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Objectives  Head and neck mucosal melanoma (HNMM) is a rare malignancy with high mortality. This study evaluates the impact of treatment delays on overall survival in HNMM. Design/Setting/Participants  A retrospective review of patients with surgically managed HNMM treated with adjuvant radiation was performed from the 2004-2016 National Cancer Database. Main Outcome Measures  Durations of diagnosis-to-treatment initiation (DTI), surgery-to-radiotherapy initiation (SRT), duration of radiotherapy (RTD), surgery-to-immunotherapy initiation (SIT), diagnosis-to-treatment end (DTE), and total treatment package (TTP) were calculated. Results  A total of 1,011 patients (50.7% female, 90.5% Caucasian) met inclusion criteria. Median DTI, SRT, RTD, SIT, DTE, and TTP were 30, 49, 41, 102, 119, and 87 days, respectively. Only longer DTE was associated with decreased mortality (hazard ratio, 0.720; 95% confidence interval, 0.536-0.965; p  = 0.028). Conclusion  DTI, SRT, RTD, SIT, and TTP do not significantly affect overall survival in patients with HNMM who undergo surgery and adjuvant radiation. Longer DTE is associated with improved survival in this population. Level of Evidence  4.

Abstract Green fluorescent protein (GFP) is widely utilized as a fluorescent tag in biochemical fields. Whereas the intermediate (I) state has been proposed in the photoreaction cycle in addition to the A and B states, until now the structure of I has only been estimated by computational studies. In this paper, we report the crystal structures of the I stabilizing variants of GFP at high resolutions where respective atoms can be observed separately. Comparison with the structures in the other states highlights the structural feature of the I state. The side chain of one of the substituted residues, Val203, adopts the gauche- conformation observed for Thr203 in the A state, which is different from the B state. On the other hand, His148 interacts with the chromophore by ordinary hydrogen bonding with a distance of 2.85 Å, while the weaker interaction by longer distances is observed in the A state. Therefore, it was indicated that it is possible to distinguish three states A, B and I by the two hydrogen bond distances Oγ-Thr203···Oη-chromophore and Nδ1-His148···Oη-chromophore. We discuss the characteristics of the I intermediate of wild-type GFP on the bases of the structure estimated from the variant structures by quantum chemical calculations.

A 74-year-old man presented with persistent hiccups and headache persisting for 2 days. An anticoagulant was administered for his coronary heart disease. Cranial computed tomography (CT) revealed an intracerebral hemorrhage (ICH) located in the right occipital lobe, without any abnormal findings around the brainstem. The patient underwent endoscopic hematoma evacuation via a burr hole, resulting in immediate resolution of hiccups. Following an uneventful postoperative course, the patient experienced recurrent hiccups on the 47th day postsurgery. A subsequent CT scan taken on the 50th day revealed a compressive chronic subdural hematoma (CSDH) situated in the right frontoparietal convexity. The patient underwent burr-hole irrigation, leading to prompt cessation of the hiccups. Persistent hiccup should be recognized as potential manifestation of supratentorial lesions, including ICH or CSDH. Surgical evacuation of such lesions can rapidly alleviate hiccups associated with these pathologies.

