Reproductive organ involvement in women undergoing radical cystectomy for urothelial bladder cancer: a nationwide multicenter study.

BACKGROUND: Radical cystectomy in women generally includes the removal of the uterus, ovaries, and anterior vaginal wall, but the criteria for reproductive organ sparing are not clear. METHODS: A total of 2674 patients with bladder cancer were retrospectively reviewed, having undergone cystectomy at this nationwide multicenter from January 2013 to December 2019. We evaluated the incidence of malignancy in reproductive organs in a cohort of 417 women and analyzed the clinicopathological features of reproductive organ involvement. Recurrence-free survival and overall survival were reported using Kaplan-Meier survival curves. RESULTS: Median follow-up was 36.9 months. Of the 417 patients with urothelial carcinoma of the bladder, 325 underwent hysterectomy, and 92 had a spared uterus and anterior wall of the vagina. Twenty-nine (8.9%) patients exhibited reproductive organ involvement; this consisted of 22 (6.8%) uteri, 16 (4.9%) vaginas, and two (0.6%) ovaries. Incidental primary reproductive malignancies were found in only two (0.6%) patients. Recurrence-free survival and overall survival were significantly shorter in patients with reproductive organ involvement than in those without. Patients with reproductive organ involvement were more likely to have tumors with ≥ cT3 or sub-localization at the posterior/trigone/bladder neck. CONCLUSIONS: The risk of reproductive organ involvement cannot be ignored in women undergoing radical cystectomy for urothelial carcinoma of the bladder, therefore, the eligibility criteria for reproductive organ preservation should be considered carefully.

Real-world assessment of comprehensive genome profiling impact on clinical outcomes: A single-institution study in Japan.

INTRODUCTION: Comprehensive genome profiling (CGP) has revolutionized healthcare by offering personalized medicine opportunities. However, its real-world utility and impact remain incompletely understood. This study examined the extent to which CGP leads to genomically matched therapy and its effectiveness. METHODS: We analyzed data from advanced solid tumor patients who underwent CGP panel between December 2019 and May 2023 at the Osaka International Cancer Institute. Patient demographics, specimen details, and expert panel assessments were collected. Turnaround time (TAT) and genomically matched therapy outcomes were analyzed. Gene alterations and their co-occurrence patterns were also assessed. RESULTS: Among 1437 patients, 1096 results were available for analysis. The median TAT was 63 [28-182] days. There were 667 (60.9%) cases wherein recommended clinical trials were presented and there were 12 (1.1%) cases that could be enrolled in the trial and 25 (2.3%) cases that could lead to therapies under insurance reimbursement. The median progression free survival of the trial treatment was 1.58 months (95% CI: 0.66-4.37) in clinical trials and 3.66 months (95% CI: 2.14-7.13) in treatment under insurance. Pathologic germline variants were confirmed in 15 patients (1.3%). Co-alteration of CDKN2A, CDKN2B, and MTAP was significantly observed in overall population. CONCLUSION: The effectiveness of the genomically matched therapy based on the CGP panel was unsatisfactory. Expansion of clinical trials and utilization of remote clinical trials are required to ensure that the results of the CGP panel can be fully returned to patients.

Serum D-asparagine concentration adjusted for eGFR could serve as a novel screening tool for urothelial carcinoma.

The sensitivity of currently available screening tools for urothelial carcinoma (UC) remains unsatisfactory particularly at early stages. Hence, we aimed to establish a novel blood-based screening tool for urothelial carcinoma. We measured serum d-amino acid levels in 108 and 192 patients with and without UC individuals in the derivation cohort, and 15 and 25 patients with and without UC in the validation cohort. Serum d-asparagine levels were significantly higher in patients with UC than in those without UC (p < 0.0001). We developed a novel screening equation for the diagnosis of urothelial carcinoma using d-asparagine in serum and estimated the glomerular filtration rate (eGFR). Serum d-asparagine levels adjusted for eGFR exhibited high performance in the diagnosis of UC (AUC-ROC, 0.869; sensitivity, 80.6 %; specificity, 82.7 %), even in early-stage UC (AUC-ROC: 0.859, sensitivity: 83.3 %, specificity: 82.3 %), which were previously misdiagnosed via urinary occult blood or urine cytology. This established strategy combined with urinary occult blood, improves diagnostic ability (sensitivity: 93.7 %, specificity: 70.1 %).

