[Comparison of Surgical Outcome of Laparoscopic Sacrocolpopexy between the Novice and Experienced Surgeon in Laparoscopic Surgery].

We retrospectively analyzed the safety and surgical outcomes of laparoscopic sacrocolpopexy (LSC) by the novice surgeon (performed ＜5 laparoscopic surgery). Between November 2017 and December 2020, there were 15 cases in which the novice surgeon performed part of LSC, 8 cases in which the novice performed all of LSC, and 50 cases in which the experienced surgeon (performed ＞100 laparoscopic surgery) performed all of LSC. We compared surgical outcome of the 50 cases operated by the experienced surgeon and 23 cases operated by the novice. The laparoscopic time was longer when performed by the novice than by the experienced surgeon (median 208 minutes vs 189 minutes, p＝0.039). Cases of pelvic organ prolapse quantification system (POP-Q) stage 4 were operated more often by the experienced surgeon than by the novice (28% vs 4.8%, p＝0.027). There were no significant differences in the complications and recurrence of pelvic organ prolapse (POP-Q≧2). The LSC process was divided into five steps. The laparoscopic time of all steps was longer when performed by the novice than by the experienced surgeon except the step of lifting up the sigmoid colon and hysterectomy. As the number of cases performed by the novice increased, the laparoscopic time of all steps decreased. The short-term surgical outcomes for cases operated by the novice and experienced surgeon were comparable when the novice avoided cases of POP-Q stage 4. LSC has been said to be difficult, but in this study, even novice surgeons in laparoscopic surgery may be able to perform LSC by accumulating cases. Although this study is not generalizable due to limitations, we believe it will inspire many young doctors to perform LSC.

Preoperative risk classification for intravesical recurrence after laparoscopic radical nephroureterectomy for upper tract urothelial carcinoma in a multi-institutional cohort.

INTRODUCTION: This study aimed to identify preoperative risk factors and create a risk classification for intravesical recurrence of upper urinary tract urothelial carcinoma only after laparoscopic radical nephroureterectomy in a multi-institutional cohort. METHODS: We retrospectively analyzed 283 patients who had undergone laparoscopic radical nephroureterectomy for nonmetastatic upper tract urothelial cancer between March 2002 and March 2020. The cumulative incidence of intravesical recurrence for 224 patients without previous or concomitant bladder cancer was examined using multivariate Fine-Gray competing risks proportional hazards models. A risk stratification model was created to predict subsequent patient outcomes based on the results. RESULTS: The median follow-up duration was 33.3 months, and 71 (31.7%) patients experienced intravesical recurrence. The estimated cumulative incidence of intravesical recurrence at one and 5 years was 23.5% and 36.4%, respectively. In multivariate analysis, the presence of ureter tumors and multiple tumors were shown to be independently significant predictive factors for intravesical recurrence. Based on the results, we classified patients into three risk groups. The cumulative incidence rates of intravesical recurrence within 5 years after surgery were 24.4%, 42.5%, and 66.7% in the low-, intermediate-, and high-risk groups, respectively. CONCLUSIONS: We identified risk factors and created a risk classification model for intravesical recurrence of upper urinary tract urothelial carcinoma only after laparoscopic radical nephroureterectomy. Based on this model, an individualized surveillance protocol or adjuvant therapy could be provided.

Atypical Oncologic Failure After Laparoscopic Radical Nephroureterectomy in a Japanese Multicenter Study.

