Mapping naso-ocular symptom scores to EQ-5D-5L utility values in Japanese cedar pollinosis.

BACKGROUND: The total naso-ocular symptom score (TSS) is widely used as an endpoint to evaluate the severity of seasonal allergic rhinitis. However, it is not a generic preference-based measure. We sought to develop an algorithm for mapping between the TSS and health utility in Japanese cedar pollinosis (JCP). We also performed a cost-utility analysis of sublingual immunotherapy (SLIT) for JCP by using this algorithm. METHODS: Patients with JCP filled out the TSS questionnaire and EQ-5D-5L simultaneously during the pollen season in 2019 and in 2020. We estimated a direct utility mapping model by regressing responses to individual TSS questions directly onto utility. The incremental cost-effectiveness ratio (ICER) of active SLIT to a placebo was determined by examining the drug expense and the estimated quality-adjusted life year (QALY) using a dataset from a double-blind placebo-controlled clinical trial. RESULTS: A total of 238 records were included for analysis. The estimated utility decreased with increasing severity of rhinitis. Patients with comorbid asthma showed lower utility. A negative and significant correlation was seen between the TSS and utility in both 2019 and 2020. The estimated equations were: Y(utility) = -0.0161∗X(TSS) + 1.005 in non-asthmatic JCP patients. The ICER of active SLIT to the placebo was estimated to be 4,049,720 and 6,011,218 JPY/QALY in the first and second year, respectively. CONCLUSIONS: It is possible to reasonably predict utility from the total naso-ocular symptom score by using regression models. In the estimated algorithm, pre-seasonal SLIT for JCP is cost-effective.

An Adult Case of Nasal Chondromesenchymal Hamartoma: Imaging Characteristics Including Diffusion-Weighted Images.

Nasal chondromesenchymal hamartoma (NCMH), a rare, benign, nasal cavity tumor, typically occurs in children. Differential diagnosis is difficult because NCMH often presents with non-specific findings, including cystic components and invasion of the surrounding area on T2-weighted magnetic resonance images. Here, we present a rare adult case of NCMH, with no clear hyperintensity on diffusion-weighted images (DWI), and bone remodeling on the tumor margins on computed tomography. To the best of our knowledge, this is the first report of DWI on NCMH, and these findings, which suggest benign disease, may be useful in diagnosing NCMH.

Role of whole saliva in the efficacy of sublingual immunotherapy in seasonal allergic rhinitis.

BACKGROUND: The development of methods to predict the clinical effectiveness of sublingual immunotherapy (SLIT) for allergic diseases is a crucial matter. We sought to determine whether whole saliva, which is the first body component that contacts allergen extracts during SLIT, is associated with the clinical effectiveness of SLIT in Japanese cedar pollinosis. METHODS: Blood monocytes or monocytic THP-1 cells were cultured in the presence or absence of either whole saliva or pure saliva with or without treatments including filtration and blockade of TLR2 and/or TLR4 signaling. IL-10 levels in the supernatants were then measured. Whole saliva-induced IL-10 production by THP-1 cells was compared between asymptomatic and disease-onset patients during peak pollen dispersal after SLIT. RESULTS: Both monocytes and THP-1 cells produced substantial amounts of IL-10 in response to whole saliva. IL-10 production was significantly reduced in response to pure saliva and 0.2 µm-filtered saliva. Simultaneous treatment with polymyxin B and TL2.1, a neutralizing antibody against TLR2, also reduced IL-10 production. IL-10 levels produced by THP-1 cells in response to whole saliva collected prior to SLIT were significantly higher in asymptomatic patients determined by symptom-medication scores than disease-onset patients following SLIT. Such differences were not seen in saliva collected 3 months after the initiation of SLIT or saliva collected during peak pollen dispersal. CONCLUSIONS: Our results provide a basis for why the sublingual route is effective and preferable in allergen immunotherapy. Saliva-induced IL-10 levels produced by THP-1 cells may be a predictive marker for clinical remission after SLIT.

Effect of prostaglandin D2 on VEGF release by nasal polyp fibroblasts.

