Hypoxia-Inducible Factor-Dependent and Independent Mechanisms Underlying Chemoresistance of Hypoxic Cancer Cells.

In hypoxic regions of malignant solid tumors, cancer cells acquire resistance to conventional therapies, such as chemotherapy and radiotherapy, causing poor prognosis in patients with cancer. It is widely recognized that some of the key genes behind this are hypoxia-inducible transcription factors, e.g., hypoxia-inducible factor 1 (HIF-1). Since HIF-1 activity is suppressed by two representative 2-oxoglutarate-dependent dioxygenases (2-OGDDs), PHDs (prolyl-4-hydroxylases), and FIH-1 (factor inhibiting hypoxia-inducible factor 1), the inactivation of 2-OGDD has been associated with cancer therapy resistance by the activation of HIF-1. Recent studies have also revealed the importance of hypoxia-responsive mechanisms independent of HIF-1 and its isoforms (collectively, HIFs). In this article, we collate the accumulated knowledge of HIF-1-dependent and independent mechanisms responsible for resistance of hypoxic cancer cells to anticancer drugs and briefly discuss the interplay between hypoxia responses, like EMT and UPR, and chemoresistance. In addition, we introduce a novel HIF-independent mechanism, which is epigenetically mediated by an acetylated histone reader protein, ATAD2, which we recently clarified.

Ureteroscopy for urolithiasis in bedridden patients: it is feasible and acceptable.

PURPOSE: To investigate the safety of transurethral ureteroscopy (URS) for urolithiasis in bedridden patients and to identify bedridden patient-specific risk factors for postoperative complications. METHODS: The patients who underwent URS for urolithiasis were divided into bedridden patients and good performance status (PS) patients, and the groups were compared regarding their clinical characteristics and postoperative complications. A multivariable logistic regression analysis was performed to evaluate independent predictors of postoperative febrile urinary tract infection (fUTI). RESULTS: A total of 1626 patients were included, 276 in the bedridden patient group, and 1350 in the good PS patient group. The bedridden patient group had a significantly higher age and higher proportion of females and had multiple comorbidities. In 77 patients (27.9%), 88 postoperative complications developed for the bedridden patient group. Clavien-Dindo grade III or IV complications were observed in only 8 patients. No grade V complications were observed. The most common complication was fUTI. The frequency of fUTI with grade III or IV for the bedridden patient group (2.2%) was higher compared with the good PS patient group (0.5%), but the difference was not statistically significant (p = 0.13). Bedridden patient-specific risk factors for fUTI included female sex, diabetes mellitus, cerebrovascular comorbidities, lower extremity contracture, and prolonged operative time. CONCLUSION: URS for urolithiasis is a feasible and acceptable procedure in bedridden patients, despite the moderate rate of postoperative complications. The identified risk factors provide a framework for risk stratification and individualized care in this unique patient population.

Hydronephrosis severity as a predictor of postoperative renal function decline following laparoscopic radical nephroureterectomy.

BACKGROUND: This study aimed to investigate factors, including the degree of hydronephrosis, that may be associated with decreased renal function after radical nephroureterectomy (RNU). METHODS: This study included 252 patients who underwent laparoscopic RNU with an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2 in three institutions. We assessed the association between hydronephrosis grade and perioperative renal function and performed a stepwise multivariate linear regression analysis to identify factors associated with postoperative eGFR. Patients with preoperative eGFR ≥ 50 ml/min/1.73 m2 were divided into a training set and an independent external validation set to develop a predictive model for postoperative renal function. RESULTS: The median preoperative and postoperative eGFR were 61.1 and 46.4 ml/min/1.73 m2, respectively. The eGFR preservation rates were 66.9%, 66.6%, 88.1%, and 100.0% in groups without, with mild, moderate, and severe hydronephrosis, respectively, and this difference was statistically significant (p < 0.001). Multivariate analysis revealed that factors predictive of postoperative eGFR included sex, preoperative eGFR, clinical T stage (cT3-4), and the presence of moderate or severe hydronephrosis. Our predictive model, based on these factors, positively correlated with actual postoperative renal function, and the similarity in categories with or without renal function insufficiency between predicted and actual postoperative renal functions was 78% in both training and validation sets. CONCLUSION: Moderate or severe hydronephrosis is associated with a modest postoperative decline in renal function, while mild hydronephrosis is not. Our predictive model may be useful in predicting postoperative renal function insufficiency and guiding decision-making for perioperative medical treatment.

