Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration.

Vacuolar protein sorting 35 (VPS35), the core component of the retromer complex which regulates endosomal trafficking, is genetically linked with Parkinson's disease (PD). Impaired vision is a common non-motor manifestation of PD. Here, we show mouse retinas with VPS35-deficient rods exhibit synapse loss and visual deficit, followed by progressive degeneration concomitant with the emergence of Lewy body-like inclusions and phospho-α-synuclein (P-αSyn) aggregation. Ultrastructural analyses reveal VPS35-deficient rods accumulate aggregates in late endosomes, deposited as lipofuscins bound to P-αSyn. Mechanistically, we uncover a protein network of VPS35 and its interaction with HSC70. VPS35 deficiency promotes sequestration of HSC70 and P-αSyn aggregation in late endosomes. Microglia which engulf lipofuscins and P-αSyn aggregates are activated, displaying autofluorescence, observed as bright dots in fundus imaging of live animals, coinciding with pathology onset and progression. The Rod∆Vps35 mouse line is a valuable tool for further mechanistic investigation of αSyn lesions and retinal degenerative diseases.

Safety of Endoscopic Surgery for Spontaneous Intracerebral Hemorrhage in the Registry of Intracerebral Hemorrhage Treated by Endoscopic Hematoma Evacuation in Japan.

OBJECTIVE: The long history of treatment for intracerebral hemorrhage (ICH) includes the development of surgical procedures. However, few studies have demonstrated that surgery improved the functional outcome. The present study used the prospective Registry of Intracerebral hemorrhage treated by endoscopic hematoma evacuation of the outcomes in endoscopic surgery, which is widely followed in Japan, to try to establish clinical evidence. METHODS: The Registry of Intracerebral hemorrhage treated by endoscopic hematoma evacuation is a multicenter, prospective registry in Japan, and included 143 surgical cases treated by certified neurosurgeons. The etiology and the location of ICH was evaluated by univariate and multivariate analyses as follows: deep, surface, intraventricular hemorrhage, cerebellum, and surgical outcome. RESULTS: Hematoma location was deep in 44.8% of cases, intraventricular hemorrhage in 19.6%, surface in 21.7%, and cerebellum in 14.0%. Most cases were treated in the ultraearly stage within 8 hours. Mean hematoma evacuation rate was 83.6% and median residual hematoma volume was 3.0 ml. Duration of surgery was median 78 minutes. Rebleeding as a complication was observed in 6.7%, but only 2.9% were symptomatic. 2 cases required reoperation. Favorable outcome at 6 months was achieved in 35.8% of cases, with a mortality rate of 5.6%. CONCLUSIONS: Endoscopic surgery for spontaneous ICH is safe and comparable to conventional surgery. The time required for the procedure was significantly reduced, demonstrating the minimally invasive character of the surgical burden. However, this study did not establish whether minimally invasive surgery is superior to conservative treatment. Future randomized controlled trials should clarify the effectiveness of the treatment.

Predictors of surgical difficulty according to surgical proficiency in robot-assisted radical prostatectomy.

BACKGROUND: Robot-assisted radical prostatectomy (RARP) is a standard treatment for localized prostate cancer. We previously reported that a large amount of pelvic visceral fat and a small working space, as measured by three-dimensional image analysis, were significantly associated with prolonged console time in RARP, and these factors could be alternatives to the more clinically practical body mass index (BMI) and pelvic width (PW), respectively. Herein, we further investigated whether surgical proficiency affected surgical difficulty as measured by console time. METHODS: Medical records of 413 patients who underwent RARP between 2014 and 2020 at our institution were reviewed. Surgeons who had experience with over and under 100 cases were defined as "experienced" and "non-experienced," respectively. Multivariate logistic regression analyses were performed to identify factors that prolonged console time. RESULTS: The median console times for RARP by experienced and non-experienced surgeons were 87.5 and 149.0 min, respectively; a difficult case was defined as one requiring time greater than the median. Among inexperienced surgeons, higher BMI (p < 0.001, odds ratio: 1.89) and smaller PW (p = 0.001, odds ratio: 1.86) were significant factors that increased console time; the complication rate was increased in patients with these factors. However, these factors did not significantly affect the console time or complication rate among experienced surgeons. CONCLUSION: This study demonstrates that experienced surgeons may be able to overcome obesity- and small workspace-related surgical difficulties. The current analysis may provide useful information regarding unpredictable surgical risks and identify suitable cases for novices.

