[The development of innovative therapeutic drugs targeting hypoxia responses].

The 2019 Nobel Prize in Physiology or Medicine was awarded to Dr. William G. Kaelin Jr, Dr. Peter J. Ratcliffe, and Dr. Gregg L. Semenza for their elucidation of new physiological mechanisms "How cells sense and adapt to oxygen availability". Moreover, two different drugs, HIF-PH inhibitors and HIF-2 inhibitors were also developed based on the discovery. Interestingly, those three doctors have different backgrounds as a medical oncologist, a nephrologist, and a pediatrician, respectively. They have started the research based on their own unique perspectives and eventually merged as "the elucidation of the response mechanism of living organisms to hypoxic environments". In this review, we will explain how the translational research that has begun to solve unmet clinical needs successfully contributed to the development of innovative therapeutic drugs.

Clinical characteristics and survival outcomes of elderly patients with de novo metastatic germ cell tumors.

OBJECTIVES: To determine the outcomes for elderly patients with de novo metastatic germ cell tumors and the influence of patient age on adherence to standard chemotherapy. METHODS: A total of 150 patients who were initially diagnosed with metastatic germ cell tumors and treated at our institution between 2007 and 2021 were included. Patients were classified according to three age groups: aged <40, 40-49, and ≥50 years. Clinicopathological features, adherence to standard first-line chemotherapy, overall survival, and disease-free survival were compared between these groups. We also analyzed the outcomes of patients who received low-intensity induction chemotherapy due to adverse events and/or comorbidities. RESULTS: There was no significant difference in any of the survival outcomes and in the rate of adherence to standard first-line chemotherapy between the three age groups, although elderly patients with intermediate/poor prognosis group tended to receive less-intense chemotherapies. The rate of febrile neutropenia as a chemotherapy-related adverse event was significantly higher in patients aged ≥50 years. No statistical significance in survival outcomes was detected between the group of patients who received relatively low-intensity induction chemotherapy and those who received adequately intensive planned chemotherapy. CONCLUSIONS: The adherence rate of standard fist-line chemotherapy of elderly patients is almost comparable to that of younger patients, although some adverse events should be carefully managed. Even elderly patients with metastatic germ cell tumors can aim for equivalently good survival outcome like younger populations, with effort to adhere to standard chemotherapy.

Transvesical bladder diverticulectomy via bladder neck opening during robot-assisted radical prostatectomy.

INTRODUCTION: As bladder diverticula in older adults are often secondary to bladder outlet obstruction, bladder diverticulectomy is often performed with prostate treatment. Cases of sequentially performed robot-assisted bladder diverticulectomy and prostatectomy have been reported; however, performing cystotomy for each procedure may increase the risk of complications and prolong operative time. MATERIALS AND SURGICAL TECHNIQUE: We reported the cases of three patients who underwent diverticulectomy without additional cystotomy via the bladder opening during robot-assisted laparoscopic radical prostatectomy in our hospital. DISCUSSION: This technique corresponds to a transvesical approach through the bladder neck opening. Hence, it is especially useful for well-visualized diverticula close to the ureteral orifice or on the posterior wall. Although other approaches may be better depending on the location of the diverticulum, it is considered a reasonable approach that does not require an additional cystotomy.

Significant reduction in burden of metastatic disease by intermittent docetaxel therapy in a patient with castration-resistant prostate cancer.

Intermittent docetaxel therapy (IDT) is rarely used nowadays as a treatment option for men with metastatic castration-resistant prostate cancer (mCRPC) because of the widespread availability of androgen receptor axis-targeted therapy, which is less toxic. Therefore, there is limited information available on whether IDT has a clinical benefit in the treatment of men with mCRPC. This report describes the case of a 66-year-old man with a diagnosis of cT2N1M0 prostate cancer who underwent neoadjuvant combined androgen blockade and whole-pelvis radiation therapy. However, the tumor had progressed to mCRPC with metastasis to the bladder and a left pelvic lymph node within 2 years. Docetaxel had been administered as first-line chemotherapy, and the patient achieved a complete response in terms of the bladder metastasis. Docetaxel was stopped after 15 cycles. When a durable response had been maintained for more than 2 years, during which only androgen deprivation therapy was administered, the patient was switched to observation only. However, his prostate-specific antigen level gradually increased. Abiraterone was started as second-line therapy, during which there was a rapid increase in the PSA level. Computed tomography revealed further enlargement of the left pelvic lymph node, bladder metastasis, metastasis to the left common iliac lymph nodes, and several disseminated nodules around the bladder. Docetaxel was reintroduced as IDT for third-line therapy, and a complete response was achieved for all metastases, with the exception of the metastasis in the left pelvic lymph node. Thus far, the patient has survived for more than 7 years after starting docetaxel as first-line therapy for mCRPC. IDT is potentially useful in a subgroup of patients with mCRPC and could achieve long-term survival. Comprehensive genomic profiling may help physicians to select patients with mCRPC who are more likely to benefit from docetaxel than other systemic therapy.