Minimally invasive total pelvic exenteration for symptomatic locally advanced prostate cancer with rectal invasion: Indications and technical considerations.

In cases of rectal invasion by locally invasive prostate cancer (LAPC) leading to severe pain or bleeding, total pelvic exenteration (TPE) is necessary. Here, we present two cases of successful minimally invasive TPE: one performed laparoscopically for local recurrence with rectal bleeding after laparoscopic radical prostatectomy, and another done robotically for LAPC (clinical T4N1M0) accompanied by rectal bleeding. Medical treatments were ineffective in the latter case, and the tumor occupied a significant portion of the pelvis. We adopted a simultaneous transperineal approach and performed intracorporeal ileal conduit formation. Our cases highlight the challenging nature of minimally invasive TPE for symptomatic LAPC. Despite its complexity, these techniques prove viable and valuable in managing LAPC-related symptoms, emphasizing their practical utility in clinical settings.

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.

The useful technique of laparoscopic segmental ureterectomy with ureteral reimplantation for distal upper tract urothelial carcinoma.

INTRODUCTION: Segmental ureterectomy (SU) has been proven effective in cases of distal upper tract urothelial carcinoma (UTUC). Nonetheless, SU has been performed infrequently in the real world, and there is no consensus on the preferred surgical technique in laparoscopic surgery. We describe our first experience of laparoscopic segmental ureterectomy (LSU) with psoas hitch ureteral reimplantation. MATERIALS AND SURGICAL TECHNIQUE: LSU starts using a fan-shaped, five-port, transperitoneal approach. First, the cancerous ureter segment is clipped to avoid tumor seeding, and then the diseased segment is dissected. Second, the psoas hitch is performed by fixing the external part of the ipsilateral dome of the bladder to the psoas muscle and its tendon. Third, at the top of the bladder, an incision is made in the muscle layer and mucosa. The ureter is then spatulated. A guide wire is used to place a retrograde ureteral double J stent. Finally, the anastomosis of the bladder and ureter mucosa is performed by interrupted suturing of both ends, followed by continuous suturing, and the muscular layer of the bladder is closed in a double layer. We performed LSU for distal UTUC in 10 patients. There was no decrease in renal function before or after surgery. During follow-up, three patients experienced a recurrence of urothelial carcinoma in the bladder and one patient had a local recurrence. DISCUSSION: LSU is a safe and feasible procedure in our experience, and it can be recommended for selected cases of distal UTUC with optimal perioperative, renal functional, and oncologic outcomes.

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.

The efficacy of ultrasonography for the detection of upper tract urothelial carcinoma.

PURPOSE: Ultrasonography and computed tomography urography are two commonly used modalities to image the upper tracts for the evaluation of hematuria. This study evaluated the efficacy of ultrasonography for the detection of upper tract urothelial carcinoma compared to computed tomography urography as a standard reference. METHODS: This retrospective study included patients with urothelial carcinoma of the renal pelvis and/or ureter who were diagnosed using computed tomography urography and underwent surgical treatment. We calculated the sensitivity of ultrasonography in upper tract urothelial carcinoma diagnosis, further classified the degree of hydronephrosis on ultrasonography, and analyzed the relationship between the sensitivity and the degree of hydronephrosis and tumor location. Additionally, the usefulness of the combination of the screening ultrasonography findings, the presence of gross hematuria, and/or urine cytology was analyzed. RESULTS: This study included 136 patients with upper urothelial carcinoma. Ultrasonography in the diagnosis had 45.6% sensitivity, and ultrasonography findings, including the detection of hydronephrosis, were present in 72.8%. The presence of hydronephrosis and tumor location were associated with detection by ultrasonography. The tumor was identified in a total of 134 (98.5%) patients by combining tumor detection and hydronephrosis using ultrasonography with gross hematuria and positive urine cytology as screening. CONCLUSION: Ultrasonography showed acceptable sensitivity for upper tract urothelial carcinoma diagnosis. Considering the hydronephrosis findings, ultrasonography is a useful screening tool for upper tract urothelial carcinoma. Additionally, excessive computed tomography examinations can be reduced by adding gross hematuria and positive urine cytology.

Safety and efficacy of ureteroscopy for urolithiasis in octogenarians.

