ABSTRACT
Hypertrophic pachymeningitis (HP) is a rare inflammatory disease characterized by thickening of the dura mater. HP develops with several inflammatory diseases. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and IgG4 related disease are reported as 2 major causes. With hematologic diseases, only 3 cases have been reported. We report the case of myelodysplastic syndrome (MDS) developing HP. Our case provides a thought-provoking hypothesis regarding the potential relationship between MDS and HP.
ABSTRACT
The gut-skin axis has recently been widely recognized, and both the gut and skin have been found to affect each other through a bidirectional connection; however, the precise mechanisms remain to be elucidated. Therefore, we aimed to investigate the effects of chronic skin damage (CSD) on mouse intestines. Following the CSD model, 4% sodium dodecyl sulfate was applied to the back-shaved murine skin six times for 2 weeks after tape stripping. The small and large intestines were analyzed histologically and immunologically, respectively. Intestinal permeability was measured using fluorescein isothiocyanate-conjugated-dextran. The role of interleukin-13 (IL-13) in the ileum was investigated using an anti-IL-13 antibody. Apoptotic intestinal cells were analyzed using TUNEL staining. Villus atrophy was observed in the small intestine in the CSD model, along with increased permeability. Mast cells, but not T cells, eosinophils, or innate lymph cell-2, were increased in the intestinal mucosa. However, no significant changes were observed in the large intestine. mRNA expression of IL-13 was increased only in the ileum of the CSD model. Apoptotic intestinal epithelial cells were significantly increased in the ileum of the CSD model. Administration of an anti-IL-13 antibody ameliorated the intestinal damage caused by CSD, along with decreased apoptotic cells and mast cell infiltration. Skin damage causes morphological changes in the small intestine, accompanied by increased intestinal permeability, possibly through the IL-13-induced apoptosis of mast cells in the epithelium. Surfactant-mediated mechanical skin damage can cause a leaky gut.
Subject(s)
Apoptosis , Interleukin-13 , Intestinal Mucosa , Animals , Apoptosis/drug effects , Interleukin-13/metabolism , Mice , Intestinal Mucosa/pathology , Intestinal Mucosa/immunology , Intestinal Mucosa/drug effects , Skin/pathology , Skin/immunology , Mast Cells/immunology , Intestine, Small/immunology , Intestine, Small/pathology , Male , Sodium Dodecyl Sulfate , Disease Models, Animal , Permeability , Ileum/pathology , Ileum/immunology , Ileum/metabolism , Mice, Inbred C57BL , Chronic Disease , Atrophy , Skin Diseases/pathology , Skin Diseases/immunologyABSTRACT
The anti-CD38 antibody daratumumab (Dara) has been reported to improve the prognosis of multiple myeloma (MM) patients, but its use before autologous stem cell transplantation (ASCT) remains controversial. To clarify the prognostic impact of Dara before ASCT on MM, we performed a retrospective observational analysis. We analyzed 2626 patients who underwent ASCT between 2017 and 2020. In the comparison between patients not administered Dara (Dara- group) and those administered Dara (Dara+ group), the 1-year progression-free survival (PFS) rates were 87.4% and 77.3% and the 1-year overall survival (OS) rates were 96.7% and 90.0%, respectively. In multivariate analysis, age <65 years (p = 0.015), low international staging system (ISS) stage (p < 0.001), absence of unfavorable cytogenic abnormalities (p < 0.001), no Dara use before ASCT (p = 0.037), and good treatment response before ASCT (p < 0.001) were independently associated with superior PFS. In matched pair analysis, the PFS/OS of the Dara- group were also significantly superior. For MM patients who achieved complete or very good partial response (CR/VGPR) by Dara addition before ASCT, both PFS and OS significantly improved. However, in patients who did not achieve CR/VGPR before ASCT, the PFS/OS of the Dara+ group were significantly inferior to those of the Dara- group.
Subject(s)
Antibodies, Monoclonal , Multiple Myeloma , Transplantation, Autologous , Humans , Multiple Myeloma/therapy , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Female , Male , Middle Aged , Retrospective Studies , Aged , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/administration & dosage , Adult , Hematopoietic Stem Cell Transplantation/methods , Prognosis , Progression-Free Survival , Treatment OutcomeABSTRACT
Patients with advanced cancer are frequently burdened with a severe sensation of fatigue called cancer-related fatigue (CRF). CRF is induced at various stages and treatments, such as cachexia and chemotherapy, and reduces the overall survival of patients. Objective and quantitative assessment of CRF could contribute to the diagnosis and prediction of treatment efficacy. However, such studies have not been intensively performed, particularly regarding metabolic profiles. Here, we conducted plasma metabolomics of 15 patients with urological cancer. The patients with and without fatigue, including those with cachexia or chemotherapy-induced fatigue, were compared. Significantly lower concentrations of valine and tryptophan were observed in fatigued patients than in non-fatigued patients. In addition, significantly higher concentrations of polyamine pathway metabolites were observed in patients with fatigue and cachexia than in those without cachexia. Patients with exacerbated fatigue due to chemotherapy showed significantly decreased cysteine and methionine metabolism before chemotherapy compared with those without fatigue exacerbation. These findings suggest that plasma metabolic profiles could help improve the diagnosis and monitoring of CRF.