Shifts in neural tuning systematically alter sensorimotor learning ability.

Sensorimotor learning can change the tuning of neurons in motor-related brain areas and rotate their preferred directions (PDs). These PD rotations are commonly interpreted as reflecting motor command changes; however, cortical neurons that display PD rotations also contribute to sensorimotor learning. Sensorimotor learning should, therefore, alter not only motor commands but also the tuning of neurons responsible for this learning, and thus impact subsequent learning ability. Here, we investigate this possibility with computational modeling and by directly measuring adaptive responses during sensorimotor learning in humans. Modeling shows that the PD rotations induced by sensorimotor learning, predict specific anisotropic changes in PD distributions that in turn predict a specific spatial pattern of changes in learning ability. Remarkably, experiments in humans then reveal large, systematic changes in learning ability in a spatial pattern that precisely reflects these model-predicted changes. We find that this pattern defies conventional wisdom and implements Newton's method, a learning rule where the step size is inversely proportional rather than proportional to the learning gradient's amplitude, limiting overshooting in the adaptive response. Our findings indicate that PD rotation provides a mechanism whereby the motor system can simultaneously learn how to move and learn how to learn.

Prognostic impact of histological discordance between transurethral resection and radical cystectomy.

OBJECTIVE: To analyse the impact of histological discordance of subtypes (subtypes or divergent differentiation [DD]) in specimens from transurethral resection (TUR) and radical cystectomy (RC) on the outcome of the patients with bladder cancer receiving RC. PATIENTS AND METHODS: We analysed data for 2570 patients from a Japanese nationwide cohort with bladder cancer treated with RC between January 2013 and December 2019 at 36 institutions. The non-urinary tract recurrence-free survival (NUTR-FS) and overall survival (OS) stratified by TUR or RC specimen histology were determined. We also elucidated the predictive factors for OS in patients with subtype/DD bladder cancer. RESULTS: At median follow-up of 36.9 months, 835 (32.4%) patients had NUTR, and 691 (26.9%) died. No statistically significant disparities in OS or NUTR-FS were observed when TUR specimens were classified as pure-urothelial carcinoma (UC), subtypes, DD, or non-UC. Among 2449 patients diagnosed with pure-UC or subtype/DD in their TUR specimens, there was discordance between the pathological diagnosis in TUR and RC specimens. Histological subtypes in RC specimens had a significant prognostic impact. When we focused on 345 patients with subtype/DD in TUR specimens, a multivariate Cox regression analysis identified pre-RC neutrophil-lymphocyte ratio and pathological stage as independent prognostic factors for OS (P = 0.016 and P = 0.001, respectively). The presence of sarcomatoid subtype in TUR specimens and lymphovascular invasion in RC specimens had a marginal effect (P = 0.069 and P = 0.056, respectively). CONCLUSION: This study demonstrated that the presence of subtype/DD in RC specimens but not in TUR specimens indicated a poor prognosis. In patients with subtype/DD in TUR specimens, pre-RC neutrophil-lymphocyte ratio and pathological stage were independent prognostic factors for OS.

Relapsing cytokine release syndrome in a patient with metastatic renal cell carcinoma treated with pembrolizumab and axitinib therapy.