A case report of a 5 mm port site hernia that occurred at the drain insertion site after laparoscopic right nephrectomy.

A 5 mm port site hernia during laparoscopic surgery is rarer than a 12 mm port site hernia. Here, we report the case of a 5 mm port site hernia in an 85-year-old woman who underwent long-term steroid therapy and laparoscopic right nephrectomy. There was also a hernia at the port site where the drain was placed. Due to the 5 mm port at the drain removal site, fascial suturing was impossible after removal of the drain, and countermeasures were difficult. However, we believe that patients at a higher risk of port need suturing wound patients like this and should be carefully observed.

Transcatheter renal arterial embolization for intractable urinary fistula occurring after robot-assisted partial nephrectomy: a case report.

Partial nephrectomy is the standard surgical procedure for small renal tumors. Since the advent of robot-assisted partial nephrectomy (RAPN), the number of cases of renal tumors undergoing the procedure has increased exponentially. Urinary fistula is a complication of partial nephrectomy. Conservative management using ureteral stents is useful in most cases of urinary fistulas. However, some patients develop intractable urinary fistulas. Herein, we report a case in which vascular embolization was useful for treating an infected and intractable urinary fistula that developed after RAPN. A 59-year-old man was accidentally found to have a right renal tumor (approximately 3 cm in diameter) during a physical examination. Pathology was clear cell carcinoma. RAPN was performed owing to the small size of the renal tumor; however, postoperatively, an intractable urinary fistula with an isolated calyx developed, which was successfully treated with transcatheter renal arterial embolization (TAE). We encountered a rare case of infected refractory urinary fistula with an isolated calyx in which TAE was successful. TAE seems useful in treating intractable urinary fistulas with an isolated calyx occurring after RAPN.

Robot-assisted radical prostatectomy in a patient with prostate cancer complicated by benign prostate hypertrophy with middle lobe hypertrophy.

Robot-assisted radical prostatectomy (RARP) is difficult in patients with benign prostatic hyperplasia (BPH), a condition causing frequent urination, because of the large prostate volume and particularly true when BPH is accompanied by an enlarged middle lobe. To overcome this difficulty, some surgeons elevate the middle lobe with a third arm or tow the urethral catheter to the edge to identify the resection line. Herein, we describe a method for lifting a prostate with an enlarged middle lobe, which was successfully applied in a patient with prostate cancer and BPH. This technique can help identify the resection line between the bladder and prostate, reducing surgical difficulty and the number of unnecessary sutures.

Patient with Diffuse Midline Glioma, H3 K27-altered, Carrying an FGFR1 Mutation Who Experienced Thalamic Hemorrhage: A Case Report and Literature Review.

Diffuse midline glioma (DMG), H3 K27M-altered, is a tumor with a poor prognosis mainly found in children. An adolescent patient presented with thalamic hemorrhage, which initially could not be diagnosed as DMG by pathological analysis. A neoplasm in the lateral ventricle close to the previous thalamic hemorrhagic lesion was detected 12 months after the hemorrhage. Thus, endoscopic resection was performed, and a diagnosis was made. Gene expression profiling demonstrated mutation in genes, such as H3F3A and FGFR1. FGFR1 mutation was associated with intratumoral hemorrhage in low-grade gliomas and contributed to longer survival than wild-type FGFR1 in DMG H3K27M. Our findings suggest that patients with DMG, H3 K27-altered, with FGFR1 mutation may be predisposed to intratumoral hemorrhaging and/or have a longer survival time than patients without FGFR1 mutation.

