Comparison of Oncological Outcomes between Transperitoneal and Retroperitoneal Approaches in Laparoscopic Nephroureterectomies for Upper Tract Urothelial Carcinoma.

Background and Objectives: Our aim was to clarify the oncological outcomes of the two different approaches to laparoscopic nephroureterectomies (LNUs) in Japan, and to examine whether there were any significant differences between the transperitoneal approach and the retroperitoneal approach. Materials and Methods: We retrospectively evaluated patients who underwent an LNU for upper tract urothelial carcinoma (UTUC) from January 2013 to December 2022. We identified 52 patients who underwent a transperitoneal LNU (tLNU) and 93 who underwent a retroperitoneal LNU (rLNU). We adopted age, smoking, and pT-stage matching, and 43 patients were classified in each group. We investigated the time from surgery to recurrence (RFS: recurrence-free survival), the time to death (OS: overall survival), and the time to non-urothelial-tract recurrence-free survival (NUTRFS). A Cox regression analysis was performed to evaluate the risk factors that influenced recurrence. Results: There were no significant differences in the RFS, OS, and NUTRFS between the two matched groups. In the multivariate Cox regression analysis, the pT stage (pT3≥ vs. pT2≤) had an HR = 2.09 and a p = 0.01, and was an independent prognostic risk factor regarding cancer recurrence. Conclusions: There were no significant differences in the oncological outcomes between the tLNU and rLNU groups. It is suggested that the transperitoneal approach should be selected for LNUs.

High species diversity of Phintella and Phintella-like spiders (Araneae: Salticidae) in Vietnam revealed by DNA-based species delimitation analyses.

Salticidae (jumping spiders) usually exhibit pronounced sexual dimorphism in adult morphology, particularly body coloration and size and shape of the first legs. Consequently, the male and female from the same species might be erroneously assigned to different species or even different genera, which could generate synonymies in classification if only morphological data were used. Phintella is a species-rich genus of Salticidae, which currently exhibits 76 named species. However, the male-female counterpart is unknown for nearly half of the species. In this study, we used a molecular approach to delineate the species boundaries for Phintella and Phintella-like specimens collected in Vietnam, using morphological information as supporting data. We used three gene fragments (mitochondrial COI, 16S-ND1, and nuclear 28S) and biogeographical considerations for species delimitation. A total of 22 putative species were recognized: 18 species of the genus Phintella, one species of the genus Lechia (L. squamata), and three species of the genus Phinteloides. Eleven undescribed species were discovered, of which seven have a male-female combination, two species have only males, and two species have only females. The crown age of Phintella was estimated at the Serravallian stage of the Miocene after the increase of species number around 16 MYA. The crown ages of most putative species recognized in this study were estimated in the Pleistocene, and the divergence among sister species likely occurred from the mid-Miocene to the Pliocene. Our ancestral range reconstruction results showed that the diversification of our ingroup was governed by progressive dispersal events, i.e., Phintella and their related species in Vietnam diversified while expanding their range on the continent. Our results provide fundamental biodiversity data for a high-diversity genus in Vietnamese Phintella spiders.

New-onset Kidney Biopsy-proven Membranous Nephropathy Induced End-stage Kidney Disease in a Living Donor: A Case Report.

Thirteen years after kidney donation, a 70-year-old man was referred to a nephrologist because of proteinuria. The serum creatinine, albumin, and urinary protein levels were 2.39 mg/dL, 3.0 g/dL, and 6.72 g/gCr, respectively. A kidney biopsy revealed thickening of the glomerular basement membrane with sub-epithelial deposits, suggesting membranous nephropathy. Considering the apparent interstitial fibrosis and diffuse glomerulosclerosis, supportive treatment was chosen. However, 11 months after the kidney biopsy, hemodialysis was required. The present case constitutes an important teaching point, as glomerular disease can occur in living donors and require careful and long-term medical checkup examinations.

Trend in overall survival from the start of first-line chemotherapy in patients with metastatic urothelial carcinoma.