BACKGROUND: Vascular endothelial growth factor (VEGF) is known to be associated with the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). VEGF is produced by a variety of cells including fibroblasts. It was recently reported that prostaglandin (PG) E2 induces VEGF release by nasal polyp fibroblasts. However, little is known regarding possible regulation of VEGF by other PGs. We have reported that molecules that regulate PGD2 metabolism play roles in the pathogenesis of CRS including in local eosinophilia and type 2 cytokine production. In the present study, we sought to determine whether PGD2 regulates VEGF release by nasal polyp fibroblasts. METHODS: Nasal polyp fibroblasts were established from nasal polyps. These fibroblasts were stimulated with serial dilutions of PGD2 or PGD2 receptor (DP/CRTH2)-selective agonists in the presence or absence of receptor-selective antagonists. The concentration of VEGF in the culture supernatants was determined using ELISA. RESULTS: 5 µM of PGD2 significantly induced VEGF release by nasal polyp fibroblasts. VEGF release was also obtained by stimulation with a DP receptor-selective, but not with a CRTH2 receptor-selective agonist. In addition, PGD2-induced VEGF release was significantly inhibited by pre-treatment with DP receptor-selective antagonists. In contrast, pre-treatment with a CRTH2 receptor-selective antagonist significantly enhanced PGD2-induced VEGF release. CONCLUSIONS: PGD2 stimulates VEGF production via DP but not CRTH2 receptors in nasal polyp fibroblasts.

A Study of Cases of Brainstem/cerebellar Infarction Detected as False Negatives by Initial MRI.

Brainstem/cerebellar infarction is known to cause various cranial nerve symptoms that may require otorhinolaryngological evaluation. Acute-phase cerebellar infarction is evaluated by MRI with diffusion-weighted imaging (MRI-DWI). However, in the acute phase, MRI-DWI may show false-negative results, because of which patients are referred to the department of otolaryngology for further evaluation of the cranial nerve symptoms. We investigated 250 cases of brainstem/cerebellar infarction in 245 patients who were admitted to our hospital between 2010 and 2015. Of the 250 cases, eight cases were diagnosed at the department of otolaryngology after detailed evaluators for dizziness or dysphagia, and three of them were false negative on initial MRI-DWI. In total, we examined 16 cases detected as false negatives upon initial MRI-DWI. Of the 16 cases, 12 were brainstem infarctions, three were cerebellar infarctions, and one was infarction of the brainstem and cerebellum. All 16 cases were evaluated by initial MRI-DWI within 12 h of onset. Careful observation of the neurological findings and follow-up MRI-DWI are useful for the detailed evaluation of patients suspected to have a cerebellar infarction.

A rare case of primary clear cell sarcoma of the pubic bone resembling small round cell tumor: an unusual morphological variant.

BACKGROUND: Clear cell sarcoma (CCS) and malignant melanoma share overlapping immunohistochemistry with regard to the melanocytic markers HMB45, S100, and Melan-A. However, the translocation t(12; 22)(q13; q12) is specific to CCS. Therefore, although these neoplasms are closely related, they are now considered to be distinct entities. However, the translocation is apparently detectable only in 50%-70% of CCS cases. Therefore, the absence of a detectable EWS/AFT1 rearrangement may occasionally lead to erroneous exclusion of a translocation-negative CCS. Therefore, histological assessment is essential for the correct diagnosis of CCS. Primary CCS of the bone is exceedingly rare. Only a few cases of primary CCS arising in the ulna, metatarsals, ribs, radius, sacrum, and humerus have been reported, and primary CCS arising in the pubic bone has not been reported till date. CASE PRESENTATION: We present the case of an 81-year-old man with primary CCS of the pubic bone. Histological examination of the pubic bone revealed monomorphic small-sized cells arranged predominantly as a diffuse sheet with round, hyperchromatic nuclei and inconspicuous nucleoli. The cells had scant cytoplasm, and the biopsy findings indicated small round cell tumor (SRCT). Immunohistochemical staining revealed the tumor cells to be positive for HMB45, S100, and Melan-A but negative for cytokeratin (AE1/AE3) and epithelial membrane antigen. To the best of our knowledge, this is the first case report of primary CCS of the pubic bone resembling SRCT. This ambiguous appearance underscores the difficulties encountered during the histological diagnosis of this rare variant of CCS. CONCLUSION: Awareness of primary CCS of the bone is clinically important for accurate diagnosis and management when the tumor is located in unusual locations such as the pubic bone and when the translocation t(12; 22)(q13; q12) is absent.