Two Cases of Intractable Radiation-Induced Hemorrhagic Cystitis Treated with Transcatheter Embolization.

Radiation-induced hemorrhagic cystitis is a late complication of radiotherapy, and in rare cases, refractory. Refractory bleeding may not be resolved by transurethral electrocoagulation (TUEC) or hyperbaric oxygen (HBO) therapy and requires transcatheter arterial embolization (TAE) or urinary diversion. Here, we report two cases of radiation-induced hemorrhagic cystitis successfully treated with TAE. Case 1 was a 61-yearold man who underwent total prostatectomy for prostate cancer followed by salvage radiation therapy. The patient developed radiation-induced hemorrhagic cystitis 2 years and 3 months after radiotherapy. After no improvement with TUEC and HBO, TAE was performed. Case 2 was a 78-year-old man who underwent total prostatectomy followed by salvage radiation therapy and developed radiation-induced hemorrhagic cystitis 12 years later. TAE was performed after no improvement with HBO. TAE proved successful in both patients, and there was no relapse. TAE is a potential treatment option for refractory radiation-induced hemorrhagic cystitis.

Current status and future outlook of ultrasound treatment for prostate cancer.

Radical prostatectomy and radiation therapy are the standard treatment options for localized prostate cancer (PC). However, radical prostatectomy may cause the deterioration of urinary and sexual function, and radiation-induced hemorrhagic cystitis and severe rectal bleeding are risk factors for fatal conditions in patients after radiation therapy. With the recent development of magnetic resonance imaging (MRI) for the localization of clinically significant PC (csPC) and treatment modalities, "focal therapy", which cures csPC while preserving anatomical structures related to urinary and sexual functions, has become a minimally invasive treatment for localized PC. Based on the clinical results of transrectal high-intensity focused ultrasound (HIFU) for localized PC in the whole gland and focal therapy, HIFU is considered an attractive treatment option for focal therapy. Recently, the short-term clinical results of transurethral high-intensity directional ultrasound (HIDU) have been reported. With the resolution of some issues, HIDU may be commonly used for PC treatment similar to HIFU. Because HIFU and HIDU have limitations regarding the treatment of patients with large prostate calcifications and large prostate volumes, the proper use of these modalities will enable the treatment of any target area in the prostate. To establish a standard treatment strategy for localized PC, pair-matched and historically controlled studies are required to verify the oncological and functional outcomes of ultrasound treatment for patients with localized PC.

Differentiation Capacity of Porcine Skeletal Muscle-Derived Stem Cells as Intermediate Species between Mice and Humans.

Large animal experiments are important for preclinical studies of regenerative stem cell transplantation therapy. Therefore, we investigated the differentiation capacity of pig skeletal muscle-derived stem cells (Sk-MSCs) as an intermediate model between mice and humans for nerve muscle regenerative therapy. Enzymatically extracted cells were obtained from green-fluorescence transgenic micro-mini pigs (GFP-Tg MMP) and sorted as CD34+/45- (Sk-34) and CD34-/45-/29+ (Sk-DN) fractions. The ability to differentiate into skeletal muscle, peripheral nerve, and vascular cell lineages was examined via in vitro cell culture and in vivo cell transplantation into the damaged tibialis anterior muscle and sciatic nerves of nude mice and rats. Protein and mRNA levels were analyzed using RT-PCR, immunohistochemistry, and immunoelectron microscopy. The myogenic potential, which was tested by Pax7 and MyoD expression and the formation of muscle fibers, was higher in Sk-DN cells than in Sk-34 cells but remained weak in the latter. In contrast, the capacity to differentiate into peripheral nerve and vascular cell lineages was significantly stronger in Sk-34 cells. In particular, Sk-DN cells did not engraft to the damaged nerve, whereas Sk-34 cells showed active engraftment and differentiation into perineurial/endoneurial cells, endothelial cells, and vascular smooth muscle cells, similar to the human case, as previously reported. Therefore, we concluded that Sk-34 and Sk-DN cells in pigs are closer to those in humans than to those in mice.