New approaches involving immune checkpoint inhibitors and antibody-drug conjugates prolong overall survival in patients with metastatic urothelial carcinoma. However, the access to such systemic therapy in clinical practice is suboptimal, and whether these agents improve overall survival in patients with metastatic urothelial carcinoma over time remains unclear. Hence, we investigated the overall survival trend from the initiation of first-line therapy with these agents to identify changes due to the medication and time of treatment initiation. We retrospectively evaluated 195 patients from a single center. They were treated with chemotherapy, pembrolizumab, or avelumab or enfortumab vedotin. The treatment was categorized into chemotherapy, pembrolizumab or avelumab/enfortumab vedotin period. The new agents prolonged overall survival from the start of first-line therapy. Furthermore, sequential treatment with these agents in real-world clinical practice has been reported to prolong overall survival. These study results will have major implications when a new first-line therapy is approved in the future.

Investigation of eligibility for adjuvant therapy from real-world data of patients with urothelial carcinoma undergoing radical cystectomy and radical nephroureterectomy.

OBJECTIVE: Adjuvant nivolumab prolonged disease-free survival compared with placebo in patients at high risk of recurrence following radical cystectomy or radical nephroureterectomy in the CheckMate 274 trial. However, the ideal eligibility criteria for adjuvant therapy in real-world clinical practice remain controversial. METHODS: We retrospectively analyzed clinical data of 409 patients who underwent radical cystectomy (n = 252) or radical nephroureterectomy (n = 157) and validated the risk of recurrence based on the classification used in the CheckMate 274 trial. We also investigated the impact of perioperative chemotherapy, lymph node dissection and pathological factors on prognosis. RESULTS: The median follow-up time was 37.5 and 32.1 months in bladder cancer and upper tract urothelial carcinoma, respectively. Among the high-risk patients based on CheckMate 274 trial, disease-free survival was considerably shorter for bladder cancer and upper tract urothelial carcinoma patients than for low-risk patients (hazard ratios: 4.132 and 7.101, respectively). The prevalence of adjuvant chemotherapy in high-risk patients was low (24 and 38% for bladder cancer and upper tract urothelial carcinoma, respectively). The extent of lymph node dissection in bladder cancer and presence of lymph node dissection in upper tract urothelial carcinoma did not affect prognosis. Cox proportional multivariate analysis revealed CheckMate 274-high-risk as a poor prognostic factor in bladder cancer and upper tract urothelial carcinoma. CONCLUSIONS: This study validated the risk classification for recurrence following radical cystectomy and radical nephroureterectomy using the CheckMate 274 criteria in real-world practice. Further research would help assess the degree of benefit obtained from adjuvant nivolumab.

Phylogenomic data reveal three new families of poorly studied Solifugae (camel spiders).

The systematics of the arachnid order Solifugae have been an enigma, owing to challenges in interpreting morphology, a paucity of molecular phylogenetic studies sampling across the group, and a dearth of taxonomic attention for many lineages. Recent work has suggested that solifuge families largely exhibit contiguous distributions and reflect patterns of vicariance, with the exception of three families: Melanoblossidae, Daesiidae and Gylippidae. Morphological studies have cast doubt on their existing circumscriptions and the present composition of these taxa renders their distributions as disjunct. We leveraged ultraconserved elements (UCEs) to test the phylogenetic placement of three key lineages of Solifugae that cause these anomalous distributions: Dinorhax rostrumpsittaci (putative melanoblossid), Namibesia (putative daesiid), and Trichotoma (putative gylippid). Phylogenetic placement of these three genera based on UCEs rendered the families that harbor them as para- or polyphyletic, recovering instead relationships that better accord with a biogeographic history driven by vicariance. Toward a stable and phylogenetically informed classification of Solifugae, we establish three new families, Dinorhaxidae new rank, Namibesiidae new rank and Lipophagidae new rank.