As immune checkpoint inhibitors become more widely available, the optimal management of immune-related adverse events (irAEs) is becoming increasingly important. Although irAEs are diverse, reports on cytokine release syndrome are rare. Here, we report a case of a 48-year-old man with relapsing cytokine release syndrome after receiving pembrolizumab and axitinib combination therapy for metastatic renal cell carcinoma. During dose reduction of prednisolone for immune-related hepatitis on day 33 after starting pembrolizumab plus axitinib, the patient suddenly developed abdominal pain, and a few hours later became hypotensive and poorly oxygenated. Despite the use of a ventilator and high doses of catecholamines, blood pressure and oxygenation could not be maintained. Extracorporeal membrane oxygenation and intra-aortic balloon pumping were also administered. The cytokine release syndrome (CRS) was treated with tocilizumab, and his general condition improved. Lower-grade CRS relapsed four times despite a moderate dose of oral prednisolone with mycophenolate mofetil or tacrolimus. After gradual reduction in prednisolone over 5 months, the patient was discharged from the hospital. Partial remission of renal cell carcinoma continued for 21 months, and salvage radical nephrectomy was performed. The patient remained disease-free without the need for further treatment 9 months after surgery.

Outcomes in patients with high- and very high-risk localized prostate cancer treated with definitive IMRT and long-term hormone therapy.

BACKGROUND: The aim of this study was to evaluate the effectiveness of intensity-modulated radiation therapy in combination with long-term androgen deprivation therapy for high-risk and very high-risk localized prostate cancer while also investigating factors associated with the therapeutic effect. METHODS: Men who fulfilled criteria for the National Comprehensive Cancer Network high-risk or very high-risk localized prostate cancer and were treated with definitive intensity-modulated radiation therapy (74-78 Gy) of the prostate and the seminal vesicle combined with androgen deprivation therapy in our institution from 2007 to 2016 were identified (n = 197). In principle, patients received androgen deprivation therapy for 3-6 months before radiation, concurrently, and for 2 years after completion of intensity-modulated radiation therapy. RESULTS: The median follow-up period was 96 months. The 5-year and 10-year overall survival rates in the overall population were 96.9% and 89.3%, respectively. The 5-year and 10-year cumulative incidence rates of biochemical failure were 2.5% and 16.3% in the high-risk group, and 8.6% and 32.0% in the very high-risk group, respectively, indicating a significant difference between the two groups (P = 0.023). Grade Group 5 and younger age (cutoff: 70 years old) were independent predictors of recurrence (P = 0.016 and 0.017, respectively). Patients exhibiting biochemical failure within <18 months after completion of androgen deprivation therapy displayed an increased risk of cancer-specific mortality (P = 0.039) when contrasted with those who had a longer interval to biochemical failure. CONCLUSIONS: Patients with the National Comprehensive Cancer Network very high-risk prostate cancer, particularly those with Grade Group 5 and younger age, showed worse outcomes following intensity-modulated radiation therapy and long-term androgen deprivation therapy.

Divisively normalized neuronal processing of uncertain visual feedback for visuomotor learning.

When encountering a visual error during a reaching movement, the motor system improves the motor command for the subsequent trial. This improvement is impaired by visual error uncertainty, which is considered evidence that the motor system optimally estimates the error. However, how such statistical computation is accomplished remains unclear. Here, we propose an alternative scheme implemented with a divisive normalization (DN): the responses of neuronal elements are normalized by the summed activity of the population. This scheme assumes that when an uncertain visual error is provided by multiple cursors, the motor system processes the error conveyed by each cursor and integrates the information using DN. The DN model reproduced the patterns of learning response to 1-3 cursor errors and the impairment of learning response with visual error uncertainty. This study provides a new perspective on how the motor system updates motor commands according to uncertain visual error information.

[A Case of Primary Signet Ring Cell Carcinoma of the Urinary Bladder Showing Effectiveness of Chemotherapy with Gemcitabine and Cisplatin].

