Impacts of Complete Endophytic Renal Tumors on Surgical, Functional, and Oncological Outcomes of Robot-Assisted Partial Nephrectomy.

Objective: Complete endophytic renal tumors (CERTs) are the most challenging for robot-assisted partial nephrectomy (RAPN). This study aimed to determine the impact of CERT on outcomes of RAPN. Methods: All RAPN cases for localized renal tumor undertaken at Yokohama City University Hospital between 2016 and 2023 were enrolled. Tumor characteristics and surgical, functional, and oncologic outcomes of RAPN were compared between CERT and non-CERT groups. Results: Consecutive 666 patients were enrolled, and 76 (11.4%) were identified as CERT (3 points of "E" score). CERT showed smaller tumor diameters (p < 0.001), more predominant hilar tumor (p = 0.029), higher "N" scores (p < 0.001) and "L" scores (p = 0.006) than non-CERT. The CERT group showed longer warm ischemia times (p < 0.001), more frequent positive surgical margins (p = 0.028), and relatively lower trifecta achievement rates (p = 0.101) than the non-CERT group. In multivariable analysis, the CERT was an independent predictor for trifecta achievement but not for pentafecta achievement. Conclusions: CERT was associated with longer warm ischemia time, positive surgical margin, and lower trifecta achievement, but not with surgical complication and pentafecta achievement in RAPN. This study suggested that CERT had limited influence on long-term renal functional preservation; however, it had strong impacts on short-term surgical outcome.

Predictive factors for pentafecta achievement in robot-assisted partial nephrectomy for intermediate highly complex RENAL tumors (RENAL score ≥ 7).

OBJECTIVES: To investigate the predictive factors for pentafecta achievement of robot-assisted partial nephrectomy (RAPN) for intermediate highly complex renal tumors (RENAL score ≥ 7). METHODS: We retrospectively analyzed the data of 247 patients with renal tumors with a RENAL score ≥ 7 who underwent RAPN. Baseline characteristics and perioperative outcomes were compared between the pentafecta achieved group and the unachieved group. A multivariable logistic regression model was used to identify the predictive factors for pentafecta achievement for cT1 renal tumors with a RENAL score ≥ 7. RESULTS: Of the 247 patients, 75 (30.3%) patients were in the achieved group and 172 (69.7%) patients were in the unachieved group. The median warm ischemia time and total operation time were 18 min versus 23 min (p < 0.001) and 179 min versus 201 min (p < 0.001) in the achieved and unachieved groups, respectively. In the unachieved group, six patients (3.4%) had major perioperative complications (Clavien-Dindo classification system ≥3). The median preservation rates of estimated GFR at the 1-year postoperative period were 96.5% versus 83.0% (p < 0.001) in the achieved and unachieved groups. Multivariable logistic regression models revealed that age and tumor size were independent predictive factors for pentafecta achievement for cT1 renal tumors with a RENAL score ≥ 7. There were no significant differences in cancer-free survival between the two groups (p = 0.456). CONCLUSION: Age and tumor size were independent predictive factors for pentafecta achievement, although there was no difference in oncological outcomes between the pentafecta achieved group and the unachieved group in RAPN for cT1 renal tumors with a RENAL score ≥ 7.

[A Case of Long-Term Survival Following Multidisciplinary Therapy for Small Intestinal Metastasis of Bladder Cancer].

The patient was a 70-year-old man who underwent transurethral resection of a bladder tumor. The pathological diagnosis was urothelial carcinoma (UC) with sarcomatoid variant, ≧pT2. After neoadjuvant chemotherapy using gemcitabine and cisplatin (GC), radical cystectomy was performed. The histopathological diagnosis was no tumor remnant (ypT0ypN0). Seven months later, the patient underwent an emergency partial ileectomy for ileal occlusion, after sudden complaints of vomiting and abdominal pain and fullness. Postoperatively, two cycles of adjuvant GC chemotherapy were administered. Approximately 10 months after ileal metastasis, a mesenteric tumor appeared. After seven cycles of methotrexate/epirubicin/nedaplatin and 32 cycles of pembrolizumab therapy, the mesentery was resected. The pathological diagnosis was UC with sarcomatoid variant. No recurrence was noted for 2 years after resection of the mesentery.