Impact of renal sinus protrusions on achieving trifecta in robot-assisted partial nephrectomy.

Objective: The objective of this work is to assess the relationship between the morphological characteristics of a central tumour and the perioperative outcomes of robot-assisted partial nephrectomy (RAPN). Subjects and Methods: We retrospectively analysed the data from 186 patients with central tumours involving the renal sinus, who underwent RAPN in a single-centre study between February 2015 and June 2022. All cases were assigned a RENAL nephrometry score based on preoperative images. The shape of the protruding portion of the tumour was classified into four types: 'flat', 'spherical', 'single-hump', and 'complex-hump', and was independently assessed by two readers. The trifecta is defined as the warm ischemia time within 25 min, negative surgical margins, and no major postoperative complications. Univariate and multivariate analyses were performed to identify the factors associated with the failing trifecta. Results: Trifecta was achieved in 113 cases (60.8%), and the achievement rate in flat, spherical, single-hump, and complex-hump types was 83.3%, 74.5%, 64.3%, and 21.3%, respectively. Prolonged warm ischemia time was the primary cause of the failure to achieve the trifecta. The rate of positive surgical margins and upstage to pathological T3a was greater for complex humps while the rate of major complications and postoperative GFR preservation did not differ between shapes. On multivariate analysis for failing trifecta achievement, the complex-hump protrusion was found to be an independent positive predictor (odds ratio: 15.8; p < 0.001), whereas the height and width of protrusion were not significantly related. Conclusions: The degree of difficulty varied among central tumours, and it was not possible to precisely measure it with existing scoring systems. Complex-hump protrusions strongly correlate with failure to achieve the trifecta. Preoperative assessment of the morphology of protrusion is useful for predicting outcomes.

[A Case of Retroperitoneal Lymphangioleiomyomatosis].

Contrast-enhanced computed tomography (CT) revealed a multilocular cystic mass extending from the level of the renal artery origin to the internal and external iliac artery regions in a woman in her 40s who presented with vomiting and diarrhea. A percutaneous biopsy was performed, and histopathological examination revealed bundle-like proliferations of spindle-shaped cells with oval nuclei in acidophilic cytoplasm. Immunohistochemical staining was positive for HMB-45, alpha-smooth muscle actin, E-cadherin, and estrogen and progesterone receptors; the provisional diagnosis was perivascular epithelioid cell tumor. Considering the patient's age and sex, the final diagnosis was primary retroperitoneal lymphangioleiomyomatosis (LAM). She did not meet the diagnostic criteria for tuberous sclerosis complex and was considered to have sporadic LAM. As complete surgical resection was considered to be impossible and no lung lesions, which indicate poor prognosis, were observed, we decided to keep her under surveillance. The patient was asymptomatic, with no significant changes on imaging for 6 months.

[A Case of m0CRPC after Hormone Therapy for Pelvic Lymph Node Metastasis in which Salvage RARP was Effective].

The patient was a 63-year-old man with biopsy Gleason score of 4＋5 prostate cancer with an initial prostate specific antigen level of (PSA) 51.2ng/ml. On imaging examination, extracapsular invasion, rectal invasion, and pararectal lymph node metastasis were found (cT4N1M0). After 4 years of androgen deprivation therapy, PSA decreased to 0.631ng/ml, and then increased gradually to1.2ng/ml. Computed tomographic scan showed that the primary tumor had shrunk and lymph node metastasis had disappeared; so salvage robot-assisted resection of the prostate (RARP) was performed for non-metastatic castration-resistant prostate cancer (m0CRPC). Since PSA decreased to an undetactable level, hormone therapy was terminated at 1 year. The patient remained recurrence-free for 3 years after surgery. RARP may be effective for m0CRPC, enabling discontinuation of androgen deprivation therapy.

Necessity of prophylactic drainage tube in retroperitoneal laparoscopic nephroureterectomy with open distal ureterectomy: A matched-pair analysis.