OBJECTIVE: To examine the safety and efficacy of ureteroscopy (URS) for urolithiasis in octogenarians, and identify preoperative risk factors for the incidence of postoperative complications. METHODS: The patients who underwent URS for urolithiasis were divided into octogenarians and younger patients (age: <80 years), and the groups were compared regarding their clinical characteristics, intraoperative and postoperative complications, and stone-free rate. The predictors of postoperative complications were evaluated using logistic regression models. RESULTS: A total of 1207 patients were included, 166 in the octogenarian patient group and 1041 in the younger patient group. The proportion of female patients (p < 0.001), American Society of Anesthesiologists (ASA) score (p < 0.001), rate of preoperative pyelonephritis (p < 0.001), and diabetes mellitus (p = 0.003) were higher in the octogenarian group. No statistically significant differences were found between the two groups regarding stone size, location, and intraoperative complications. Postoperative complications, which reached a significant difference, were observed in 34 (20.5%) octogenarians and 117 (11.2%) younger patients (p = 0.002). However, age itself was not significantly associated with postoperative fever, the most frequent postoperative complication, in multivariate analysis. Female sex, ASA score of ≥3, history of diabetes mellitus, and prolonged operative time (≥120 min) were the significant predictors of fever. The stone-free rate in the octogenarian group was superior to that in the younger patient group (80.1% vs. 70.6%, respectively; p = 0.035). CONCLUSION: Our results suggest that URS for urolithiasis can be safely and effectively applied to octogenarians in selected cases.

Extremely slow, half-number shockwave lithotripsy for ureteral stones.

To elucidate and compare the efficacy and safety of the reduced (30 shocks/min with 1200 shocks/session) and standard protocols (60 shocks/min with 2400 shocks/session) of extracorporeal shockwave lithotripsy (SWL) for ureteral stones treatment. This study was a retrospective review of 2410 SWL procedures with reduced or standard protocols (groups R and S) in 1106 patients for ureteral stones between March 2014 and March 2021. The primary outcome was treatment success, defined as the absence of residual fragments on ultrasonography and plain radiography within 30 and 90 days. A multivariate logistic regression and propensity score matching analysis evaluated the association between the reduced protocol and treatment success. This study included 311 and 544 patients in the reduced (R) and standard (S) protocol groups, respectively. The patient's characteristics were comparable, excluding the lithotripter machine. No significant difference was observed between groups R and S in treatment success rates within 30 (63.3 vs. 65.8%, p = 0.50) and 90 days (88.7 vs. 91.5%, p = 0.18). The multivariate analysis indicated no significant association between reduced protocol and treatment success within 30 and 90 days (p = 0.44 and p = 0.68, respectively). Propensity score matching showed no significant difference in the treatment success rates within 30 and 90 days. The Extremely slow, half number protocol outcomes are comparable to those of the standard protocol for treating ureteral stones.

[Risk Factors for Febrile Urinary Tract Infection after Transurethral Ureterolithotripsy : ANALYSIS of Treatment Outcomes of 1,235 Patients at a Single Center].

Recently, ureteroscopic lithotripsy remains the standard treatment for urolithiasis, with postoperative febrile upper urinary tract infection (fUTI) being one of its most significant complications. The current study sought to investigate the treatment outcomes of ureterorenoscopy (URS), morbidity and risk factors of postoperative fUTI at our hospital. A total of 1,235 patients who underwent URS (including those who underwent only semi-rigid URS) for upper urinary tract stones at our hospital between October 2011 and December 2019 were retrospectively analyzed. Patients had a median age of 63 years and a median stone length of 11.4 mm. F-URS was performed in 1,188 cases (96.2%) among whom 92.1% were stone-free or had stones that fractured into dust. Postoperative fUTI and sepsis occurred in 127 (10.3%) and 18 (1.5%) patients, respectively. Multivariate analysis identified female sex, American Society of Anesthesiologists (ASA) score ≥ 3, calculus length ≥ 20 mm, history of diabetes mellitus, and history of obstructive pyelonephritis as risk factors for postoperative fUTI. The scoring system (range 0-4) were positively correlated with the postoperative fUTI rate (score 0 : 3.1%, 1 : 12.4%, 2 : 14.1%, 3 : 23.7%, 4 : 40%). A significant difference in the rates was noted between those with a score of 0 (low-risk group), 1-2 (intermediate-risk group), and 3-4 scores (high-risk group). In conclusion, the overall incidence of postoperative fUTI was 10.3%, which was associated with sex, poor ASA scores, stone size, presence of diabetes mellitus, and history of pyelonephritis. The scoring system created using these factors can be useful in predicting postoperative fUTI.