Diagnosis of Peripheral Facial Palsy Associated with Parvovirus B19 Infection by Polymerase Chain Reaction.

Human parvovirus B19 (PVB19) infection causes neurological manifestations, including encephalitis, meningitis, and neuropathy, but facial nerve palsy is rare. Moreover, no case of facial nerve palsy related to PVB19 infection that was diagnosed by PCR and serology has been reported. A 19-month-old boy without the medical history developed facial nerve palsy and was treated with prednisolone and valacyclovir. On the 19th day, erythema appeared on his body, and the PVB19-specific IgM and PVB19 DNA were detected in the serum, leading to the diagnosis of infectious erythema associated with PVB19 infection. This case indicates that PVB19 may be one of the causative agents of facial nerve palsy.

[Malignant Peritoneal Mesothelioma Diagnosed as an Inguinal Mass : A Case Report].

Malignant peritoneal mesothelioma is generally characterized by chief complaints such as abdominal mass and abdominal pain. We report a case of malignant peritoneal mesothelioma diagnosed as an inguinal mass. A 69-year-old man was referred to our hospital complaining of abdominal distension and swelling in the right inguinal region. Abdominal/pelvic contrast-enhanced computed tomography revealed a 22 cm tumor from the right inguinal canal to the peritoneal cavity and a large amount of ascites. Because imaging analyses revealed no metastasis, we planned tumor resection. We resected the tumor with the peritoneum and right testis and sampled some nodules in the mesentery. Histopathological examination of the tumor led to the diagnosis of epithelial malignant mesothelioma. Adhering to chemotherapy guidelines for pleural malignant mesothelioma, six courses of pemetrexed and cisplatin combination chemotherapy were performed. He is alive with no evidence of new local tumor or nodules in the mesentery 1 year postoperatively.

Behavioral profile in a Dctn1G71A knock-in mouse model of Perry disease.

Perry disease (Perry syndrome) is a rare, rapidly progressive, autosomal dominant neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and respiratory symptoms including central hypoventilation. It is caused by missense mutations (e.g. p.G71A) in the DCTN1 gene. We previously generated transgenic mice that expressed human DCTN1G71A mutant protein under the control of Thy1 promoter. These mice exhibited apathy-like behavior and parkinsonism. However, it is possible that this phenotype was due to a gene-dosage imbalance or transgene insertion position. To circumvent these potential caveats, we have generated a knock-in mouse model carrying a p.G71A mutation in Dctn1. Heterozygous Dctn1G71A and wild-type littermates were subjected to a battery of behavioral analyses. Furthermore, immunohistochemistry for tyrosine hydroxylase (TH) was performed on brain sections of these mice, and TH signal intensity in substantia nigral neurons was quantified. Dctn1G71A mice were immobile for longer than wild-type mice of the same age and sex in the tail-suspension test, revealing depressive characteristics. In addition, the beam-walking test and pole test detected motor deficits in Dctn1G71A female mice. Finally, immunostaining revealed a decrease in TH immunoreactivity in neurons of the substantia nigra in the Dctn1G71A mice. Collectively, heterozygous Dctn1G71A mice showed depression-like behavior, motor deficits, and a functional reduction in substantia nigral neurons, as judged by TH immunostaining, thereby exhibiting multiple features of Perry disease. Hence, this mouse model will be useful in elucidating pathological mechanisms of Perry disease and for developing novel therapeutic strategies against it.

CLP290 promotes the sedative effects of midazolam in neonatal rats in a KCC2-dependent manner: A laboratory study in rats.