OBJECTIVES: To assess the necessity of prophylactic drain placement in retroperitoneal laparoscopic nephroureterectomy with open distal ureterectomy for upper tract urothelial cancer. METHODS: Between July 2011 and March 2021, 200 patients with localized clinical Tis-T3 upper urinary tract urothelial carcinoma underwent laparoscopic nephroureterectomy with open distal ureterectomy. After removing the specimen, drainage tubes were placed on the renal beds and/or in the retrovesical spaces. Drain tubes were omitted for most patients after 2017. We compared the postoperative outcomes between the patients with drain placement (D+ group) and without drain placement (D- group) using propensity score matching. RESULTS: A total of 164 patients (90 in the D+ group and 74 in the D- group) were enrolled, and matched pairs of 108 patients were analyzed. There was no significant difference in the incidence of complications according to Clavien-Dindo grade in the two groups after the propensity score matching. There was no significant difference in the incidence of postoperative lymphocele (n = 5 vs. 9, p = 0.395) and symptomatic lymphocele (n = 1 vs. 1, p = 1) between the two groups. The length of hospital stay was significantly shorter in the D- group (11 vs. 8 days, p < 0.0001). CONCLUSIONS: We found that omitting the drainage tube after laparoscopic radical nephroureterectomy did not increase postoperative complications or lymphocele and shortened the post-hospital stay.

Effect of continued perioperative antithrombotic therapy on bleeding outcomes following laparoscopic nephrectomy and nephroureterectomy.

INTRODUCTION: In this study, we aimed to assess the impact of perioperative continuation of antithrombotic therapy on bleeding and complications in patients undergoing laparoscopic radical nephrectomy (LRN) and nephroureterectomy (LNU). METHODS: This was a retrospective observational study. Patients who underwent LRN and LNU between January 2017 and July 2019 at our institution were recruited. All patients taking antithrombotic agents continued taking them during the perioperative phase (AA group). Surgical outcomes of patients in the AA group were compared with those of patients who were not taking antithrombotic agents (NA group). The primary outcome was the rate of bleeding complications. Secondary outcomes included intraoperative estimated blood loss, transfusion rate, and complications for up to 90 days. RESULTS: A total of 100 patients were included in the analysis, with 36 and 64 patients assigned to the AA and NA groups, respectively. Patients in the AA group were found to have more severe comorbidities than those in the NA group, with a Charlson Comorbidity Index ≥5, totaling 14 (39%) and 12 (19%), respectively (P = .03). According to surgical outcomes, none of the patients in the AA group required secondary procedures for bleeding complications. Moreover, there were no significant differences between the groups in intraoperative blood loss, hemoglobin deficit, rate of perioperative transfusion, readmission rate, or high-grade complications. DISCUSSION: These results indicate that perioperative use of antithrombotic agents does not increase the risk of bleeding and can be considered safe during LRN and LNU.

Robot-assisted transperitoneal reconstruction of a retrocaval ureter: A report of two cases.

A retrocaval ureter (RCU) is a rare cause of congenital ureteral obstruction that often requires surgical repair. We report two cases of RCU in adults treated with robot-assisted laparoscopic surgery. In both cases, we performed robotic ureteroureterostomy with dissection of the entire length of the retrocaval portion of the right ureter without complications. In the second case, renal stone removal was simultaneously performed. The robot-assisted procedure we performed could be considered safe and feasible for the surgical repair of an RCU.

Surgical and functional outcomes of robot-assisted versus laparoscopic partial nephrectomy with cortical renorrhaphy omission.

To evaluate the surgical and functional outcomes between robot-assisted (CRO-RAPN) vs. laparoscopic (CRO-LPN) methods of cortical-renorrhaphy-omitting partial nephrectomy. Between July 2012 and June 2020, patients with localized clinical T1-2 renal masses who underwent CRO-RAPN or CRO-LPN were reviewed. The outcomes of the two groups were compared using propensity-score matching. Trifecta was defined as negative surgical margin, warm ischemic time < 25 min, and absence of complications of Clavien-Dindo grade III or more until three months postoperatively. The preservation rate of the estimated glomerular filtration rate (eGFR) was evaluated at six months postoperatively. Among 291 patients (CRO-RAPN, n = 210; CRO-LPN, n = 81) included in the study, 150 matched pairs of patients were analyzed. Compared to the CRO-LPN group, the CRO-RAPN group was associated with shorter warm ischemic time (13 min vs. 20 min, P < 0.001), shorter total operation time (162 min vs. 212 min, P < 0.001), less estimated blood loss (40 mL vs. 119 mL, P = 0.002), lower incidence of overall complications (3% vs. 16%, P = 0.001), higher preservation rate of eGFR at six months postoperatively (93% vs. 89%, P = 0.003), and higher trifecta achievement rate (84% vs. 64%, P = 0.004). CRO-RAPN contributed to shorter warm ischemic time, less blood loss, fewer complications, and higher preservation of renal function, all of which allowed this technique to achieve a higher rate of trifecta compared to CRO-LPN.