[Renal Subcapsular Hematoma after Transurethral Ureterolithotripsy].

Subcapsular renal hematoma is a complication of extracorporeal shock wave lithotripsy or percutaneous nephrolithotripsy. Although it can occur after transurethral ureterolithotripsy (TUL), there is no consensus on the risk factors, outcomes, and its management. This study aimed to elucidate the clinical courses of patients with subcapsular hematoma after TUL. We retrospectively investigated 1,235 patients who underwent TUL from October 2011 to December 2020 at our hospital and identified cases with subcapsular hematoma diagnosed after surgery. Subcapsular hematoma was diagnosed in 5 of the 1,235 (0.40%) patients, whose median age was 63 (49-69) years. The median operation time, hematoma diameter, and hemoglobin decrease were 66 (35-115) min, 8.2 (5.4-10.5) cm, and 1.6 (0.7-2.6) g/dl, respectively. All patients were conservatively managed without invasive interventions (eg, embolization), although one patient required blood transfusion. In conclusion, this study presented five cases with renal subcapsular hematoma after TUL that could be conservatively managed. It is important not to miss the timing of therapeutic intervention while observing the progress after diagnosis.

Proteolysis of a histone acetyl reader, ATAD2, induces chemoresistance of cancer cells under severe hypoxia by inhibiting cell cycle progression in S phase.

Cancer cells acquire chemoresistance in hypoxic regions of solid tumors, which is suggested to be at least partly due to reduction of their proliferative activity. However, molecular mechanisms behind it have not been fully elucidated. Here, we revealed the importance of active proteolysis of a histone acetylation reader, ATPase family AAA domain containing 2 (ATAD2), under hypoxia. We found that inactivation of an O2/Fe2+/α-ketoglutarate-dependent dioxygenase triggered ATAD2 proteolysis by the proteasome system upon severe hypoxia in a hypoxia-inducible factors (HIFs)-independent manner. Consistently, ATAD2 expression levels were markedly lower in perinecrotic hypoxic regions in both xenografted and clinical tumor tissues. The ATAD2 proteolysis was accompanied by a decrease in the amount of acetylated histone H3 lysine 27 and inhibited cell cycle progression from the early to late S phase under severe hypoxia. The retardation of S phase progression induced chemoresistance, which was blocked by overexpression of ATAD2. Together, these results indicate that ATAD2 proteolysis upon severe hypoxia induces chemoresistance of cancer cells through heterochromatinization and the subsequent retardation of S phase progression; therefore, inhibition of ATAD2 proteolysis is expected to be a strategy to overcome chemoresistance of hypoxic tumor cells.

Computed tomography detected pyelovenous backflow associated with complete ureteral obstruction.

INTRODUCTION: Pyelovenous backflow is a rare condition resulting from an increase in pressure in the renal pelvis due to urinary obstruction. CASE PRESENTATION: A 49-year-old woman developed high-grade fever and right-sided hydronephrosis after undergoing hysterectomy. Although the hydronephrosis was mild, retrograde pyelography revealed complete obstruction of the right ureter. Excretory phase scans of contrast-enhanced computed tomography showed pyelovenous backflow, which presumably decompressed the hydronephrosis. The pyelovenous backflow immediately disappeared after ureteroneocystostomy. CONCLUSION: We were presented with a patient showing pyelovenous backflow detected by contrast-enhanced computed tomography, which completely disappeared after ureteral obstruction release.

Standardized and Simplified Retroperitoneal Lymph Node Dissection During Retroperitoneal Laparoscopic Radical Nephroureterectomy for Urothelial Carcinoma of the Upper Ureter or Renal Pelvis: En Bloc Resection Technique.

OBJECTIVE: To describe our en bloc technique of retroperitoneal lymph node dissection (RPLND) during retroperitoneal laparoscopic radical nephroureterectomy for upper urinary tract urothelial carcinoma and evaluate perioperative outcomes. METHODS: From 2002 to 2015, 114 patients with urinary tract urothelial carcinoma located at the pelvis or upper or middle ureter underwent retroperitoneal laparoscopic radical nephroureterectomy at 2 institutions. Performance of RPLND began in February 2009. The template of RPLND included the renal hilar and para-aortic lymph nodes (left side) and the renal hilar, paracaval, retrocaval, and intra-aortocaval lymph nodes (right side). After incising Gerota fascia longitudinally, the aorta (left side) or inferior vena cava (right side) was exposed, and the lymphatic and surrounding fatty tissue in the template and kidney was dissected in a single monoblock. Preoperative data were compared between the RPLND and the no-RPLND groups using propensity score matching. RESULTS: In total, 32 matched pairs were evaluated. RPLND was successfully accomplished without open conversion in all cases. The operative time in the RPLND group was approximately 100 minutes longer than that in the no-RPLND group, but there was no significant difference in the blood loss volume or complication rate. The pathologic stages were similar in both groups. The mean number of retrieved lymph nodes was 10.7 (range 3-27), and lymph node metastasis was detected in 5 (16%) cases. CONCLUSION: Retroperitoneoscopic en bloc RPLND permits complete and radical removal of the lymphatic tissue contained in the RPLND template. Our en bloc technique is a safe and feasible procedure with comparable blood loss and complication rates.