Abstract Background Pancreatic ductal adenocarcinoma tumors exhibit resistance to chemotherapy, targeted therapies, and even immunotherapy. Dendritic cells use glucose to support their effector functions and play a key role in anti-tumor immunity by promoting cytotoxic CD8+ T cell activity. However, the effects of glucose and lactate levels on dendritic cells in pancreatic ductal adenocarcinoma are unclear. In this study, we aimed to clarify how glucose and lactate can impact the dendritic cell antigen-presenting function and elucidate the relevant mechanisms. Methods Glycolytic activity and immune cell infiltration in pancreatic ductal adenocarcinoma were evaluated using patient-derived organoids and resected specimens. Cell lines with increased or decreased glycolysis were established from KPC mice. Flow cytometry and single-cell RNA sequencing were used to evaluate the impacts on the tumor microenvironment. The effects of glucose and lactate on the bone marrow-derived dendritic cell antigen-presenting function were detected by flow cytometry. Results The pancreatic ductal adenocarcinoma tumor microenvironment exhibited low glucose and high lactate concentrations from varying levels of glycolytic activity in cancer cells. In mouse transplantation models, tumors with increased glycolysis showed enhanced myeloid-derived suppressor cell infiltration and reduced dendritic cell and CD8+ T cell infiltration, whereas tumors with decreased glycolysis displayed the opposite trends. In three-dimensional co-culture, increased glycolysis in cancer cells suppressed the antigen-presenting function of bone marrow-derived dendritic cells. In addition, low-glucose and high-lactate media inhibited the antigen-presenting and mitochondrial functions of bone marrow-derived dendritic cells. Conclusions Our study demonstrates the impact of dynamic glycolytic reprogramming on the composition of immune cells in the tumor microenvironment of pancreatic ductal adenocarcinoma, especially on the antigen-presenting function of dendritic cells.

This study investigated the effects of platelet-rich plasma (PRP) treatment on ovarian function and pregnancy outcomes in three patients with severe reduction of ovarian reserve. The patients had previously undergone multiple cycles of assisted reproductive technology (ART) without favorable results. Prior to PRP treatment, follicle-stimulating hormone (FSH), estradiol (E2), and anti-Mullerian hormone (AMH) levels were assessed. PRP was administered through intraovarian injection. Hormonal assessments were performed at 6–7 months after the first PRP injection. The results showed major improvements in ovarian function, as evidenced by decreased FSH levels and increased AMH levels in all three patients. The number of mature oocytes retrieved per cycle and the ovum-to-blastocyst rate were also improved. All the patients achieved successful pregnancies and gave birth to healthy infants. These findings suggest that PRP may enhance ovarian function, oocyte quality, and pregnancy outcomes in patients with severely reduced ovarian reserve. Further research is necessary to validate these results and explore the underlying mechanisms.

Abstract Rapid on-site cytopathology evaluation (ROSE) has been considered an effective method to increase the diagnostic ability of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA); however, ROSE is unavailable in most institutes worldwide due to the shortage of cytopathologists. To overcome this situation, we created an artificial intelligence (AI)-based system (the ROSE-AI system), which was trained with the augmented data to evaluate the slide images acquired by EUS-FNA. This study aimed to clarify the effects of such data-augmentation on establishing an effective ROSE-AI system by comparing the efficacy of various data-augmentation techniques. The ROSE-AI system was trained with increased data obtained by the various data-augmentation techniques, including geometric transformation, color space transformation, and kernel filtering. By performing five-fold cross-validation, we compared the efficacy of each data-augmentation technique on the increasing diagnostic abilities of the ROSE-AI system. We collected 4059 divided EUS-FNA slide images from 36 patients with pancreatic cancer and nine patients with non-pancreatic cancer. The diagnostic ability of the ROSE-AI system without data augmentation had a sensitivity, specificity, and accuracy of 87.5%, 79.7%, and 83.7%, respectively. While, some data-augmentation techniques decreased diagnostic ability, the ROSE-AI system trained only with the augmented data using the geometric transformation technique had the highest diagnostic accuracy (88.2%). We successfully developed a prototype ROSE-AI system with high diagnostic ability. Each data-augmentation technique may have various compatibilities with AI-mediated diagnostics, and the geometric transformation was the most effective for the ROSE-AI system.