Gateway reflexes describe novel neuro-immune communications that establish immune cell gateways at specific vessels.

Neuroinflammation is an important biological process induced by complex interactions between immune cells and neuronal cells in the central nervous system (CNS). Recent research on the bidirectional communication between neuronal and immunological systems has provided evidence for how immune and inflammatory processes are regulated by nerve activation. One example is the gateway reflex, in which immune cells bypass the blood brain barrier and infiltrate the CNS to cause neuroinflammation. We have found several modes of the gateway reflex in mouse models, in which gateways for immune cells are established at specific blood vessels in the spinal cords and brain in experimental autoimmune encephalomyelitis and systemic lupus erythematosus models, at retinal blood vessels in an experimental autoimmune uveitis model, and the ankle joints in an inflammatory arthritis model. Several environmental stimulations, including physical and psychological stresses, activate neurological pathways that alter immunological responses via the gateway reflex, thus contributing to the development/suppression of autoimmune diseases. In the manuscript, we describe the discovery of the gateway reflex and recent insights on how they regulate disease development. We hypothesize that artificial manipulation of specific neural pathways can establish and/or close the gateways to control the development of autoimmune diseases.

An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds.

Inflammatory colorectal polyp (ICRP) in miniature dachshunds (MDs) is a chronic inflammatory bowel disease (IBD) characterized by granulomatous inflammation that consists of neutrophil infiltration and goblet cell hyperplasia in the colon. Recently, we identified five MD-associated single-nucleotide polymorphisms (SNPs), namely PLG, TCOF1, TG, COL9A2, and COL4A4, by whole-exome sequencing. Here, we investigated whether TG c.4567C>T (p.R1523W) is associated with the ICRP pathology. We found that the frequency of the T/T SNP risk allele was significantly increased in MDs with ICRP. In vitro experiments showed that TG expression in non-immune cells was increased by inducing the IL-6 amplifier with IL-6 and TNF-α. On the other hand, a deficiency of TG suppressed the IL-6 amplifier. Moreover, recombinant TG treatment enhanced the activation of the IL-6 amplifier, suggesting that TG is both a positive regulator and a target of the IL-6 amplifier. We also found that TG expression together with two NF-κB targets, IL6 and CCL2, was increased in colon samples isolated from MDs with the T/T risk allele compared to those with the C/C non-risk allele, but serum TG was not increased. Cumulatively, these results suggest that the T/T SNP is an expression quantitative trait locus (eQTL) of TG mRNA in the colon, and local TG expression triggered by this SNP increases the risk of ICRP in MDs via the IL-6 amplifier. Therefore, TG c.4567C>T is a diagnostic target for ICRP in MDs, and TG-mediated IL-6 amplifier activation in the colon is a possible therapeutic target for ICRP.

GM-CSF Promotes the Survival of Peripheral-Derived Myeloid Cells in the Central Nervous System for Pain-Induced Relapse of Neuroinflammation.

We recently discovered a (to our knowledge) new neuroimmune interaction named the gateway reflex, in which the activation of specific neural circuits establishes immune cell gateways at specific vessel sites in organs, leading to the development of tissue-specific autoimmune diseases, including a multiple sclerosis (MS) mouse model, experimental autoimmune encephalomyelitis (EAE). We have reported that peripheral-derived myeloid cells, which are CD11b+MHC class II+ and accumulate in the fifth lumbar (L5) cord during the onset of a transfer model of EAE (tEAE), play a role in the pain-mediated relapse via the pain-gateway reflex. In this study, we investigated how these cells survive during the remission phase to cause the relapse. We show that peripheral-derived myeloid cells accumulated in the L5 cord after tEAE induction and survive more than other immune cells. These myeloid cells, which highly expressed GM-CSFRα with common ß chain molecules, grew in number and expressed more Bcl-xL after GM-CSF treatment but decreased in number by blockade of the GM-CSF pathway, which suppressed pain-mediated relapse of neuroinflammation. Therefore, GM-CSF is a survival factor for these cells. Moreover, these cells were colocalized with blood endothelial cells (BECs) around the L5 cord, and BECs expressed a high level of GM-CSF. Thus, GM-CSF from BECs may have an important role in the pain-mediated tEAE relapse caused by peripheral-derived myeloid cells in the CNS. Finally, we found that blockade of the GM-CSF pathway after pain induction suppressed EAE development. Therefore, GM-CSF suppression is a possible therapeutic approach in inflammatory CNS diseases with relapse, such as MS.