Lung metastasis of ta bladder cancer: a case report and literature review.

A 66-year-old man with a history of multiple transurethral resections for recurrent bladder tumors, staged as Ta according to the International Union Against Cancer staging guidelines, presented with a complaint of dry cough. A round nodule with a diameter of 7.5 cm was detected in the lung by chest computed tomography, and a video-assisted thoracoscopic lobectomy was performed. Pulmonary metastasis of recurrent bladder cancer was diagnosed by immunohistochemistry staining for the urothelium-specific protein uroplakin Ia. Subsequently, 2 cycles of systemic chemotherapy were administered. Two and a half years after treatment, no recurrence of pulmonary lesions has been detected. A combination of complete resection of pulmonary lesions and systemic chemotherapy may result in a good prognosis for patients with non-muscle-invasive bladder cancer.

[A case of ureteral malignant lymphoma with concentric thickening of the ureteral wall].

A 59-year-old man was referred to our hospital with right hydronephrosis, which was diagnosed from a medical examination. On imaging studies, he had concentric thickness of the right ureteral wall, and retroperitoneal and mesenteric lymphadenopathy. Urine cytology was negative, and an ureteroscopic biopsy showed no malignancy. We performed laparoscopic biopsy of the retroperitoneal lymphadenopathy, and the histopathological diagnosis was B-cell follicular lymphoma. The patient received four cycles of RCVP (rituximab, cyclophosphamide, vincristine, prednisolone) chemotherapy and four cycles of rituximab monotherapy and then he obtained complete remission. If concentric thickness of the ureteral wall is found, physicians should be aware of the possibility of malignant lymphoma and should consider laparoscopic biopsy for diagnosis.

Posterior musculofascial plate reconstruction promotes early restoration of continence and prevents severe incontinence in patients undergoing laparoscopic radical prostatectomy.

The objective of the present study was to assess the efficacy of posterior reconstruction of Denonvilliers' musculofascial plate for restoring urinary continence after laparoscopic radical prostatectomy. A total of 48 consecutive patients who underwent laparoscopic radical prostatectomy were retrospectively reviewed. Of them, 23 underwent laparoscopic radical prostatectomy without posterior reconstruction of Denonvilliers' musculofascial plate (group 1) and 25 underwent laparoscopic radical prostatectomy with posterior reconstruction of Denonvilliers' musculofascial plate (group 2). Patients' demographics were analyzed and continence rates between the two groups at 1, 3, 6 and 12 months after surgery were compared. Patients in group 2 had significantly larger prostates than in group 1. There were no significant differences between the two groups in terms of the other patient characteristics. The urinary continence rates were significantly higher in group 2 than in group 1 at 1, 3 and 12 months after surgery, and the rates of severe incontinence were significantly lower in group 2 at all time-points considered. These findings suggest that posterior reconstruction of Denonvilliers' musculofascial plate helps in restoring early continence and decreasing severe incontinence in patients undergoing laparoscopic radical prostatectomy.

Diffuse alveolar hemorrhage in lupus nephritis complicated by microscopic polyangiitis.

Diffuse alveolar hemorrhage (DAH) is a rare but fatal complication in patients with systemic lupus erythematosus (SLE). We describe a case of a 74-year-old woman who presented with DAH as an initial presentation of SLE. She also had microscopic polyangiitis clinically manifesting as crescentic glomerulonephritis and purpura with positive myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA). The patient transiently improved when treated with plasma exchange and methylprednisolone pulse therapy; however, she died of recurrent pulmonary hemorrhage and concurrent cryptococcal pneumonia. This case indicates that MPO-ANCA is associated with severe organ involvement such as pulmonary hemorrhage and crescentic glomerulonephritis in SLE.