A 55-year-old female presented to the hospital with a complaint of gross hematuria. Transurethral resection of bladder tumor was performed. The specimens pathologically showed signet ring cells and no urothelial carcinoma components. Magnetic resonance imaging and computed tomographic (CT) scan revealed bladder tumor, cervical metastasis, bilateral ovarian metastasis, and multiple lymph node metastasis. She was diagnosed with a primary signet ring cell carcinoma of the urinary bladder with cT3bN2M1, and was treated with chemotherapy of gemcitabine and cisplatin combination (GC). After 2 cycles of GC, the value of CEA which was elevated to 106 ng/ml before treatment, became negative. CT scan showed that her disease had successfully responded to the chemotherapy, and remained efficacious till the end of 6 cycles. The patient subsequently received 1 cycle of gemcitabine and nedaplatin and 3 cycles of avelumab due to renal insufficiency. Yet, 14 months after diagnosis, cerebellar metastases appeared and the patient died of meningeal carcinomatosis.

Utility of Comprehensive Genomic Profiling Tests for Patients with Incurable Pancreatic Cancer in Clinical Practice.

Although comprehensive genomic profiling (CGP) tests have been covered under the Japanese national health insurance program since 2018, the utility and issues of CGP tests have not been clarified. We retrospectively reviewed 115 patients with incurable pancreatic cancer (IPC) who underwent CGP tests in a Japanese cancer referral center from November 2019 to August 2021. We evaluated the results of CGP tests, treatments based on CGP tests, and survival time. Eight cases (6.9%) were diagnosed as tumor mutation burden-high (TMB-H) and/or microsatellite instability-high (MSI-H). The gene mutation rates of KRAS/TP53/CDKN2A/SMAD4 were 93.0/83.0/53.0/25.2%, respectively. Twenty-five patients (21.7%) had homologous recombination deficiency (HRD)-related genetic mutations. Four patients (3.5%) having TMB-H and/or MSI-H were treated with pembrolizumab, and only two patients (1.7%) participated in the clinical trials. Patient characteristics were not significantly different between patients with and without HRD-related gene mutations. The median OS was significantly longer in the HRD (+) group than in the HRD (-) group (749 days vs. 519 days, p = 0.047). In multivariate analysis, HRD-related gene mutation was an independent prognostic factor associated with favorable OS. CGP tests for patients with IPC have the potential utility of detecting HRD-related gene mutations as prognostic factors as well as a therapeutic search.

Efficacy of cabazitaxel in patients with metastatic castration-resistant prostate cancer: A single-center study in Japan.

OBJECTIVES: Cabazitaxel is a next-generation taxane that can prolong overall survival after docetaxel treatment in patients with metastatic castration-resistant prostate cancer. However, the efficacy of cabazitaxel varies among these patients. The clinical indicators of the prognosis after cabazitaxel treatment were analyzed. METHODS: A retrospective review of patients who received cabazitaxel between February 2015 and June 2021 was performed. All patients had metastatic castration-resistant prostate cancer. Prognostic factors for prostate-specific antigen progression-free and overall survival were analyzed by Cox proportional-hazards analysis and the log-rank test. RESULTS: The study comprised 57 patients who received cabazitaxel (median 4 cycles, range 1-27) at a starting dose of 15-25 mg/m2 . The median age and follow-up duration were 70 years and 9.2 months. The median prostate-specific antigen progression-free survival and overall survival were 2.6 and 10.5 months, respectively. Univariate analysis showed that previous androgen receptor-axis-targeted therapy before cabazitaxel treatment was the only significant risk factor (hazard ratio 2.784, p = 0.022) for prostate-specific antigen progression-free survival. Multivariate analysis for overall survival revealed that poor performance status (≥1) (hazard ratio 2.107, p = 0.039), low hemoglobin (hazard ratio 0.142, p = 0.010), and high neutrophil-lymphocyte ratio (hazard ratio 9.150, p = 0.032) at baseline were significantly associated with a poor prognosis. CONCLUSIONS: Previous androgen receptor-axis-targeted therapy was the only risk factor for biochemical progression. Poor performance status, anemia, and high neutrophil-lymphocyte ratio were risk factors for poor prognosis in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel. These risk factors seem useful for identifying patients with survival benefit from cabazitaxel treatment.