Objectives: To investigate the recurrence patterns and the atypical oncologic failure (AOF) defined as the presence of atypical recurrences, such as retroperitoneal carcinomatosis or port-site recurrence, after laparoscopic radical nephroureterectomy (LRNU). Methods: LRNU performed at three institutions were included in this retrospective study. The primary endpoints were the first recurrence site and recurrence-free survival. The recurrence sites were classified as atypical recurrences, such as retroperitoneal carcinomatosis or port-site recurrence, as well as distant, local, and intravesical. The Kaplan-Meier curves were obtained to elucidate the time until recurrence and survival. Results: A total of 283 patients were included in the final analysis. Postoperative pathology was T3 or higher in 112 (40%) patients. The median follow-up period was 31 months, and the 3-year recurrence-free, cancer-specific, and overall survival rates were 69.6%, 78.1%, and 72.0%, respectively. The first recurrence sites involved distant, local, atypical, and intravesical recurrences in 51 (18%), 36 (13%), 14 (5%), and 94 (33%) patients, respectively. Of the 14 patients with AOF, 12 had pathologically locally advanced tumors, but seven patients had a preoperative diagnosis of clinical stage T2 or less. Conclusion: A small number of AOF cases were found after LRNU for patients with upper tract urothelial carcinoma. Careful patient selection is critical for AOF prevention.

Clinical outcomes following laparoscopic radical nephroureterectomy in octogenarians.

BACKGROUND: This study aimed to compare the incidence of postoperative complications occurring within 30 days of surgery between octogenarians and younger patients and identify preoperative risk factors for the incidence of postoperative complications. Moreover, we also compared the oncological outcomes between octogenarians and younger patients. METHODS: This retrospective study included 283 patients who underwent laparoscopic radical nephroureterectomy for upper tract urothelial carcinoma from 2002 to 2020. The patients were divided into octogenarians and younger patients (age: < 80 years), and their clinical characteristics, perioperative parameters, and postoperative complications were evaluated. The predictors of postoperative complications were evaluated using logistic regression models. Recurrence-free survival, cancer-specific survival, and overall survival were measured using the Kaplan-Meier method. RESULTS: Twelve (17.1%) octogenarians and 40 (18.7%) younger patients had postoperative complications. No significant difference in the incidence of postoperative complications was observed between octogenarians and younger patients (p = 0.14). A high body mass index was a significant risk factor for complications (p = 0.03). The 5-year recurrence-free survival, cancer-specific survival, and overall survival rates for octogenarians and younger patients were 72% and 64% (p = 0.31), 76% and 63% (p = 0.63), and 43% and 63% (p = 0.06), respectively. CONCLUSION: Laparoscopic radical nephroureterectomy can be performed in octogenarians with complication rates similar to those in younger patients. Similarly, the outcomes of laparoscopic radical nephroureterectomy for oncological control do not differ significantly between octogenarians and younger patients. This procedure is safe and effective for selected octogenarians.

Oncological Outcomes of Retroperitoneal Lymph Node Dissection During Retroperitoneal Laparoscopic Radical Nephroureterectomy for Renal Pelvic or Upper Ureteral Tumors: Matched-Pair Analysis.

Objectives: The aim of this study was to investigate the oncological outcomes and recurrence patterns in clinically node-negative patients with renal pelvic and/or upper or middle ureteral tumors after template-based retroperitoneal lymph node dissection (RPLND) in conjunction with retroperitoneal laparoscopic radical nephroureterectomy (LRNU). Materials and Methods: A total of 283 patients who received LRNU with and without RPLND at three Japanese institutions were enrolled. The template for RPLND included the renal hilar and para-aortic lymph nodes (LNs) (left side) and renal hilar, paracaval, retrocaval, and intra-aortocaval LNs (right side). The LNs and kidneys were removed en bloc. The primary endpoint was set as recurrence-free survival. All RPLND cases were matched one-to-one with no-RPLND cases using a propensity score matching approach, and 47 matched pairs were included in analyses. Results: Compared with the control group, significant differences were not observed in the RPLND group in terms of operation time, blood loss, postoperative complication rate, and pathological findings. The estimated 5-year recurrence-free survival was significantly higher in the RPLND group (86.8%) compared with the group without RPLND (64.2%) (p = 0.014). The estimated 5-year cancer-specific survival showed a similar tendency; however, it did not reach a statistically significant difference (87.5% vs 71.3%, respectively; p = 0.168). As for the first recurrence site, the RPLND group showed a lower incidence of distant recurrence, while no significant difference was observed in the rate of regional LN recurrence. Conclusions: This study suggests that template-based RPLND in conjunction with retroperitoneal LRNU efficiently improves recurrence-free survival by reducing distant recurrences.