Subject(s)
Cachexia , Neoplasms , Humans , Cachexia/etiology , Cachexia/diagnosis , Neoplasms/complications , Neoplasms/drug therapy , Metabolomics , Metabolome , Fatigue/etiologyABSTRACT
Multiple myeloma (MM) is a cancer of plasma cells. Normal (NL) cells are considered to pass through a precancerous state, such as monoclonal gammopathy of undetermined significance (MGUS), before transitioning to MM. In the present study, we acquired Raman spectra at three stages-834 NL, 711 MGUS, and 970 MM spectra-and applied the dynamical network biomarker (DNB) theory to these spectra. The DNB analysis identified MGUS as the unstable pre-disease state of MM and extracted Raman shifts at 1149 and 1527-1530 cm-1 as DNB variables. The distribution of DNB scores for each patient showed a significant difference between the mean values for MGUS and MM patients. Furthermore, an energy landscape (EL) analysis showed that the NL and MM stages were likely to become stable states. Raman spectroscopy, the DNB theory, and, complementarily, the EL analysis will be applicable to the identification of the pre-disease state in clinical samples.
Subject(s)
Monoclonal Gammopathy of Undetermined Significance , Multiple Myeloma , Paraproteinemias , Humans , Multiple Myeloma/diagnosis , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Spectrum Analysis, Raman , Paraproteinemias/diagnosis , Biomarkers , Disease ProgressionABSTRACT
Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. Prior IAPi such as LCL161 has high affinity to cIAP1 and cIAP2 resulting in inferior inhibiting activity against XIAP. A novel dimeric IAPi, AZD5582 (C58H78N8O8), have high binding potency to XIAP with EC50 dose of 15 nM, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition and inhibited JAK-STAT signaling triggered by IL-6. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy.
Subject(s)
Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Interleukin-6 , Cell Line, Tumor , Apoptosis , Inhibitor of Apoptosis Proteins/metabolism , Inhibitor of Apoptosis Proteins/pharmacology , X-Linked Inhibitor of Apoptosis Protein/metabolism , X-Linked Inhibitor of Apoptosis Protein/pharmacologyABSTRACT
Chimeric-antigen-receptor (CAR) T-cell therapy for CD19-expressing B-cell malignancies is already widely adopted in clinical practice. On the other hand, the development of CAR-T-cell therapy for T-cell malignancies is in its nascent stage. One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110. We generated second (CD28) and third (CD28/4-1BB) generation CD26-targeted CAR-T-cells (CD26-2G/3G) using YS110 as the single-chain variable fragment. When co-cultured with CD26-overexpressing target cells, CD26-2G/3G strongly expressed the activation marker CD69 and secreted IFNgamma. In vitro studies targeting the T-cell leukemia cell line HSB2 showed that CD26-2G/3G exhibited significant anti-leukemia effects with the secretion of granzymeB, TNFα, and IL-8, with 3G being superior to 2G. CD26-2G/3G was also highly effective against T-cell lymphoma cells derived from patients. In an in vivo mouse model in which a T-cell lymphoma cell line, KARPAS299, was transplanted subcutaneously, CD26-3G inhibited tumor growth, whereas 2G had no effect. Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies.
Subject(s)
Lymphoma, T-Cell , Receptors, Chimeric Antigen , Animals , Mice , T-Lymphocytes , CD28 Antigens , Dipeptidyl Peptidase 4 , Antibodies, Monoclonal , Cell- and Tissue-Based TherapyABSTRACT
A potential association between hematopoietic stem cell status in bone marrow and surrounding bone tissue has been hypothesized, and some studies have investigated the link between blood count and bone mineral density (BMD), although their exact relationship remains controversial. Moreover, biological factors linking the two are largely unknown. In our present study, we found no clear association between platelet count and BMD in the female group, with aging having a very strong effect on BMD. On the other hand, a significant negative correlation was found between platelet count and BMD in the male group. As a potential mechanism, we examined whether megakaryocytes, the source of platelet production, secrete cytokines that regulate BMD, namely OPG, M-CSF, and RANKL. We detected the production of these cytokines by megakaryocytes derived from bone marrow mononuclear cells, and found that RANKL was negatively correlated with BMD. This finding suggests that RANKL production by megakaryocytes may mediate the negative correlation between platelet count and BMD. To our knowledge, this is the first report to analyze bone marrow cells as a mechanism for the association between blood count and BMD. Our study may provide new insights into the development and potential treatment of osteoporosis.