Complete remission of renal cell carcinoma with lung carcinomatous lymphangiosis after primary therapy with immune checkpoint inhibitors followed by partial nephrectomy for surgical consolidation.

Introduction: Cytoreductive nephrectomy has been used in combination with systemic therapy for the treatment of metastatic renal cell carcinoma, although its efficacy in the era of immune checkpoint inhibitors remains controversial. Case presentation: A 57-year-old woman was diagnosed with left renal cell carcinoma and lung carcinomatous lymphangiosis (cT3aN0M1). After receiving combined immunotherapy, she achieved complete response for the lung metastases and partial response for the primary tumor. After five months of systemic therapy, she underwent partial nephrectomy to remove the primary tumor, followed by eight courses of nivolumab monotherapy. One year postoperatively, she remained recurrence-free. Conclusion: Cytoreductive partial nephrectomy for surgical consolidation may be a treatment option for metastatic renal cell carcinoma.

Rapidly Progressive Bladder Cancer Diagnosed because of Spontaneous Bladder Rupture.

Background: Spontaneous bladder rupture (SBR) is very rare and can be associated with advanced bladder cancer. Because of its rarity, the optimal management of bladder cancer with SBR has not been established. Herein, we report a case of SBR due to locally advanced bladder cancer, which rapidly invaded the ileum and caused peritoneal dissemination. Case Presentation. An 86-year-old man presented with sudden-onset lower abdominal pain and distension. The patient was diagnosed with bladder perforation and bladder tumor on contrast-enhanced computed tomography (CECT). Transurethral resection of the bladder tumor revealed an invasive urothelial carcinoma with squamous differentiation. Although radical cystectomy with lymph node dissection was planned, preoperative CECT and magnetic resonance imaging revealed enlargement of the bilateral iliac regional lymph nodes, multiple peritoneal nodules, and invasion of the bladder tumor to the ileocecum. Therefore, cystectomy and resection of ileocecum with palliative intent and bilateral cutaneous ureterostomy were performed. However, the patient's general condition rapidly worsened after surgery, and he died 74 days after the initial diagnosis. Conclusions: We encountered a case of SBR accompanied by bladder cancer with extremely rapid progression, which suggested the importance of short-interval repeat imaging examinations. Emergency surgery should be considered when bladder cancer is suspected in patients with SBR so as not to miss the window period of a possible cure.

A case of microsatellite instability-high clinically advanced castration-resistant prostate cancer showing a remarkable response to pembrolizumab sustained over at least 18 months.

Defective DNA mismatch repair genes can lead to microsatellite instability (MSI)-high status in prostate cancer (PC). Accumulation of replication errors in DNA leads to the production of abundant neoantigens, which could be targets for immune checkpoint inhibitors (CPIs). However, the incidence of MSI-high PC is low, and not all patients show a satisfactory therapeutic response to CPIs. Here, we present the case of a patient with MSI-high castration-resistant PC who showed a remarkable and durable response to pembrolizumab. The patient was resistant to abiraterone, docetaxel, and cabazitaxel and was suffering from multiple tumor-associated or treatment-related complications, such as urinary tract infection, infective endocarditis, and uncontrollable prostatic hemorrhage. Soon after the start of pembrolizumab therapy, the patient showed a dramatic decrease in prostate-specific antigen from 35.67 ng/mL to an undetectable level and a remarkable reduction in the size of a massive prostate mass and lymph node metastases, with an absence of treatment-related complications. Specimens from the transurethral resection of prostate cancer during cabazitaxel treatment for control of prostate bleeding and also that from the prostate biopsy at initial diagnosis revealed MSI-high status. Immunohistochemistry showed loss of MSH2 and MSH6, and whole-exome sequencing revealed an approximate tumor mutation burden of 61 mutations/Mb as well as biallelic loss of MSH2 Pembrolizumab could show a significant effect even in a heavily treated patient with MSI-high advanced PC. Accumulation of detailed clinical and genomic information of cases of MSI-high PC treated with pembrolizumab is necessary for optimal patient selection.

Comparison between 5-aminolevulinic acid photodynamic diagnosis and narrow-band imaging for bladder cancer detection.