Complications and their management following retroperitoneal lymph node dissection in conjunction with retroperitoneal laparoscopic radical nephroureterectomy.

OBJECTIVES: To describe the detailed perioperative complications and their management after retroperitoneal lymph node dissection with retroperitoneal laparoscopic radical nephroureterectomy for patients with upper tract urothelial carcinoma at three institutions. METHODS: Retroperitoneal lymph node dissection was performed on patients with upper tract urothelial carcinoma located at the pelvis and/or upper or middle ureter, and its template included the renal hilar and para-aortic lymph nodes (left side) and the renal hilar, paracaval, retrocaval, and intra-aortocaval lymph nodes (right side). The lymph nodes and kidneys were removed en bloc. The primary endpoint was postoperative complication rates, and the secondary endpoints were intraoperative findings and chylous leakage management. The associations of retroperitoneal lymph node dissection with postoperative complications were examined using logistic regression with propensity score techniques. RESULTS: Eighty-eight (31%) and 195 (69%) patients underwent and did not undergo retroperitoneal lymph node dissection, respectively. There was no significant difference in postoperative complications and other perioperative findings in the entire cohort, except for prolonged operation time. Retroperitoneal lymph node dissection was not statistically significantly associated with total and serious complications in propensity score analyses. Postoperative chylous leakage could be conservatively managed even though it is common in patients with retroperitoneal lymph node dissection (14/88 (16%)). The incidence of chylous leakage was significantly lower in patients whose lymphatic vessels were meticulously clipped completely during retroperitoneal lymph node dissection (5.3% vs 24%; P = 0.017). CONCLUSION: There was no association between retroperitoneal lymph node dissection with laparoscopic radical nephroureterectomy and postoperative complications. However, chylous leakage is often observed after retroperitoneal lymph node dissection and careful management is highly required. The use of clips during retroperitoneal lymph node dissection is recommended to minimize chylous leakage risk.

[Factors Predicting Difficulty of Morcellation during Holmium Laser Enucleation of the Prostate].

To identify which patients will have difficulty during morcellation in holmium laser enucleation of the prostate (HoLEP), we analyzedthe association of preoperative factors with morcellation efficiency retrospectively. Between March 2015 andMay 2019, 129 patients with benign prostatic hyperplasia (BPH) underwent HoLEP at our institution. Based on the morcellation efficiency (morcellation volume per minute), they were classifiedinto easy (≥3 g/min, n＝81) andd ifficult (＜3 g/min, n＝48) groups. In patients who underwent computed tomography (CT) before the surgery, CT values of the prostatic adenomas were measured. The preoperative parameters were comparedbetween the two groups. Comparedwith the easy group, the morcellation time in the difficult group was significantly longer (median, 11 vs 18.5 min, ＜0.001), though prostate volume was not significantly different (median, 76.3 vs 69.3 ml, p＝0.116). The body mass index (BMI) was significantly lower in the difficult group (median, 23.2 vs 21.9 kg/m2, p＝0.007), andit was positively correlatedwith morcellation efficiency. The difference between the maximum andaverage CT values tended to be lower in the difficult group (median, 43.6 vs 39.2 HU, p＝0.066), andit was positively correlatedwith BMI andmorcellation efficiency. Morcellation appearedto be difficult in BPH patients with low BMI because of the homogeneous hardness of prostatic adenoma.

[Investigation of the Risk for Biochemical Recurrence after Radical Prostatectomy Using the Length of the Positive Surgical Margin Microscopically Measured from the Surgical Specimen].

Radical prostatectomy is one of the major treatment options for patients with localized prostate cancer, and biochemical recurrence (BCR) after surgery is regarded as one of the representative indicators of the oncological outcome. The positive surgical margin (PSM) of the surgical specimen is considered to be one of the risk factors for BCR and its length (LPSM) was reported to be positively correlated with the risk for BCR. We retrospectively investigated the relationship between BCR and LPSM in 115 patients who underwent radical retropubic prostatectomy or laparoscopic radical prostatectomy without neoadjuvant hormone therapy at Shimada Municipal Hospital between 2008 and 2016. We found that the patients with a LPSM of 3 mm or longer had a higher risk for BCR than those with a LPSM shorter than 3 mm (HR 10.98, 95% confidence interval : 3.09-39.06, p <0.001), and patients with pT3 disease with a LPSM of 3 mm or longer had a higher risk for early BCR. Therefore, the LPSM may be a useful parameter to predict BCR after radical prostatectomy.