Abstract Background Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is a rare disease characterized by a persistent increase in NK cells in peripheral blood and is generally asymptomatic. If present, symptoms may include fatigue, B symptoms (fever, night sweats, and unintentional weight loss), autoimmune-associated diseases, splenomegaly, and infection due to neutropenia. Peripheral neuropathy, however, is uncommon with an incidence of 3%. Neurolymphomatosis is a neurological manifestation of non-Hodgkin lymphoma and leukemia in which neurotropic neoplastic cells infiltrate the nerves. Moreover, neurolymphomatosis caused by CLPD-NK is extremely rare, with even fewer cases of autonomic dysfunction. We report a case of neurolymphomatosis associated with CLPD-NK and developed autonomic dysfunction, including orthostatic hypotension and gastrointestinal symptoms. Case presentation The patient was a 61-year-old male who was referred to our hospital for leukocytosis. He was diagnosed with CLPD-NK; however, was untreated since he had no hepatosplenomegaly, and other systemic symptoms. He later developed numbness in his lower extremities. Cerebral spinal fluid examination revealed a markedly elevated protein level of 140 mg/dL, and contrast-enhanced magnetic resonance imaging showed bilateral L4 and 5 nerve roots with enlargement and contrast effect. An immune-mediated polyradiculoneuropathy was suspected, and he was treated with intravenous methylprednisolone and immunoglobulin followed by oral prednisolone and cyclosporine. Although his symptoms were relieved by the immunotherapy, significant autonomic dysfunction, including intractable diarrhea, decreased sweating, and orthostatic hypotension, appeared. Additionally, tests for onconeuronal antibodies, ganglionic nicotinic acetylcholine receptor (gAChR) antibody, NF155, CNTN1, Caspr1 antibody, and anti-ganglioside antibodies were all negative. A sural nerve biopsy revealed lymphocytic infiltration, and immunohistochemical staining of lymphocytes confirmed the infiltration of NK and T cells. Therefore, a diagnosis of neurolymphomatosis caused by CLPD-NK was made, and chemotherapy led to partial symptom improvement. Conclusions We experienced a case of pathologically diagnosed neurolymphomatosis with autonomic dysfunction associated with CLPD-NK. In cases of subacute to chronic autonomic dysfunction, paraneoplastic neuropathy, amyloidosis, and autoimmune autonomic ganglionopathy are considered; however neurolymphomatosis caused by CLPD-NK, an important cause of autonomic dysfunction, is not. In difficult to make diagnosis, aggressive nerve biopsy is required.

Abstract Background Antimicrobial agents (AMAs) are essential for treating infections. A part of AMAs chelate with metal cations (MCs), reducing their blood concentrations. That drug-drug interaction could lead to a reduction of therapeutic efficacy and the emergence of drug-resistant bacteria. However, prescriptions ordering concomitant intake (co-intake) of AMAs and MCs are frequently seen in clinical settings. A method for preventing such prescriptions is urgently needed. Methods We implemented pop-up alerts in the hospital's ordering and pharmacy dispensation support system to notify the prescriptions ordering co-intake of AMAs and MCs for physicians and pharmacists, respectively. To assess the effectiveness of the pop-up alerts, we investigated the number of prescriptions ordering co-intake of AMAs and MCs and the number of pharmacist inquiries to prevent co-intake of AMAs and MCs before and after the implementation of pop-up alerts. Results Before the implementation of pop-up alerts, 84.5% of prescriptions containing AMA and MCs ordered co-intake of AMAs and MCs. Implementing pop-up alerts time-dependently reduced the proportion of prescriptions ordering co-intake of AMAs and MCs to 43.8% and 29.5% one year and two years later, respectively. The reduction of tetracycline-containing prescriptions was mainly significant. Before the implementation of pop-up alerts, the proportion of prescriptions in which pharmacists prevented co-intake of AMAs and MCs was 3.4%. Implementing pop-up alerts time-dependently increased proportions of such prescriptions to 20.9% and 28.2% one year and two years later. Conclusion Implementing pop-up alerts reduced prescriptions ordering co-intake of AMAs and MCs and accelerated pharmacists to prevent co-intake of AMAs and MCs. The implementation of dual pop-up alerts in the hospital's ordering and pharmacy dispensation support system could help prevent co-intake of AMAs and MCs.