Irradiation plus myeloid-derived suppressor cell-targeted therapy for overcoming treatment resistance in immunologically cold urothelial carcinoma.

BACKGROUND: Radiotherapy (RT) has recently been highlighted as a partner of immune checkpoint inhibitors. The advantages of RT include activation of lymphocytes while it potentially recruits immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). This study aimed to investigate the mechanism of overcoming treatment resistance in immunologically cold tumours by combining RT and MDSC-targeted therapy. METHODS: The abscopal effects of irradiation were evaluated using MB49 and cisplatin-resistant MB49R mouse bladder cancer cells, with a focus on the frequency of immune cells and programmed cell death-ligand 1 (PD-L1) expression in a xenograft model. RESULTS: MB49R was immunologically cold compared to parental MB49 as indicated by the fewer CD8+ T cells and lower PD-L1 expression. Polymorphonuclear MDSCs increased in both MB49 and MB49R abscopal tumours, whereas the infiltration of CD8+ T cells increased only in MB49 but not in MB49R tumours. Interestingly, PD-L1 expression was not elevated in abscopal tumours. Finally, blocking MDSC in combination with RT remarkably reduced the growth of both MB49 and MB49R abscopal tumours regardless of the changes in the frequency of infiltrating CD8+ T cells. CONCLUSIONS: The combination of RT and MDSC-targeted therapy could overcome treatment resistance in immunologically cold tumours.

Zoobiquity experiments show the importance of the local MMP9-plasminogen axis in inflammatory bowel diseases in both dogs and patients.

Using a zoobiquity concept, we directly connect animal phenotypes to a human disease mechanism: the reduction of local plasminogen levels caused by matrix metalloproteinase-9 (MMP9) activity is associated with the development of inflammation in the intestines of dogs and patients with inflammatory bowel disease. We first investigated inflammatory colorectal polyps (ICRPs), which are a canine gastrointestinal disease characterized by the presence of idiopathic chronic inflammation, in Miniature Dachshund (MD) and found 31 missense disease-associated SNPs by whole-exome sequencing. We sequenced them in 10 other dog breeds and found five, PLG, TCOF1, TG, COL9A2 and COL4A4, only in MD. We then investigated two rare and breed-specific missense SNPs (T/T SNPs), PLG: c.477G > T and c.478A>T, and found that ICRPs with the T/T SNP risk alleles showed less intact plasminogen and plasmin activity in the lesions compared to ICRPs without the risk alleles but no differences in serum. Moreover, we show that MMP9, which is an NF-κB target, caused the plasminogen reduction and that intestinal epithelial cells expressing plasminogen molecules were co-localized with epithelial cells expressing MMP9 in normal colons with the risk alleles. Importantly, MMP9 expression in patients with ulcerous colitis or Crohn's disease also co-localized with epithelial cells showing enhanced NF-κB activation and less plasminogen expression. Overall, our zoobiquity experiments showed that MMP9 induces the plasminogen reduction in the intestine, contributing to the development of local inflammation and suggesting the local MMP9-plasminogen axis is a therapeutic target in both dogs and patients. Therefore, zoobiquity-type experiments could bring new perspectives for biomarkers and therapeutic targets.

Taxonomic study of Bornean species of Utivarachna Kishida, 1940 (Araneae: Trachelidae), with the description of a new species.