[Usefulness of a slow-release tacrolimus for a patient with tacrolimus-induced renal injury after hemopoietic stem cell transplantation].

In our facility, three patients developed tacrolimus (TAC)-induced renal dysfunction after allogeneic hemopoietic stem cell transplantation, although trough levels of TAC were within therapeutic ranges. They received an oral agent of slow-release TAC once a day instead of a regular form oral TAC twice a day. Following treatment with the prolonged-release agent, serum creatinine levels decreased and graft-versus-host disease (GVHD) did not occur. Use of this slow-release formulation may avoid toxic peak concentrations of TAC without the development of GVHD.

Long-term cryopreservation of pyramidalis muscle specimens as a source of striated muscle stem cells for treatment of post-prostatectomy stress urinary incontinence.

BACKGROUND: Stem-cell injection into the degenerated external urethral sphincter is a new treatment modality for stress urinary incontinence (SUI). We examined the possibility of long-term cryopreserved pyramidalis muscle (PM) specimens as a source of striated muscle stem cells for the treatment of post-prostatectomy SUI. METHODS: PM specimens were obtained from five male patients (mean age, 61-70 years) who underwent radical prostatectomy for prostate cancer. Specimens (volume, approximately 125 mm³ ) were obtained from the incisional edge, minced, and stored at -80°C in a freezing medium (Cell Banker 1®). After 24-60 months, the specimens were thawed and directly incubated at 37°C. Satellite cells were selectively cultured by magnetic affinity cell sorting using an anti-neural cell adhesion molecule (NCAM) antibody. Osteogenic and adipogenic differentiation were induced by bone morphogenic protein-7 (BMP-7) and γ-linolenic acid, respectively. RESULTS: NCAM-positive cells (>99% purity) were selectively cultured from all cryopreserved PM specimens and confirmed as being of striated muscle origin by the expression of desmin and MyoD. They fused and differentiated into multinucleated myotubes 7 days after incubation in a differentiation induction medium. Stimulation by BMP-7 and γ-linolenic acid induced expression of alkaline phosphatase (osteoblast marker) and lipid deposition within the cytoplasm (adipocyte characteristic), respectively. CONCLUSIONS: Long-term cryopreserved PM specimens can be used to culture muscle stem cells. Therefore, this method may be utilized for SUI treatment when necessary. Moreover, complete remove of the prostate gland without fear of injury to the urethral sphincter may be possible in patients with apical cancer or T3 prostate cancer.

Effect of Prostaglandin D2 on mRNA Expression of Three Isoforms of Hyaluronic Acid Synthase in Nasal Polyp Fibroblasts.

BACKGROUND: Hyaluronan is one of the major extracellular matrixes in chronic rhinosinusitis (CRS) associated with tissue remodeling. Prostaglandin D2 (PGD2) is also associated with the pathogenesis of CRS. However, little is known about whether PGD2 regulates hyaluronan production by human airway fibroblasts. OBJECTIVE: We sought to determine the effect of PGD2 on the mRNA expression of three isoforms of membrane-bound hyaluronic acid synthase (HAS1, HAS2 and HAS3) in fibroblasts, the major source of hyaluronan production, derived from CRS patients. METHODS: Nasal polyp-derived fibroblasts (NPDF) and uncinate tissue-derived fibroblasts (UTDF) were established from CRS patients with nasal polyps and those without, respectively. These fibroblasts were stimulated with PGD2 or PGD2 receptor (DP/CRTH2)-selective agonists in the presence or absence of receptor-selective antagonists. mRNA levels for HAS1, HAS2 and HAS3 were determined by real-time quantitative PCR. RESULTS: PGD2 (1 µM) significantly enhanced HAS1 but not HAS2 or HAS3 mRNA expression by NPDF. Enhanced HAS1 mRNA expression was also obtained by stimulation with a DP receptor-selective agonist, but not with a CRTH2 receptor-selective agonist. In addition, PGD2-induced HAS1 mRNA expression was significantly inhibited by pre-treatment with DP receptor-selective antagonists. Similar induction of PGD2-induced HAS1 mRNA expression was seen in UTDF. CONCLUSION: PGD2 selectively stimulates HAS1 mRNA expression in local fibroblasts in CRS via DP, but not CRTH2, receptors.