IMAGENE trial: multicenter, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy of niraparib with PD-1 inhibitor in solid cancer patients with homologous recombination repair genes mutation.

BACKGROUND: Previous clinical trials have demonstrated the potential efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) in patients with cancer involving homologous recombination repair (HRR) gene-mutation. Moreover, HRR gene-mutated cancers are effectively treated with immune checkpoint inhibitors (ICIs) with the increase in tumor mutation burden. We have proposed to conduct a multicenter, single-arm phase II trial (IMAGENE trial) for evaluating the efficacy and safety of niraparib (PARPi) plus programmed cell death-1 inhibitor combination therapy in patients with HRR gene-mutated cancers who are refractory to ICIs therapy using a next generation sequencing-based circulating tumor DNA (ctDNA) and tumor tissue analysis. METHODS: Key eligibility criteria for this trial includes HRR gene-mutated tumor determined by any cancer gene tests; progression after previous ICI treatment; and Eastern Cooperative Oncology Group Performance Status ≤ 1. The primary endpoint is the confirmed objective response rate (ORR) in all patients. The secondary endpoints include the confirmed ORR in patients with HRR gene-mutation of ctDNA using the Caris Assure (CARIS, USA). The target sample size of the IMAGENE trial is 57 patients. Biomarker analyses will be performed in parallel using the Caris Assure, proteome analysis, and T cell repertoire analysis to reveal tumor immunosurveillance in peripheral blood. EXPECTED OUTCOME: Our trial aims to confirm the clinical benefit of PARPi plus ICI combination therapy in ICI-resistant patients. Furthermore, through translational research, our trial will shed light on which patients would benefit from the targeted combination therapy for patients with HRR gene-mutated tumor even after the failure of ICIs. TRIAL REGISTRATION: The IMAGENE trial: jRCT, Clinical trial no.: jRCT2051210120, Registered date: November 9, 2021.

Clinical application of comprehensive genomic profiling panel to thoracic malignancies: A single-center retrospective study.

BACKGROUND: The usefulness of comprehensive genomic profiling (CGP) panels for thoracic malignancies after completion of the standard treatment is unclear. METHODS: The results of CGP panels for malignant thoracic diseases performed at our hospital between December 2019 and June 2022 were collected. We examined whether CGP panel results led to new treatment, correlated with the effectiveness of immune checkpoint inhibitors (ICIs), or revealed secondary findings related to hereditary tumors. RESULTS: A total of 60 patients were enrolled, of which 52 (86.6%) had lung cancer. In six (10%) patients, the panel results led to treatment with insurance-listed molecular-targeted agents; four patients had EGFR mutations not detected by the real-time polymerase chain reaction assay and two had MET ex.14 skipping mutations. In small-cell lung cancer, the tumor mutation burden was high in 4/6 (66.7%) patients and pembrolizumab was available. Another MET ex.14 skipping mutation was detected in two cases with EGFR-tyrosine kinase inhibitor resistance. ICI efficacy was ≤1 year in patients with STK-11, KEAP1, and NEF2L2 mutations. A BRCA2 mutation with a high probability of germline mutation was detected in one patient. A thymic carcinoma with no detectable oncogenic mutation responded to second-line treatment with Tegafur-Gimeracil-Oteracil Potassium (TS-1) for ≥9 years. CONCLUSIONS: CGP panels are useful in thoracic malignancies, especially lung cancer, because they can detect overlooked driver mutations and genetic alterations. We believe that the significance of conducting a CGP panel prior to treatment may also exist, as it may lead to the prediction of ICI treatment efficacy.

High-fat diet promotes prostate cancer growth through histamine signaling.