Abstract Background Tumor-associated neutrophils (TANs) constitute an abundant component among tumor-infiltrating immune cells and have recently emerged as a critical player in pancreatic ductal adenocarcinoma (PDAC) progression. This study aimed to elucidate the pro-tumor mechanisms of TAN and identify a novel target for effective immunotherapy against PDAC. Methods Microarray and cytokine array analyses were performed to identify the mechanisms underlying the function of TANs. Human and mouse TANs were obtained from differentiated HL-60 cells and orthotopically transplanted PDAC tumors, respectively. The interactions of TANs with cancer and cytotoxic T-cells were evaluated through in vitro co-culture and in vivo orthotopic or subcutaneous models. Single-cell transcriptomes from patients with PDAC were analyzed to validate the cellular findings. Results Increased neutrophil infiltration in the tumor microenvironment was associated with poor survival in patients with PDAC. TANs secreted abundant amounts of chemokine ligand 5 (CCL5), subsequently enhancing cancer cell migration and invasion. TANs subpopulations negatively correlated with cytotoxic CD8+ T-cell infiltration in PDAC and promoted T-cell dysfunction. TANs upregulated the membranous expression of Nectin2, which contributed to CD8+ T-cell exhaustion. Blocking Nectin2 improved CD8+ T-cell function and suppressed tumor progression in the mouse model. Single-cell analysis of human PDAC revealed two immunosuppressive TANs phenotypes: Nectin2+ TANs and OLR1+ TANs. Endoplasmic reticulum stress regulated the protumor activities in TANs. Conclusions TANs enhance PDAC progression by secreting CCL5 and upregulating Nectin2. Targeting the immune checkpoint Nectin2 could represent a novel strategy to enhance immunotherapy efficacy in PDAC.

With the rapid spread of telecommuting since the COVID-19 pandemic, companies have been relocating to high-end business centers, thereby enhancing the workplace experience for employees, a phenomenon called the "flight to quality." However, this trend’s impact on rents and vacancy rates in individual office buildings has not been extensively studied. To determine the effects of the flight-to-quality phenomenon on individual buildings, we examine the impact of modern amenities, which directly influence employee lifestyles, on rents and vacancy rates in the Tokyo office market. Using a propensity score-based quasi-experimental method, we find that commercial properties with such modern amenities command higher rents and experience lower vacancy rates than those without. The difference in vacancy rates has increased since 2020. However, the significance of these amenities diminishes for properties less competitive in age, size, and location. The results indicate that the "flight to quality" may further polarize the office real estate market into two categories: one for high-end buildings experiencing increasing demand, and another for those with modest amenities experiencing decreasing demand. The findings have implications for office building owners/investors and the government, make educated decisions as to whether to invest in modern amenities, join the quality competition, or encourage urban restructuring.

Abstract Background We report the final results of treatment with aripiprazole, blonanserin, and paliperidone from the Japan Useful Medication Program for Schizophrenia (JUMPs), a 104-week naturalistic study. Methods JUMPs was an open-label, three-arm, randomized, parallel-group, 104-week study. Patients aged ≥ 20 years with schizophrenia requiring antipsychotic treatment or a switch from previous therapy were enrolled. The primary endpoint was treatment discontinuation rate over 104 weeks. Secondary endpoints included remission rate, Personal and Social Performance (PSP), safety, Positive and Negative Syndrome Scale (PANSS), and quality of life (QOL; EuroQol-5 dimension). Results In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). Treatment discontinuation rates (aripiprazole, 80.5%; blonanserin, 81.2%; paliperidone, 71.4%) were not significantly different (p = 0.2385) among the treatment groups at 104 weeks; comparable outcomes were observed for endpoints, including remission (42.9%, 46.7%, and 45.8%), PANSS, and safety. In the overall cohort, while the improvement in the PSP total score at Week 104 was not significantly different from baseline, a significant improvement (p