A case of post-BCG therapy renal granuloma concurrent with ureteral carcinoma.

Intravesical administration of Bacillus Calmette-Guerin (BCG) is recommended to reduce the risk of recurrence or progression of carcinoma in situ, stage Ta tumors of high grade, or stage T1 tumors. Renal complications following intravesical BCG therapy are rare. The mechanism of renal granuloma formation may be related to vesicoureteral reflux. Vesicoureteral reflux after transurethral resection of bladder tumors (TURBT) has been reported to be higher when the tumor is located near the ureteral orifice. Herein, we report a case of a renal granuloma after BCG therapy with concurrent ipsilateral urethral carcinoma.

Features of postoperative hearing function changes in patients with cerebellopontine angle and intratemporal tumors other than vestibular schwannomas.

OBJECTIVE: Tumors around the cerebellopontine angle (CPA) and temporal bone can potentially affect hearing function. In patients with such tumors other than vestibular schwannomas (VSs), auditory tests were investigated before and after surgery to characterize the auditory effect of each tumor and to determine prognostic factors. METHODS: A total of 378 patients were retrospectively evaluated for hearing functions before and after surgery. These 378 patients included 168 with CPA meningioma, 40 with trigeminal schwannoma (TS), 55 with facial nerve schwannoma (FNS), 64 with jugular foramen schwannoma (JFS), and 51 with CPA epidermoid cyst (EPD). RESULTS: Preoperative hearing loss was observed in 124 (33%) of the 378 patients. Of these 124 patients, 38 (31%) experienced postoperative hearing improvement. Postoperative hearing deterioration occurred in 67 (18%) of the 378 patients. The prognostic factors for postoperative hearing improvement were younger age and the retrocochlear type of preoperative hearing disturbance. Tumor extension into the internal auditory canal was correlated with preoperative hearing loss and postoperative hearing deterioration. Preoperative hearing loss was observed in patients with FNS (51%), JFS (42%), and MGM (37%), and postoperative hearing improvement was observed in patients with JFS (41%), MGM (31%), and FNS (21%). Postoperative hearing deterioration was observed in patients with FNS (27%), MGM (23%), and EPD (16%). CONCLUSIONS: According to the results of this study in patients with CPA and intratemporal tumors other than VS, preoperative retrocochlear hearing disturbance was found to be a prognostic factor for hearing improvement after surgery. Among the tumor types, JFS and MGM had a particularly favorable hearing prognosis. The translabyrinthine approach and cochlear nerve section should be avoided for these tumors, regardless of the patient's preoperative hearing level.

Resection of petroclival clear cell meningioma by the anterior transpetrosal approach: diagnosis of rare pathology and improvement of preoperative hearing disturbance.

Clear cell meningioma is a rare histological variant of meningioma, which often recurs aggressively. This video demonstrates a patient with a petroclival clear cell meningioma, which was resected completely through the anterior transpetrosal approach. The absence of intratumoral spotty signal voids on preoperative susceptibility-weighted imaging (SWI) suggested that the tumor was a meningioma rather than a schwannoma, although typical imaging features of meningioma were not observed. After surgery, the patient's preoperative hearing disturbance improved from class D to class A, which the authors had sometimes experienced in cerebellopontine angle meningioma surgeries. Careful observation over a 2.5-year period revealed no tumor recurrence, without additional treatment. The video can be found here: https://stream.cadmore.media/r10.3171/2022.1.FOCVID21219.

Pediatric vestibular schwannoma without evidence of neurofibromatosis: consecutive 18 microsurgical experiences.