Western high-fat diets (HFD) are regarded as a major risk factor for prostate cancer (PCa). Using prostate-specific Pten-knockout mice as a PCa model, we previously reported that HFD promoted inflammatory PCa growth. The composition of the gut microbiota changes under the influence of diet exert various effects on the host through immunological mechanisms. Herein, we investigated the etiology of HFD-induced inflammatory cancer growth and the involvement of the gut microbiome. The expression of Hdc, the gene responsible for histamine biosynthesis, and histamine levels were upregulated in large prostate tumors of HFD-fed mice, and the number of mast cells increased around the tumor foci. Administration of fexofenadine, a histamine H1 receptor antagonist, suppressed tumor growth in HFD-fed mice by reducing the number of myeloid-derived suppressor cells and suppressing IL6/STAT3 signaling. HFD intake induced gut dysbiosis, resulting in the elevation of serum lipopolysaccharide (LPS) levels. Intraperitoneal injection of LPS increased Hdc expression in PCa. Inhibition of LPS/Toll-like receptor 4 signaling suppressed HFD-induced tumor growth. The number of mast cells increased around the cancer foci in total prostatectomy specimens of severely obese patients. In conclusion, HFD promotes PCa growth through histamine signaling via mast cells. Dietary high-fat induced gut dysbiosis might be involved in the inflammatory cancer growth.

MiR-30b-3p and miR-126-3p of urinary extracellular vesicles could be new biomarkers for prostate cancer.

BACKGROUND: Extracellular vesicles (EVs) including exosomes are present in blood, urine, and saliva and contain proteins, microRNAs, and messenger RNAs. We investigated microRNAs in urinary EVs to discover new biomarkers of prostate cancer (PCa). METHODS: We isolated EVs from urine obtained following digital rectal examination (DRE) of 14 men with elevated levels of serum prostate-specific antigen (PSA) [negative biopsy (n=4) and PCa with Gleason scores of 6 (n=3), 7 (n=3), and 8-9 (n=4)]. MicroRNAs extracted from EVs were analyzed by microRNA microarray. RESULTS: MicroRNAs miR-30b-3p and miR-126-3p were identified as being overexpressed in urinary EVs of the PCa patients versus the biopsy-negative men, but no microRNAs were associated with the Gleason score. In the independent cohort as well, these two microRNAs were overexpressed in urinary EVs from the PCa patients versus the negative-biopsy men. Logistic regression analysis adjusted by age and PSA showed that these two microRNAs were significantly associated with the prediction of PCa in biopsy specimens. Sensitivity and specificity of miR-30b-3p and miR-126-3p for the prediction of PCa were 46.4% and 88.0% and 60.7% and 80.0%, respectively, which were better than those of serum PSA (53.5% and 64.0%, respectively). CONCLUSIONS: MiR-30b-3p and miR-126-3p in urinary EVs could be potential biomarkers of PCa.

Gut Microbiota-Derived Short-Chain Fatty Acids Promote Prostate Cancer Growth via IGF1 Signaling.

Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a prostate cancer model to investigate whether there is a gut microbiota-mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer-bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including Rikenellaceae and Clostridiales, inhibited prostate cancer cell proliferation, and reduced prostate Igf1 expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 in vitro. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. SIGNIFICANCE: These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells.

Mutational Landscape and Environmental Effects in Bladder Cancer.

Bladder cancer is the most common cancer of the urinary tract. Although nonmuscle-invasive bladder cancers have a good prognosis, muscle-invasive bladder cancers promote metastases and have a poor prognosis. Comprehensive analyses using RNA sequence of clinical tumor samples in bladder cancer have been reported. These reports implicated the candidate genes and pathways that play important roles in carcinogenesis and/or progression of bladder cancer. Further investigations for the function of each mutation are warranted. There is suggestive evidence for several environmental factors as risk factors of bladder cancer. Environmental factors such as cigarette smoking, exposure to chemicals and gases, bladder inflammation due to microbial and parasitic infections, diet, and nutrition could induce several genetic mutations and alter the tumor microenvironment, such as immune cells and fibroblasts. The detailed mechanism of how these environmental factors induce carcinogenesis and/or progression of bladder cancer remains unclear. To identify the relationship between the mutations and the lifestyle could be useful for prevention and treatment of bladder cancer.