The genus Utivarachna Kishida, 1940 currently comprises 23 species, with eight described from Borneo. We examined the type materials of the Bornean species, except for U. fukasawana Kishida, 1940, as well as newly collected specimens. As a result, we describe a new species, Utivarachna itiokai sp. nov., which belongs to the dusun-group. We also provide the first description of the female of Utivarachna ichneumon and redescribe the known Utivarachna species of Borneo.

Successful case of olaparib treatment for castration-resistant prostate cancer with multiple DNA repair gene mutations: Use of comprehensive genome profiling for treatment-refractory cases.

Herein, we report a case of a 59-year-old man with advanced castration-resistant prostate cancer with rectal invasion. Multimodal treatment, including drug therapy, surgery, and radiation therapy was sequentially performed; however, lymph node metastases repeatedly occurred. Tumor genomic profiling using FoundationOne CDx identified pathogenic alterations in three DNA repair genes, including BRCA2 frameshift mutation. Olaparib, a poly-ADP ribose polymerase inhibitor, showed marked response. Castration-resistant prostate cancer with multiple DNA repair genes was successfully treated with olaparib; comprehensive genome profiling can lead to its optimal clinical management.

Fluid drag reduction by penguin-mimetic laser-ablated riblets with yaw angles.

The bodies of penguins, which swim underwater to forage, are densely covered with feathers, in which the barbs are oriented in the longitudinal direction. We hypothesize that these barbs act as riblets and reduce friction drag during swimming. Considering various real-world swim conditions, the drag reduction effect is expected to be robust against changes in the flow speed and yaw angle relative to the flow. To test this hypothesis, we created trapezoidal riblets based on the morphology of these barbs and measured the drag of flat plates with these fabricated riblets in a water tunnel. The spacing, width, and height of the barbs were found to be approximately 100, 60, and 30 µm, respectively. This spacing resulted in a nondimensional spacings+of 5.5 for a typical penguin swimming speed of 1.4 m s-1. We fabricated four types of riblets on polyimide films by ultraviolet laser ablation. The first was a small-scale riblet for which the spacing was decreased to 41 µm to simulate the surface flow condition of the usual and slower swim behaviors in our water tunnel. The other three were manufactured to the actual scale of real barbs (spacing of 100 µm) with three different rib ridge widths: 10, 25, and 50 µm. Yaw angles of 0°, 15°, 30°, and 45° were also tested with the actual-scale riblets. The drag reduction rate of the small-scale riblet was maximized to 1.97% by the smallests+of 1.59. For all three actual-scale riblets, increasing the yaw angle from zero to 15° enhanced the drag reduction rate for the full range ofs+up to 13.5. The narrow-ridge riblet reduced drag at an even higher yaw angle of 45°, but the drag increased with zero yaw angle. Overall, the medium-ridge riblet, which was representative of the barbs, was well-balanced.

[A Case of Metastatic Urothelial Carcinoma with Pseudoprogression of Liver Metastasis during the Treatment with Pembrolizumab].

A 75-year-old woman with a complaint of gross hematuria was referred to our hospital. The patient was diagnosed as having bladder cancer (cT3bN1M0) and received two cycles of chemotherapy with gemcitabine and cisplatin. Radical cystectomy with pelvic lymph node dissection and bilateral ureterostomy was performed after achieving partial response in a lymph node metastasis following chemotherapy. Based on the pathological diagnosis of high-grade (G3) urothelial carcinoma (ypT3aN2), two more cycles of adjuvant chemotherapy with gemcitabine and cisplatin were administered. Four months after completing adjuvant chemotherapy, pulmonary and hepatic metastases appeared, and treatment with pembrolizumab was initiated. The size of the lung metastasis decreased, while that of the liver metastasis increased 2 months after administering pembrolizumab. However, considering treatment beyond progression using checkpoint inhibitors, pembrolizumab was continued, resulting in marked tumor shrinkage of the liver metastasis. After that, pembrolizumab treatment was temporarily discontinued, and radiation therapy was administered for a new lymph node metastasis at the tracheal bifurcation. Eventually, the lymph node metastasis shrank, and the treatment with pembrolizumab was recommenced for 1 year and the metastases remained shrumken.