PURPOSE: Sporadic vestibular schwannoma (VS) is rare in children in contrast to adults, and detailed investigations of case series of these patients using a single fixed protocol are scarce. This study presents our surgical experience of pediatric VSs without clinical evidence of neurofibromatosis type 2 (NF2) at the initial diagnosis. METHODS: Among 1385 consecutive sporadic VS surgeries, 18 pediatric patients (1.3%; 11-18 years old) were retrospectively investigated. RESULTS: The most common initial symptom was hearing disturbance (72.2%), and 6 patients (33.3%) experienced a delayed diagnosis (over 2 years after initial symptom onset). Preoperative image characteristics of these tumors included a solid tumor, hypervascularity, and significant extension into the internal acoustic meatus, when compared with adults. Preoperative embolization was successfully accomplished for 2 recent hypervascular tumors. The tumor resection rate was 95-100% under sufficient intraoperative neuromonitoring, and no additional surgery was required during the follow-up period (average: 57.9 months). No patients experienced permanent facial nerve palsy, and serviceable hearing function was preserved in 6 of 11 patients. Signs of NF2, such as bilateral VSs, were not identified in any patients during the follow-up. CONCLUSION: Safe and sufficient tumor resection was achieved under detailed neuromonitoring in pediatric patients with sporadic VS, although this tends to be difficult owing to hypervascularity, a small cranium, and significant meatal extension. Preoperative embolization may help safe resection of hypervascular tumors. Subsequent development of NF2 has not been observed up to the most recent follow-up, but careful observation is essential for these younger patients.

Risk factors for recurrence after operation in patients with pT1a renal cell carcinoma: sub-analysis of the multi-institutional national database of the Japanese Urological Association.

BACKGROUND: More patients with renal cell carcinoma are now diagnosed with the disease in its early stages. Although patients with pT1a renal cell carcinoma have a good prognosis and low recurrence rate, a few patients still experience recurrence. Herein, we evaluated the clinicopathological risk factors for postoperative recurrence of pT1aN0M0 renal cell carcinoma. METHODS: An renal cell carcinoma survey was conducted by the Japanese Urological Association to register newly diagnosed cases of renal cell carcinoma. A total of 1418 patients diagnosed with pT1aN0M0 renal cell carcinoma who underwent surgery as the primary surgical treatment were included. We analyzed the recurrence-free survival using the Kaplan-Meier method and clinicopathological factors for recurrence using Cox proportional hazards models. RESULTS: Among 1418 patients, 58 (4.1%) had recurrences after a median follow-up of 62.8 months. The median time to recurrence was 31.0 months. Metastases to the lungs and the bone were observed in 20 and 10 cases, respectively. Significant differences in sex, tumor size, Eastern Cooperative Oncology Group performance status, and dialysis history, preoperative hemoglobin levels, C-reactive protein levels and creatinine levels were observed between the recurrence and non-recurrence groups. Multivariate analysis identified male sex, high C-reactive protein level and tumor size ≥3 cm as independent risk factors. The 5-year recurrence-free survival of patients with 0, 1, 2 and 3 risk factors was 99.0, 97.2, 93.1 and 80.7%, respectively. CONCLUSIONS: Male sex, tumor diameter and a high C-reactive protein level were independent recurrence risk factors for pT1a renal cell carcinoma; special attention should be paid to patients with these risk factors during postoperative follow-up.

Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Dry AMD has unclear etiology and no treatment. Lipid-rich drusen are the hallmark of dry AMD. An AMD mouse model and insights into drusenogenesis are keys to better understanding of this disease. Chloride intracellular channel 4 (CLIC4) is a pleomorphic protein regulating diverse biological functions. Here we show that retinal pigment epithelium (RPE)-specific Clic4 knockout mice exhibit a full spectrum of functional and pathological hallmarks of dry AMD. Multidisciplinary longitudinal studies of disease progression in these mice support a mechanistic model that links RPE cell-autonomous aberrant lipid metabolism and transport to drusen formation.

Preoperative Facial Nerve Palsy in Patients With Vestibular Schwannoma: Clinical Features and Postoperative Functional Prognosis in a Case Series of 34 Among 1228 Consecutive Patients.