BACKGROUND: To compare 5-aminolevulinic acid (5-ALA)-mediated photodynamic diagnosis (PDD) with narrow-band imaging (NBI) for cancer detection during transurethral resection of bladder tumour (TURBT). METHODS: Between June 2018 and October 2020, 114 patients and 282 lesions were included in the analysis. Patients were orally administered 5-ALA (20 mg/kg) 2 h before TURBT. The bladder was inspected with white light (WL), PDD, and NBI for each patient, and all areas positive by at least one method were resected or biopsied. The imaging data were then compared to the pathology results. RESULTS: The sensitivities of WL, PDD, and NBI for detecting urothelial carcinoma were 88.1%, 89.6%, and 76.2%, respectively. The specificity, positive predictive value, and negative predictive value for detecting urothelial carcinoma were 47.5%, 80.9%, and 61.3%, respectively, for WL; 22.5%, 74.5%, and 46.2%, respectively, for PDD; and 46.3%, 78.2%, and 43.5%, respectively, for NBI. PDD was significantly more sensitive than NBI for all lesions (p < 0.001) and carcinoma in situ (CIS) lesions (94.6% vs. 54.1%, p < 0.001). CONCLUSIONS: PDD can increase the detection rate of bladder cancer, compared to NBI, by greater than 10%. Therefore, 100% of CIS lesions can be detected by adding PDD to WL.

[Complete Remission of Metastatic Renal Cell Carcinoma with Invasion of the Duodenum and Pancreas after Treatment with Nivolumab Plus Ipilimumab Followed by Axitinib and Surgery : A Case Report].

A man in his 60s was diagnosed with clear cell carcinoma of the right kidney with multiple lung metastases, tumor thrombus of the inferior vena cava (IVC), and invasion of the duodenum and pancreas. Ipilimumab plus nivolumab was administered as first-line therapy. After 3 treatment courses, computed tomography (CT) demonstrated a slight decrease in the size of the primary tumor and lung metastases. However, the patient became hemodynamically unstable due to persistent duodenal bleeding during treatment despite frequent blood transfusions. Axitinib was then initiated as second-line therapy. The duodenal bleeding ceased 10 days after starting axitinib and his anemia remissed. Subsequent CT showed further decrease in the size of the primary tumor and lung metastases. The patient underwent right nephrectomy after improvement of nutrition. IVC thrombectomy, and pancreaticoduodenectomy. The lung metastases disappeared on postoperative imaging and no additional treatment was provided. Twelve months after surgery, he was in good health and showed no signs of recurrence.

Apalutamide-induced severe interstitial lung disease: A report of two cases from Japan.

Apalutamide, a competitive inhibitor of the androgen receptor, is being increasingly used for the treatment of prostate cancer. There have been few reports of interstitial lung disease in clinical trials of apalutamide. However, two cases of apalutamide-induced interstitial lung disease with respiratory failure in Japanese males, who were successfully treated with high-dose corticosteroids, are presented here. These cases suggest that clinicians should be alert to the potentially life-threatening risk of pulmonary toxicity associated with apalutamide treatment.

Effect of Continued Perioperative Anticoagulant Therapy on Bleeding Outcomes Following Robot-assisted Radical Prostatectomy.

OBJECTIVE: To assess the impact of continued perioperative anticoagulant drug administration on bleeding and complications in patients undergoing robot-assisted radical prostatectomy. METHODS: Between January 2014 and January 2020, 620 patients with prostate cancer underwent robot-assisted radical prostatectomies and were retrospectively reviewed. Fourteen patients who discontinued antithrombotic therapy were excluded. Among the 606 included patients, 31 continued anticoagulant therapy during the perioperative phase (anticoagulant group). The anticoagulant group outcomes were compared with those of patients who continued clopidogrel and prasugrel (thienopyridine group = 13), aspirin monotherapy (aspirin group = 61), and no chronic antithrombotic agent (control group = 501). The primary outcome was the incidence of bleeding complications requiring transfusion, additional intervention, or readmission. Secondary outcomes were the incidence of thrombotic complications, estimated blood loss, and overall complication rates. RESULTS: Among the 31 patients in the anticoagulant group, 20 (65%) used directed oral anticoagulants, 11 (35%) used warfarin, and 5 used combined aspirin. Only 1 (3%) patient in the anticoagulant group required postoperative transfusion, and none required additional interventions or readmission. No significant differences were detected between the anticoagulant and other groups (anticoagulant vs thienopyridine, aspirin, and control groups) regarding bleeding complications (3% vs 8%, P = .51; 0%, P = .34; 0.4%, P = .17, respectively), thrombotic complications (3% vs 0%, P = .70; 2%, P = .56; 0.2%, P = .11, respectively), estimated blood loss (200 vs 100 mL, P = .63; 175 mL, P = .64; 165 mL, P = .74, respectively), or other high-grade complications (6% vs 0%, P = .49; 2%, P = .26; 3%, P = .24, respectively). CONCLUSION: Perioperative continuation of anticoagulant use is feasible for patients undergoing robot-assisted radical prostatectomy.