Allogeneic hematopoietic cell transplantation using fludarabine plus myeloablative busulfan and melphalan confers promising survival in high-risk hematopoietic neoplasms: a single-center retrospective analysis.

OBJECTIVES: Optimal selection of pretransplant conditioning is crucially vital for improving survival and quality-of-life of patients who receive allogeneic hematopoietic cell transplantation (allo-HCT), particularly in those with high-risk diseases. In this study, we evaluated the efficacy and safety of recently-developed reduced-toxicity myeloablative regimen that combines fludarabine, intravenous busulfan, and melphalan (FBM). METHODS: We conducted a single-center retrospective analysis of 39 patients (23 with myeloid neoplasms and 16 with lymphoid neoplasms), with a median age of 50 (range, 17-68) years, who underwent their first allo-HCT using the FBM regimen. Graft types were bone marrow in 11, peripheral blood in 11, and cord blood in 17 patients. Cyclosporine- or tacrolimus-based graft-versus-host disease (GVHD) prophylaxis was administered. The primary end point of the study was the overall survival rate at 2-year after transplantation. RESULTS: After a median follow-up of 910 days for the surviving patients, 2-year overall survival was 62% for the entire cohort; 73% in the low-to-intermediate-risk group and 44% in the high-to-very high-risk group classified by the refined CIBMTR Disease Risk Index. Cumulative incidences of engraftment, grade II-IV acute GVHD, chronic GVHD, relapse, and non-relapse mortality were 95%, 56%, 56%, 31%, and 17%, respectively. CONCLUSION: These results suggest that our FBM regimen can be applied to allo-HCT using various graft types and yields acceptable outcomes with relatively low non-relapse mortality in both myeloid and lymphoid neoplasms. Also, we observed a promising survival in the group of patients with high-risk diseases, warranting more accumulation of patients and longer follow-up.

Growth inhibition and apoptosis induction by tumor necrosis factor-α in human urethral rhabdosphincter satellite cells.

PURPOSE: A decrease in the human urethral rhabdosphincter is reported with aging due to apoptosis, which may be a cause of urinary incontinence in the elderly population. To explore this mechanism we investigated the effects of tumor necrosis factor-alpha (Upstate, Temecula, California) on human urethral rhabdosphincter satellite cells. MATERIALS AND METHODS: Human urethral rhabdosphincter satellite cells were cultured and selected by magnetic affinity cell sorting, extended their life span. Apoptosis induction was examined by flow cytometry and immunocytochemistry. Caspase cascade activation was determined by Western blot analysis. After tumor necrosis factor receptor expression was confirmed we determined the tumor necrosis factor signaling pathway. RESULTS: Tumor necrosis factor-alpha inhibited human urethral rhabdosphincter satellite cell proliferation. It caused some cells to stain positive for annexin V-fluorescein isothiocyanate but not for propidium iodide, suggesting the induction of early phase apoptosis. Flow cytometry revealed an increased sub-G1 fraction. Western blot analysis showed activation of caspase-8 and 3, and cleavage of poly (adenosine diphosphate-ribose) polymerase. Tumor necrosis factor receptor expression at the mRNA and protein levels was confirmed by reverse transcriptase-polymerase chain reaction and Western blot analysis, respectively. IkappaBalpha phosphorylation was noted within 2 to 5 minutes after tumor necrosis factor-alpha treatment. The tumor necrosis factor-alpha antagonist etanercept (Wyeth, Collegeville, Pennsylvania) inhibited IkappaBalpha activation and reversed tumor necrosis factor-alpha effects on human urethral rhabdosphincter satellite cells. CONCLUSIONS: Since tumor necrosis factor-alpha induces growth inhibition and apoptosis of human urethral rhabdosphincter satellite cells via tumor necrosis factor receptor activation, it may be involved in age related decreases in the number of human urethral rhabdosphincter cells and be a causative factor for urinary incontinence in the elderly population.