[A Case Of cT3bN2M0 Pleomorphic Giant Cell Carcinoma of the Bladder without Recurrence after Neoadjuvant Chemotherapy and Radical Cystectomy for 4 Years].

Pleomorphic giant cell carcinoma of the bladder is a highly malignant subtype and its prognosis is very poor. Among 22 previously reported cases, 14 cases were diagnosed as muscle-invasive tumors and the 10 patients died within 1.5 years after the initial diagnosis. We herein report a long-surviving patient with cT3bN2M0 pleomorphic giant cell carcinoma of the bladder without recurrence. A 73-year-old man presented with macroscopic hematuria and cystoscopy revealed a papillary nodular tumor 45 millimeters in diameter at the right bladder wall. Bilateral external iliac lymph node metastases were found on computed tomography (CT) and magnetic resonance imaging (MRI). The histopathological diagnosis of the transurethral resection specimen was pleomorphic giant cell urothelial carcinoma, high-grade, G3, pT2 or higher. The pleomorphic giant cells were composed of large epithelioid cells with single or multiple bizarre nuclei. The patient underwent 2 cycles of neoadjuvant chemotherapy using gemcitabine and cisplatin. Follow-up CT and MRI revealed disappearance of iliac lymph node matastases. Laparoscopic radical cystectomy and lymphadenectomy were performed. The histopathological diagnosis was pleomorphic giant cell urothelial carcinoma, ypT3aN0M0, RM0. Giant cells were found in 70% of the tumor. No recurrence has been found for 4 years after surgery. If neoadjuvant chemotherapy is effective, long-term survival without recurrence may be possible after radical cystectomy even in cases of muscle-invasive or N2 pleomorphic giant cell carcinoma of the bladder.

[A Case of Dedifferentiated Liposarcoma of the Spermatic Cord].

A74-year-old man was referred to the department of general surgery in our hospital because of a painless right scrotal swelling persisting for three months. On physical examination, the patient was found to have an inguinal hernia. The patient underwent laparoscopic transabdominal preperitoneal repair, but no inguinal hernia was detected. The patient was referred to our department for a suspected tumor of the spermatic cord. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a clearbordered and homogeneous mass without fat in the right spermatic cord. The findings from the imaging indicated that the mass was benign, but we suspected a malignant tumor because of the rapid enlargement. We performed a right high orchiectomy with a wide excision. Histopathological diagnosis was dedifferentiated liposarcoma with a myxofibrosarcoma-like pattern. He is alive one year after surgery with no recurrence. When a spermatic cord tumor is detected, we need to keep in mind the possibility of malignancy, because it is difficult to make a diagnosis from imaging alone.

[A Case of PT1 Plasmacytoid Variant Bladder Cancer Treated by Bladder Conserving Therapy].

Plasmacytoid variant bladder cancer is a highly malignant subtype associated with a high propensity for invasion, metastasis and poor prognosis. Among approximately 100 reported cases, most were diagnosed at an advanced stage and only 10 were diagnosed at a non-muscle-invasive stage. Due to the limited data on clinical features of non-muscle-invasive plasmacytoid variant bladder cancer, its treatment has not been established. We report a long-surviving patient with pT1 plasmacytoid variant bladder cancer in whom the bladder was conserved after detailed pathological examinations of the transurethral resection (TUR) specimen and intensive follow-up. A 65-year-old man presented with macroscopic hematuria. Cystoscopy revealed a nodular tumor 11 millimeters in diameter and no metastasis was observed on computed tomography. The histopathological diagnosis of the TUR specimen was pT1 plasmacytoid variant urothelial carcinoma of the bladder. Microvascular invasion was not found by immunohistochemical staining and histopathological examination of the specimen from the second TUR indicated no residual cancer. The patient strongly desired bladder conservation and additionally underwent intravesical instillation therapy with 40 mg of mitomycin C weekly for 6 consecutive weeks. Follow-up cystoscopy demonstrated 3 small papillary tumors 12 months after intravesical instillation therapy, but histopathologically, the recurrent tumors were pTa with pTis urothelial carcinomas without plasmacytoid components. To treat pTis disease, he subsequently underwent intravesical BCG instillation therapy. The plasmacytoid variant bladder cancer has not recurred for 26 months since the initial diagnosis. Non-muscle-invasive and localized plasmacytoid variant bladder cancer may be treated with bladder conserving therapy.