BACKGROUND: Facial nerve palsy is a rare presenting symptom of vestibular schwannomas and has not been investigated in detail. OBJECTIVE: To investigate the incidence, clinical features, and postoperative long-term outcomes of facial nerve function in patients with vestibular schwannomas causing preoperative facial nerve palsy. METHODS: After excluding patients with neurofibromatosis type 2 and those with prior treatment, 1228 consecutive patients who underwent vestibular schwannoma surgery were retrospectively investigated. Patients with and without preoperative facial nerve palsy were compared statistically to clarify their clinical features. RESULTS: Preoperative tumoral facial nerve palsy was seen in 34 patients (2.8%). Their clinical features included older age, having large cystic tumors with significant meatal extension, and showing abnormal electrogustometric responses, compared with patients without preoperative facial nerve palsy. Owing to the frequent insufficient intraoperative responses on facial nerve electromyography, the tumor resection rate was lower in the group with preoperative facial nerve palsy (mean: 95.2%). Among the 33 patients with sufficient follow-up data (mean: 63.9 mo), additional treatment was required only in 1 patient and facial nerve function improved in 25 patients (75.8%) within 2 yr postoperatively. CONCLUSION: Facial nerve palsy is a rare preoperative symptom that occurs in less than 3% of patients with vestibular schwannoma. Tumor resection in such patients tends to be challenging owing to their advanced age, having large cystic tumors with significant meatal extension, and difficulties in intraoperative facial nerve monitoring, but surgical decompression of the facial nerve can assist in the improvement of their long-term functions.

Intraoperative Continuous Neuromonitoring for Vestibular Schwannoma Surgery: Real-Time, Quantitative, and Functional Evaluation.

In vestibular schwannoma surgery, neuromonitoring is essential to accomplish sufficient tumor resection while avoiding neurologic damage.1-3 An ideal neuromonitoring method should include a real-time alert system, quantitative evaluation, and functional (not mechanical) assessment.4Video 1 demonstrates facial and hearing preservation surgery for vestibular schwannoma by the retrosigmoid transmeatal approach, under intraoperative continuous facial nerve monitoring and auditory brainstem response. Using a ball-type stimulating electrode placed on the proximal facial nerve, the evoked facial nerve electromyograms were continuously monitored by direct 1-Hz stimulation throughout the near-total tumor resection. The patient had no postoperative facial or hearing deterioration. The patient consented to the procedure before the surgery.

Effects of psoas major muscle volume in predicting the prognosis of patients with upper urinary tract urothelial carcinoma treated with radical nephroureterectomy.

BACKGROUND: This study evaluated the impact of sarcopenia and psoas major muscle volume on the survival of patients with upper urinary tract urothelial carcinoma who had undergone radical nephroureterectomy. METHODS: We reviewed data from 110 patients treated with radical nephroureterectomy in our department between June 2007 and February 2017. Psoas major muscle volume was quantified based on computed tomography data using Synapse Vincent software. The psoas major muscle volume index was calculated as psoas major muscle volume/height squared (cm3/m2). We analysed relapse-free survival, cancer-specific survival and overall survival after radical nephroureterectomy to identify factors that predicted patient survival. RESULTS: The median psoas major muscle volume index was 121.5 cm3/m2, and the psoas major muscle volume index was <100 cm3/m2 in 34 of 110 patients (30.9%). Multivariate analysis indicated that ≥pT3-stage cancer, lymphovascular invasion and a psoas major muscle volume index of <100 cm3/m2 were independent predictors of shorter relapse-free survival, cancer-specific survival and overall survival. Using these factors, patients were stratified into three groups: low, intermediate and high risks for relapse-free survival, cancer-specific survival and overall survival. CONCLUSIONS: Low psoas major muscle volume resulting from sarcopenia, high T stage and the presence of lymphovascular invasion was associated with poor survival in patients with urinary tract urothelial carcinoma who had undergone radical nephroureterectomy, supporting the use of psoas major muscle volume as a new objective prognostic marker.