Primary cutaneous diffuse large B-cell lymphoma, leg type, with features simulating POEMS syndrome.

A 91-year-old woman presented with a rapidly proliferative cutaneous lesion on the left lower limb, which was identified as a primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type, on biopsy. The patient also showed complications of hepatomegaly, endocrinopathy, edema, skin change, and polyneuropathy without monoclonal plasma cell proliferative disorder, and was therefore diagnosed with POEMS-like syndrome owing to the lack of monoclonal plasma cell proliferative disorder. Levels of serum vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) were high with the lymphoma cells immunostained positively for VEGF and IL-6. To the best of our knowledge, this is the first case report of PCLBCL, leg type, with POEMS-like syndrome. The findings in this case suggest that the symptoms of POEMS-like syndrome might be caused by the cytokines produced by the lymphoma cells. Furthermore, a wider range of diagnostic criteria associated with the result of abnormal secretion of cytokine may have to be considered for the diagnosis and evaluation of patients with possible POEMS syndrome, as against the present criteria specifying monoclonal plasma cell proliferative disorder as the essential criterion.

The effects of hepatocyte growth factor and insulin-like growth factor-1 on the myogenic differentiation of satellite cells in human urethral rhabdosphincter.

AIMS: To examine the effects of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) on the myogenic differentiation of human urethral rhabdosphincter (RS) satellite cells. METHODS: Human RS was obtained from patients undergoing radical prostatectomy for prostate cancer. Selectively cultured RS satellite cells, transfected with temperature sensitive simian virus-40 T antigen (ts-SV40 Tag) to extend their lifespan, were cultured at 33 degrees C, and then incubated at 39 degrees C to induce myogenic differentiation. Varying concentrations of HGF and IGF-1 were added to the differentiation medium. Inactivation of SV40 Tag and evaluations of myogenic differentiation were examined by immunocytochemistry, western blotting and real-time RT-PCR. RESULTS: At 39 degrees C, ts-SV40 Tag-transfected RS satellite cells slowly proliferated, fused to form multinucleated myotubes, and expressed myosin heavy chain (MHC) in association with the temperature-dependent inactivation of SV40 Tag. IGF-1 significantly accelerated the MHC expression in a dose-dependent fashion through activation of the PI3-kinase pathway. Conversely, HGF did not promote MHC expression due a reduction in phosphorylation of both the MAP-kinase and the PI3-kinase pathways, a pattern of response different than the response of proliferating RS satellite cells to HGF. CONCLUSIONS: HGF did not induce myogenic differentiation of RS satellite cells. Conversely, IGF-1 promoted myogenic differentiation of RS satellite cells via the PI3-K pathway likewise proliferating RS satellite cells. These findings may be useful for developing novel techniques for regenerating the human RS to treat urinary incontinence.

Retroperitoneoscopic treatment of ovarian vein syndrome.

In this paper, we describe a case of ovarian vein syndrome (OVS) successfully treated with retroperitoneoscopic techniques. A 41-year-old woman complained with right flank pain, especially with a recumbent position. OVS was diagnosed and ureterolysis and ovarian vein resection were successfully performed, using retroperitoneoscopic techniques. The patient has been completely pain free for 36 months of follow-up. To our knowledge, no previous reports have described the retroperitoneoscopic treatment of OVS. With the minimally invasive approach, postoperative recovery and patient quality of life were markedly improved.