Delayed diagnosis of an upper cervical epidural abscess masked due to crowned dens syndrome.

An 87-year-old Japanese man presented to our hospital with a 5-day history of fever and neck pain. On physical examination, his stiff neck indicated restricted movement, especially on rotation. CT of the head revealed calcification of the atlantoaxial joint consistent with crowned dens syndrome, and celecoxib was started. Four days later, he returned to our emergency department as his neck pain and fever had not improved. Pneumonia and a urinary tract infection were suspected. The day following admission, blood culture results were positive for methicillin-resistant Staphylococcus aureus A contrast-enhanced CT revealed an upper cervical epidural abscess at the level of C1-C2. He was discharged following 8 weeks of antibiotic treatment.

Divisively Normalized Integration of Multisensory Error Information Develops Motor Memories Specific to Vision and Proprioception.

Both visual and proprioceptive information contribute to the accuracy of limb movement, but the mechanism of integration of these different modality signals for movement control and learning remains controversial. We aimed to elucidate the mechanism of multisensory integration for motor adaptation by evaluating single-trial adaptation (i.e., aftereffect) induced by visual and proprioceptive perturbations while male and female human participants performed reaching movements. The force-channel method was used to precisely impose several combinations of visual and proprioceptive perturbations (i.e., error), including an instance when the directions of perturbation in both stimuli opposed each another. In the subsequent probe force-channel trial, the lateral force against the channel was quantified as the aftereffect to clarify the mechanism by which the motor adaptation system corrects movement in the event of visual and proprioceptive errors. We observed that the aftereffects had complex dependence on the visual and proprioceptive errors. Although this pattern could not be explained by previously proposed computational models based on the reliability of sensory information, we found that it could be reasonably explained by a mechanism known as divisive normalization, which was the reported mechanism underlying the integration of multisensory signals in neurons. Furthermore, we discovered evidence that the motor memory for each sensory modality developed separately in accordance with a divisive normalization mechanism and that the outputs of both memories were integrated. These results provide a novel view of the utilization and integration of different sensory modality signals in motor adaptation.SIGNIFICANCE STATEMENT The mechanism of utilization of multimodal sensory information by the motor control system to perform limb movements with accuracy is a fundamental question. However, the mechanism of integration of these different sensory modalities for movement control and learning remains highly debatable. Herein, we demonstrate that multisensory integration in the motor learning system can be reasonably explained by divisive normalization, a canonical computation, ubiquitously observed in the brain (Carandini and Heeger, 2011). Moreover, we provide evidence of a novel idea that integration does not occur at the sensory information processing level, but at the motor execution level, after the motor memory for each sensory modality is separately created.

Main Inflammatory Cells and Potentials of Anti-Inflammatory Agents in Prostate Cancer.

Prostate cancer is the most common type of cancer and the leading cause of cancer deaths among men in many countries. Preventing progression is a major concern for prostate cancer patients on active surveillance, patients with recurrence after radical therapies, and patients who acquired resistance to systemic therapies. Inflammation, which is induced by various factors such as infection, microbiome, obesity, and a high-fat diet, is the major etiology in the development of prostate cancer. Inflammatory cells play important roles in tumor progression. Various immune cells including tumor-associated neutrophils, tumor-infiltrating macrophages, myeloid-derived suppressor cells, and mast cells promote prostate cancer via various intercellular signaling. Further basic studies examining the relationship between the inflammatory process and prostate cancer progression are warranted. Interventions by medications and diets to control systemic and/or local inflammation might be effective therapies for prostate cancer progression. Epidemiological investigations and basic research using human immune cells or mouse models have revealed that non-steroidal anti-inflammatory drugs, metformin, statins, soy isoflavones, and other diets are potential interventions for preventing progression of prostate cancer by suppressing inflammation. It is essential to evaluate appropriate indications and doses of each drug and diet.