Relationship between flightlessness and brain morphology among Rallidae.

Studies have suggested that the brain morphology and flight ability of Aves are interrelated; however, such a relationship has not been thoroughly investigated. This study aimed to examine whether flight ability, volant or flightless, affects brain morphology (size and shape) in the Rallidae, which has independently evolved to adapt secondary flightlessness multiple times within a single taxonomic group. Brain endocasts were extracted from computed tomography images of the crania, measured by 3D geometric morphometrics, and were analyzed using principal component analysis. The results of phylogenetic ANCOVA showed that flightless rails have brain sizes and shapes that are significantly larger than and different from those of volant rails, even after considering the effects of body mass and brain size respectively. Flightless rails tended to have a wider telencephalon and more inferiorly positioned foramen magnum than volant rails. Although the brain is an organ that requires a large amount of metabolic energy, reduced selective pressure for a lower body weight may have allowed flightless rails to have larger brains. The evolution of flightlessness may have changed the position of the foramen magnum downward, which would have allowed the support of the heavier cranium. The larger brain may have facilitated the acquisition of cognitively advanced behavior, such as tool-using behavior, among rails.

Neotype designation of the Short-tailed Albatross Phoebastria albatrus (Pallas, 1769) (Aves: Procellariiformes: Diomedeidae).

The Short-tailed Albatross Phoebastria albatrus (Pallas, 1769) is a threatened seabird widely distributed in the northern Pacific Ocean with its largest breeding sites on the Senkaku Islands and Torishima Island, Japan, which are separated by over 1700 km. A recent taxonomic revision based on morphological, behavioral, and DNA sequence evidence has revealed that this species consists of two cryptic species: a smaller species which breeds mainly in the Senkaku Islands, and a larger species which breeds mainly on Torishima Island. However, it has remained unclear to which of these species the scientific name Phoebastria albatrus applies, because the type specimens are lost. Here a neotype is designated to resolve this taxonomic issue. From now on, the scientific name Phoebastria albatrus should be applied only to the smaller species breeding on the Senkaku Islands. The name of the larger species is more problematic, as the types of each synonym of P. albatrus must be traced, found, and examined.

A retrospective study on optimal number of cycles of the first-line platinum-based chemotherapy for metastatic urothelial carcinoma.

BACKGROUND: Recently, switch maintenance with avelumab has been approved for the treatment of advanced or metastatic urothelial carcinoma (UC), with no progression after four to six cycles of first-line platinum-based chemotherapy. However, the optimal number of cycles of platinum-based chemotherapy has not been determined. OBJECTIVE: To analyze the clinical characteristics of patients with advanced UC who were treated with platinum-based chemotherapy and investigate the association between the number of cycles of the treatment and the patients' overall survival. METHODS: A total of 124 patients with advanced UC who were treated with first-line platinum-based chemotherapy at Osaka City University Hospital between April 2009 and January 2020 were retrospectively reviewed. RESULTS: Of the 124 patients, clinical information regarding overall survival was available for 115 patients. The median age was 72 years (range, 43-95 years). Only 59 patients (51.3 %) were treated with gemcitabine and cisplatin, and 52 patients (45.2 %) were treated with gemcitabine and carboplatin. The median number of cycles was three (1-8), and the percentage of patients who discontinued chemotherapy due to progressive disease was 80.3%, 64.0%, and 86.4% in those receiving one to three, four, and five or more cycles, respectively. Moreover, no difference in overall survival was observed between patients who received four cycles and those who received five or more cycles at both univariate and multivariate levels. CONCLUSIONS: The present study shows that five or more cycles of first-line platinum-based chemotherapy did not prolong overall survival compared with four cycles, suggesting that four cycles of chemotherapy might be sufficient, considering the new treatment strategy involving switch maintenance with avelumab.