[Laparoscopic resection of a retroperitoneal müllerian cyst: a case report].

A 51-year-old woman had a cystic mass in the retroperitoneal space, below the left kidney, which was incidentally detected at a medical check-up. The size of the mass was 6 cm in diameter, which was similar to that obtained by magnetic resonance imaging 4 years ago. We followed the case and found that the mass was slightly enlarged a year later. Because malignancy could not be ruled out, we performed a laparoscopic tumor excision. Histologically, the cyst was diagnosed as a Müllerian cyst, and there was no evidence of malignancy. Retroperitoneal Müllerian cyst is a rare tumor. Sixteen cases have been reported previously and this is the fourth case of a laparoscopic excision.

[Renal carcinoid tumor presenting as bladder tamponade: a case report and review of the Japanese cases].

A 65-year-old man presented with sudden onset of gross hematuria and urinary retention. Computed tomographic scan (CT) showed a cystic multilocular enhancing lesion (9 cm in diameter) at the left renal hilum causing thinning and lateral displacement of the left renal parenchyma. Left hydronephrosis and a renal calculi were observed. We performed radical nephrectomy suspecting a cystic renal cell carcinoma. Microscopic examination and immunohistochemical studies confirmed the diagnosis of the carcinoid tumor. The tumor cells were fully positive for neuron-specific enolase and keratin, and partially positive for chromogranin-A. One of the resected lymph nodes was positive for metastasis. Additional gastrointestinal tract examinations for carcinoid tumor were negative. However, he was concurrently diagnosed with poorly differentiated prostate cancer and hormonal therapy was started. He is free of recurrent carcinoid tumor nine months postoperatively. This case is the 31st report of renal carcinoid tumors in Japan.

Multiple roles of Rbx1 in the VBC-Cul2 ubiquitin ligase complex.

The importance of the ubiquitin system largely depends on ubiquitin ligases, E3s, as they determine the specificity of the system. Rbx1/ROC1/Hrt1, a RING finger protein, functions as an important component of the cullin-containing SCF and VBC-Cul2 ligases. Modification of cullins by NEDD8 (NEDDylation), has been shown to be essential for the E3 activity of both SCF and VBC-Cul2, and it was suggested that Rbx1 acts as the E3 for cullin NEDDylation. RING finger is composed of eight cysteine and histidine residues that bind to zinc ions. Rbx1 is a highly evolutionarily conserved protein; however, the eighth coordination residue in its RING finger is aspartate (D97) rather than cysteine. Substitution of D97 with each of the other 19 amino acids demonstrates that aspartate is superior to cysteine in cullin NEDDylation. Interestingly, however, different D97 mutants demonstrate different activities towards 6 cullins tested. Importantly, we were able to discriminate between the NEDDylating activity of Rbx1 and its involvement in the ubiquitylation reaction within the context of VBC-Cul2. Moreover, while Rbx1 is not involved in governing the stability of SCF, Rbx1 mutants destabilize VBC-Cul2. Taken together, these results indicate that various mechanisms regulate both the activities and the stability of cullin-based ligases.

Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2.