Objective: The aim of this study is to characterise the molecular characteristics of NDM-producing Enterobacterales, which have been on the increase in recent years in Japan, where IMP-producing bacteria are dominant among carbapenemase-producing Enterobacterales. Methods: We collected 21 strains of NDM-producing Enterobacterales detected between 2015 and 2022 at five hospitals in Tokyo and performed illumina whole genome sequencing. For the seven selected strains, nanopore long-read sequencing was also performed to characterise the plasmids harbouring blaNDM. Results: Fourteen strains were Escherichia coli and all carried blaNDM-5. Among these strains, eight and three were sequence type (ST) 410 and ST167, respectively, and both groups of strains were spread clonally in different hospitals. Two strains of Klebsiella pneumoniae ST147 carrying blaNDM-1 were detected in a hospital, and these strains had also spread clonally. The remainder included Enterobacter hormaechei, Klebsiella quasipneumoniae, Citrobacter amalonaticus, and Klebsiella michiganensis. Plasmid analysis revealed that an identical IncX3 plasmid harbouring blaNDM-5 was shared among four strains of different bacterial species (E. coli, C. amalonaticus, K. michiganensis, and E. hormaechei) detected at the same hospital. In addition, a Klebsiella quasipneumoniae strain detected at a different hospital also carried an IncX3 plasmid with a similar genetic structure. Conclusions: Nosocomial spread of multiple multidrug-resistant global clones and transmission of IncX3 plasmids harbouring blaNDM-5 among multiple species were detected as the major pathways of spread of NDM-producing Enterobacterales in Tokyo. Early detection of carriers and measures to prevent nosocomial spread are important to prevent further spread of NDM-producing organisms.

Abstract Background The objective of this study is to assess whether urethral preservation can be performed safely using frozen section analysis (FSA) of the urethral stump on urethral recurrence after radical cystectomy. Methods Between June 2012 and July 2022, we investigated consecutive male patients who underwent urethral FSA during radical cystectomy for urothelial carcinoma. For FSA‐abnormal cases, urethrectomy was performed, and for FSA‐normal cases, the urethra was preserved. The diagnostic accuracy of FSA was assessed in comparison with the pathological findings of the permanent sections of the same tissue. Postoperatively, computed tomography and urinary cytology were performed as routine surveillance of recurrence. Results Of the 77 patients included in this study, three patients with abnormal FSA underwent concurrent urethrectomy. The negative predictive value of urethral FSA was 100%. With a median postoperative follow‐up of 38 months (interquartile ranges 21–71), no urethral recurrence was observed. Conclusions FSA may be useful in determining the indication for urethrectomy.

Abstract Porcine circovirus 3 (PCV3) was first reported in the United States in 2016; this virus is considered to be involved in diverse pathologies, such as multisystem inflammation, porcine dermatitis and nephropathy syndrome, and reproductive disorders. However, successful isolation of PCV3 using cultured cells has been rare. In this study, we aimed to isolate PCV3 using primary porcine bone marrow-derived cells. Mononuclear cells were isolated from the femur bones of clinically healthy pigs. These primary cells were cultured for 6–10 days post-seeding and infected with PCV3-containing tissue homogenates. The cells were cultured for up to 37 days, and the culture medium was changed every 3–4 days. The growth curve of PCV3 in porcine bone marrow cells revealed a decline in growth during the first 10 days post-infection, followed by an increase leading to > 1010 genomic copies/mL of the cell culture supernatant; moreover, the virus was capable of passaging. The indirect fluorescent antibody assay for PCV3 infection revealed the presence of PCV3 capsid protein in the cytoplasm and nuclei of infected cells. Bone marrow cells were passaged for more than 20 generations (over 5 months), and PCV3 persistently infected the cells. PCV3-infected bone marrow cells expressed mesenchymal markers. These results reflect that primary porcine bone marrow-derived mesenchymal cells are permissive to PCV3 and continuously replicate a high copy number of the PCV3 genome. These findings regarding the high replication rate of PCV3 in bone marrow-derived mesenchymal cells could enhance our understanding of PCV3 pathogenicity.

