated using a ultrasonic lithotripter (Swiss LithoClast® Master) and the PN group was treated with a pneumatic lithotripter (Swiss LithoClast® ). We compared treatment outcomes in these groups. The US group consisted of 17 patients and the PN group 12 patients. There was no significant difference between the groups in baseline characteristics (age, sex, body mass index, side, stone size, and density). There was no significant difference in total operative time (p＝0.63), stone-free rate (p＝ 0.19), hemoglobin deficit (p＝0.49), or rate of postoperative sepsis (p＝0.99) between the two groups. However, intracorporal stone disintegration and removal time was significantly shorter in the US group than the PN group (p＝0.029). These results suggest that the ultrasonic lithotripter can be superior to the existing pneumatic lithotripter in saving intracorporal stone disintegration and removal time in percutaneous nephrolithotomy.

Amino-terminal enhancer of split gene AES encodes a tumor and metastasis suppressor of prostate cancer.

A major cause of cancer death is its metastasis to the vital organs. Few effective therapies are available for metastatic castration-resistant prostate cancer (PCa), and progressive metastatic lesions such as lymph nodes and bones cause mortality. We recently identified AES as a metastasis suppressor for colon cancer. Here, we have studied the roles of AES in PCa progression. We analyzed the relationship between AES expression and PCa stages of progression by immunohistochemistry of human needle biopsy samples. We then performed overexpression and knockdown of AES in human PCa cell lines LNCaP, DU145 and PC3, and determined the effects on proliferation, invasion and metastasis in culture and in a xenograft model. We also compared the PCa phenotypes of Aes/Pten compound knockout mice with those of Pten simple knockout mice. Expression levels of AES were inversely correlated with clinical stages of human PCa. Exogenous expression of AES suppressed the growth of LNCaP cells, whereas the AES knockdown promoted it. We also found that AES suppressed transcriptional activities of androgen receptor and Notch signaling. Notably, AES overexpression in AR-defective DU145 and PC3 cells reduced invasion and metastasis to lymph nodes and bones without affecting proliferation in culture. Consistently, prostate epithelium-specific inactivation of Aes in Ptenflox/flox mice increased expression of Snail and MMP9, and accelerated growth, invasion and lymph node metastasis of the mouse prostate tumor. These results suggest that AES plays an important role in controlling tumor growth and metastasis of PCa by regulating both AR and Notch signaling pathways.

CCL2 as a potential therapeutic target for clear cell renal cell carcinoma.

We previously reported that the pVHL-atypical PKC-JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C-C motif) ligand-2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expression for ccRCC specimens showed that upregulation of CCL2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL2 in ccRCC cells, we generated subclones of WT8 cells that overexpressed CCL2 and subclones 786-O cells in which CCL2 expression was knocked down. Although CCL2 expression did not affect cell proliferation in vitro, CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo. We then depleted macrophages from tumor xenografts by administration of clodronate liposomes to confirm the role of macrophages in ccRCC. Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting CCL2 activity in ccRCC, we administered CCL2 neutralizing antibody to primary RCC xenografts established from patient surgical specimens. Inhibition of CCL2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that CCL2 is involved in angiogenesis and macrophage infiltration in ccRCC, and that CCL2 could be a potential therapeutic target for ccRCC.

LAPAROSCOPIC RADICAL NEPHRECTOMY FOR RENAL TUMOR>7CM.

(Objectives) Laparoscopic radical nephrectomy (LRN) is now a standard care for the treatment of renal tumors, but the limitation of LRN for large tumors remains to be elucidated. In this study, we examined the safety and efficacy of LRN for >7 cm renal tumors including tumors >10 cm. (Patients and methods) From March 2001 to September 2014, 167 patients received laparoscopic surgery for renal tumors at our institution. Of these, 126 patients (≤4.0 cm: 64 cases, 4.1-7.0 cm: 40 cases, 7.1-10.0 cm: 12 cases, >10.0 cm: 10 cases) underwent LRN. Treatment outcomes including surgical and oncological outcomes among each stage were compared. (Results) Operating time for 7.1-10.0 cm tumors were similar to that <7 cm tumors but that for >10 cm tumors was significantly longer than that <10 cm tumors. There was no significant difference among each stage in terms of complication rate. As expected, recurrence-free survival rate for >10 cm tumors were worse than <10 cm tumors. (Conclusions) Our data suggests that LRN for large tumors >7 cm can be performed safely, but LRN for >10 cm tumors are technically demanding and require longer operation time.

MID-TERM ONCOLOGICAL OUTCOME AND TECHNICAL MODIFICATIONS FOR LAPAROSCOPIC RADICAL CYSTECTOMY AT OUR INSTITUTION: 60 CASES ANALYSIS.

(Objective) Although laparoscopic radical cystectomy (LRC) is becoming a standard care for invasive and high-risk non-invasive bladder cancer in Japan, the data about mid-and long-term oncological outcome is still lacking. We previously reported our initial experience of LRC compared to open radical cystectomy. In this study, we evaluated mid-term oncological outcome for LRC by updating our clinical data. In addition, we evaluated the effect of technical modifications for LRC. (Patients and methods) From March 2005 to September 2015, 60 patients underwent LRC at our institution. Treatment outcomes including surgical and oncological outcomes were analyzed. We also assessed the effect of technical modifications between first 30 cases and second 30 cases as to blood loss, operating time and complication rate. (Results) The overall complication rate was 47%, including 18% serious complications (Clavien score 3 or greater). The 5-year recurrence-free survival, cancer-specific survival, and overall survival were 56.2%, 74.4%, and 63.6%, respectively. The recurrence occurred in 19 (32%) cases, including distant metastasis in 12 (20%) cases, local recurrence in 6 (10%) cases, and both in 1 (2%) cases. As for the effect of technical modifications for LRC, the blood loss decreased and postoperative recovery was faster in second 30 cases. (Conclusion) These results indicate that LRC could be performed safely with acceptable oncological outcomes.