The ubiquitin system is involved in several basic cellular functions. Ubiquitination is carried out by a cascade of three reactions catalysed by the E1, E2 and E3 enzymes. Among these, the E3 ubiquitin-protein ligases have a pivotal role in determining the specificity of the system by recognizing the target substrates through defined targeting motifs. Although RING finger proteins constitute an important family of E3 ligases, only a few post-transcriptional modifications, including phosphorylation, proline hydroxylation and glycosylation, are known to function as recognition signals for E3. Iron regulatory protein 2 (IRP2), a modulator of iron metabolism, is regulated by iron-induced ubiquitination and degradation. Here we show that the RING finger protein HOIL-1 functions as an E3 ligase for oxidized IRP2, suggesting that oxidation is a specific recognition signal for ubiquitination. The oxidation of IRP2 is generated by haem, which binds to IRP2 in iron-rich cells, and by oxygen, indicating that the iron sensing of IRP2 depends on the synthesis and availability of haem.

Enhancement of TRAIL/Apo2L-mediated apoptosis by adriamycin through inducing DR4 and DR5 in renal cell carcinoma cells.

Renal cell carcinoma (RCC) is one of the most drug-resistant malignancies in humans. We show that adriamycin (ADR) and TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L have a synergistic cytotoxic effect against RCC cells. This synergistic cytotoxicity was obtained in ACHN, A704, Caki-1 and Caki-2 human RCC cell lines and freshly derived RCC cells from 6 patients. This synergistic effect, however, was not achieved in 5 samples of freshly isolated normal kidney cells. We further explored the mechanisms underlying this synergistic effect and found that the synergistic cytotoxicity of TRAIL/Apo2L and ADR was realized by inducing apoptosis. Sequential treatment with ADR followed by TRAIL/Apo2L induced significantly more cytotoxicity than the reverse treatment. ADR increased the expression of DR4 and DR5 in RCC cells, but not in the normal kidney cells. Furthermore, the synergistic cytotoxicity was significantly inhibited by DR4:Fc and DR5:Fc fusion proteins, which inhibit TRAIL/Apo2L-mediated apoptosis. In addition, caspase activity assays and treatment of caspase inhibitors demonstrated that the combination treatment with ADR and TRAIL/Apo2L activated caspase cascade, including caspase-9, -8, -6 and -3, which were the downstream molecules of death receptors. These findings indicate that ADR sensitizes RCC cells to TRAIL/Apo2L-mediated apoptosis through induction of DR4 and DR5, suggesting that the combination therapy of TRAIL/Apo2L and ADR might be effective for RCC therapy.

Genetic polymorphisms of the interleukin-4 receptor alpha gene are associated with an increasing risk and a poor prognosis of sporadic renal cell carcinoma in a Japanese population.

PURPOSE: It has been suggested that the immune system of the host may be capable of modulating the clinical course of renal cell carcinoma (RCC) patients. In fact, the amount of Th2 cytokines such as interleukin (IL)-4 and IL-10 in the serum of patients has been found to be an important predictor of poor prognosis. Recently, it was reported that genetic polymorphisms of the IL-4 receptor alpha (IL-4Ralpha) gene affect the strength of signaling through the receptor. In addition, these same polymorphisms were found to be associated with an increased risk of atopy by causing Th2-dominated responses of the host. The significance of the polymorphisms on the incidence and prognosis in sporadic RCC patients were examined to clarify the role of IL-4 as well as that of the Th1/Th2 immune system in this disease. EXPERIMENTAL DESIGN: A case-control study was performed with 143 sporadic RCCs in a Japanese population and 205 Japanese controls. Logistic regression models were also used to assess the genetic effects on prognosis. RESULTS: The frequencies of variant alleles that enhance signaling of IL-4 were significantly related to an increased risk of RCC. Furthermore, multivariate regression analysis showed that the genotype of the IL-4R gene was an independent prognostic factor for cause-specific survival (P = 0.018) together with M classification (P = 0.0002) and histopathological grade (P = 0.044). CONCLUSIONS: The present findings show that the preferential Th2-type response to tumors was associated with a poorer prognosis and suggest that polymorphisms of the IL-4Ralpha gene may serve as useful genetic markers for assessing the risk of the development and progression of RCC.