A 50-year-old man presented with headache and left hemiparesis. No noticeable preceding head trauma was observed. Computed tomography (CT) scans revealed a compressive chronic subdural hematoma (CSDH). The patient underwent burr-hole irrigation, during which he was considerably restless. In addition, extensive avulsion was found in the parietal dura mater posterior to the burr hole. CT performed immediately after the surgery revealed the emergence of a thick epidural hematoma (EDH) located posterior to the burr-hole. During emergency craniotomy for the EDH, there was no identifiable injury to the dura mater or the meningeal vessels. However, a review of the CT scans confirmed well-developed diploic spaces just above the center of the EDH, with connecting channels between the diploic spaces and extracranial sites. Based on these observations, we assumed that the diploic vein might have caused the EDH. Diploic veins can cause AEDH after burr hole irrigation for CSDH. Appropriate intraoperative sedation and protective irrigation maneuvers can reduce the risk of such AEDH.

We report an 85-year-old man who underwent transarterial embolization (TAE) for an infected internal iliac artery aneurysm. The patient presented with fever and left lower abdominal pain. Computed tomography (CT) revealed the expansion of a left internal iliac artery aneurysm. We planned surgical treatment for an infected internal iliac artery aneurysm; however, the patient's age and general condition made the surgery high-risk. Therefore, we performed emergency TAE. The patient was administered antibiotics for 4 weeks and discharged on day 33 after the procedure with good progression. A 3-year follow-up CT scan showed aneurysm reduction and no recurrent infections. This case report highlights that TAE can be a treatment option for patients with an infected artery aneurysm.

A 17-year-old boy presented with a high-grade fever. The patient had been previously diagnosed with Cornelia de Lange syndrome (CdLS). The patient visited a local physician and was diagnosed with sinusitis. Owing to persistent fever, the patient was referred to our hospital. At the initial presentation, his body temperature was 38.2°C, while maintaining previous living activities and neurological function. Despite changing the antibiotic to amoxicillin, the patient's fever persisted with worsened activity. At the second presentation, the patient presented with left hemiparesis. Blood examination revealed increased white blood cell count and serum C-reactive protein level. Emergency magnetic resonance imaging revealed acute cerebral infarcts in the right cerebral hemisphere, with evident stenosis in the right paraclinoid segment of the internal carotid artery (ICA). In addition, an abscess was found in the cerebellar hemisphere, which was punctured through the burr hole. Computed tomography performed after the completion of antibiotic therapy revealed a restored diameter of the stenotic ICA. Sinusitis can cause ischemic stroke due to compressive stenosis of the paraclinoid ICA, particularly in patients with CdLS. Sinusitis should be preferentially managed in patients with CdLS.

A 73-year-old man who previously underwent transsphenoidal surgery for a Rathke's cleft cyst presented with headache and fever. Ophthalmological examination revealed the progression of visual impairment. Cerebral magnetic resonance imaging revealed a cystic mass in the sellar and suprasellar regions with rim-like enhancement. An intralesional hyperintense area with temporal enlargement was identified using serial diffusion-weighted imaging. Lumbar cerebrospinal fluid tap findings indicated bacterial meningitis. The patient had undergone a transsphenoidal surgery; an intraoperatively implanted sheet of artificial dura mater from the previous surgery was identified adjacent to the sellar floor. After incising the floor, the pus material was drained and methicillin-sensitive Staphylococcus aureus was identified on culture. Consecutive antibiotic treatment resolved the pituitary abscess (PA). PA may develop as a late complication of transsphenoidal surgery, particularly when an artificial material is implanted during surgery. Clinical signs coupled with temporal findings on diffusion-weighted sequences can facilitate the diagnosis and activity of PA and serve as a guide for proper management.