Immature neurons dominantly express the Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) rather than the K+-Cl- cotransporter isoform 2 (KCC2). The intracellular chloride ion concentration ([Cl-]i) is higher in immature neurons than in mature neurons; therefore, γ-aminobutyric acid type A (GABAA) receptor activation in immature neurons does not cause chloride ion influx and subsequent hyperpolarization. In our previous work, we found that midazolam, benzodiazepine receptor agonist, causes less sedation in neonatal rats compared to adult rats and that NKCC1 blockade by bumetanide enhances the midazolam-induced sedation in neonatal, but not in adult, rats. These results suggest that GABA receptor activation requires the predominance of KCC2 over NKCC1 to exert sedative effects. In this study, we focused on CLP290, a novel KCC2-selective activator, and found that midazolam administration at 20 mg/kg after oral CLP290 intake significantly prolonged the righting reflex latency even in neonatal rats at postnatal day 7. By contrast, CLP290 alone did not exert sedative effects. Immunohistochemistry showed that midazolam combined with CLP290 decreased the number of phosphorylated cAMP response element-binding protein-positive cells in the cerebral cortex, suggesting that CLP290 reverted the inhibitory effect of midazolam. Moreover, the sedative effect of combined CLP290 and midazolam treatment was inhibited by the administration of the KCC2-selective inhibitor VU0463271, suggesting indirectly that the sedation-promoting effect of CLP290 was mediated by KCC2 activation. To our knowledge, this study is the first report showing the sedation-promoting effect of CLP290 in neonates and providing behavioral and histological evidence that CLP290 reverted the sedative effect of GABAergic drugs through the activation of KCC2. Our data suggest that the clinical application of CLP290 may provide a breakthrough in terms of midazolam-resistant sedation.

Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants.

BACKGROUND: Germline heterozygous mutations in human signal transducer and activator of transcription 1 (STAT1) can cause loss of function (LOF), as in patients with Mendelian susceptibility to mycobacterial diseases, or gain of function (GOF), as in patients with chronic mucocutaneous candidiasis. LOF and GOF mutations are equally rare and can affect the same domains of STAT1, especially the coiled-coil domain (CCD) and DNA-binding domain (DBD). Moreover, 6% of patients with chronic mucocutaneous candidiasis with a GOF STAT1 mutation have mycobacterial disease, obscuring the functional significance of the identified STAT1 mutations. Current computational approaches, such as combined annotation-dependent depletion, do not distinguish LOF and GOF variants. OBJECTIVE: We estimated variations in the CCD/DBD of STAT1. METHODS: We mutagenized 342 individual wild-type amino acids in the CCD/DBD (45.6% of full-length STAT1) to alanine and tested the mutants for STAT1 transcriptional activity. RESULTS: Of these 342 mutants, 201 were neutral, 30 were LOF, and 111 were GOF mutations in a luciferase assay. This assay system correctly estimated all previously reported LOF mutations (100%) and slightly fewer GOF mutations (78.1%) in the CCD/DBD of STAT1. We found that GOF alanine mutants occurred at the interface of the antiparallel STAT1 dimer, suggesting that they destabilize this dimer. This assay also precisely predicted the effect of 2 hypomorphic and dominant negative mutations, E157K and G250E, in the CCD of STAT1 that we found in 2 unrelated patients with Mendelian susceptibility to mycobacterial diseases. CONCLUSION: The systematic alanine-scanning assay is a useful tool to estimate the GOF or LOF status and the effect of heterozygous missense mutations in STAT1 identified in patients with severe infectious diseases, including mycobacterial and fungal diseases.

A preliminary study on the influence of obstructive sleep apnea upon cumulative parasympathetic system activity.

OBJECTIVE: Although the autonomic nervous system plays a key role in mediating cardiovascular changes during obstructive sleep apnea (OSA), parasympathetic nervous system (PNS) activity during sleep apnea has not yet been sufficiently investigated. This study is to discuss the relationship between PNS activity and OSA. METHODS: Polysomnography recording was carried out in 76 patients (71 male and 5 female) with OSA. Cumulative PNS activity during sleep for each patient was derived from time series data of electrocardiogram (ECG) and analyzed by coarse graining spectral analysis of heart rate variability. The correlation between cumulative PNS activity and apnea-hypopnea index (AHI) was then discussed. RESULTS: Cumulative PNS activity and PNS peaks during sleep were lowly but significantly correlated with OSA severity (r=-0.344, p<0.005; and r=-0.266, p<0.05 respectively), and a linear regression equation could be established. Furthermore, significant correlation was also observed in the adult groups and in the moderate and severe groups, but not in the juvenile and the elderly and mild groups. CONCLUSION: These findings indicated that PNS function was obviously influenced by OSA during sleep. Cumulative PNS activity level might also serve as a useful parameter for the evaluation of OSA.