ABSTRACT
BACKGROUND: Mild blast-induced traumatic brain injury (bTBI) induces various gut symptoms resembling human irritable bowel syndrome (IBS) as one of mental and behavioral disorders. However, the underlying mechanisms remain unclear. We investigated whether the extremely localized brain impact extracranially induced by laser-induced shock wave (LISW) evoked IBS-like phenomenon including visceral hypersensitivity and intestinal hyperpermeability in rats. METHODS: The rats were subjected to LISW on the scalp to shock the entire brain. Visceral hypersensitivity was evaluated by the threshold pressure of abdominal withdrawal reflex (AWR) using a colorectal distension test. Permeability was evaluated by the concentration of penetrating FITC-dextran from intestine and the mRNA expression levels of tight junction family proteins. Involvement of corticotropin-releasing factor receptor (CRFR) 1 and 2 was examined by evaluating mRNA expression and modulating CRFR function with agonist, recombinant CRF (10 µg/kg), and antagonist, astressin (33 µg/kg). High-throughput sequencing of the gut microbiota was performed by MiSeqIII instrument and QIIME tool. KEY RESULTS: The thresholds of the AWR were significantly lowered after LISW. Permeability was increased in small intestine by LISW along with decreased expression of tight junction ZO-1. LISW significantly increased CRFR1 expression and decreased CRFR2 expression. Visceral hypersensitivity was significantly aggravated by CRFR agonist and suppressed by CRFR antagonist. The α- and ß-diversity of the fecal microbiota was altered after LISW. CONCLUSIONS AND INFERENCES: LISW provoked visceral hypersensitivity, small intestinal hyperpermeability, altered expression of CRFRs and changes in the microbiota, suggesting that genuine bTBI caused by LISW can induce a pathophysiology comparable to that of human IBS.
Subject(s)
Brain Concussion , Irritable Bowel Syndrome , Humans , Rats , Animals , Corticotropin-Releasing Hormone/metabolism , Disease Models, Animal , RNA, MessengerABSTRACT
Background/Aims: Recent studies indicate that probiotics, which have attracted attention as a treatment for irritable bowel syndrome, affect intestinal homeostasis. In this study, we investigated whether Zygosaccharomyces sapae (strain I-6), a probiotic yeast isolated from miso (a traditional Japanese fermented food), could improve irritable bowel syndrome symptoms. Methods: Male Wistar rats were exposed to water avoidance stress (WAS). The number of defecations during WAS and the visceral hypersensitivity before and after WAS were evaluated using colorectal distension. Tight junction changes were assessed by Western blotting. Some rats were fed with strain I-6 or ß-glucan from strain I-6. Changes in the intestinal microbiota were analyzed. The effect of fecal microbiota transplantation after WAS was evaluated similarly. Caco-2 cells were stimulated with interleukin-1ß and tight junction changes were investigated after coculture with strain I-6. Results: The increased number of stool pellets and visceral hypersensitivity induced by WAS were suppressed by administering strain I-6. The decrease in tight junction protein occludin by WAS was reversed by the administration of strain I-6. ß-Glucan from strain I-6 also suppressed those changes induced by WAS. In the rat intestinal microbiota, treatment with strain I-6 altered the ß-diversity and induced changes in bacterial occupancy. Upon fecal microbiota transplantation, some symptoms caused by WAS were ameliorated. Conclusions: These results suggest that traditional fermented foods such as miso in Japan are valuable sources of probiotic yeast candidates, which may be useful for preventing and treating stress-induced visceral hypersensitivity.
ABSTRACT
DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different blood cancer cell lines. Specifically, 1G244 inhibited DPP9 to induce GSDMD-mediated-pyroptosis at low concentrations and inhibited DPP8 to cause caspase-3-mediated-apoptosis at high concentrations. HCK expression is necessary to induce susceptibility to pyroptosis but does not participate in the induction of apoptosis. To further characterize this DPP8-dependent broad-spectrum apoptosis induction effect, we evaluated the potential antineoplastic role for an analog of 1G244 with higher DPP8 selectivity, tominostat (also known as 12 m). In vitro studies demonstrated that the cytotoxic effect of 1G244 at high concentrations was enhanced in tominostat. Meanwhile, in vivo work showed tominostat exhibited antitumor activity that was more effective on a cell line sensitive to 1G244, and at higher doses, it was also effective on a cell line resistant to 1G244. Importantly, the weight loss morbidity associated with increasing doses of 1G244 was not observed with tominostat. These results suggest the possible development of novel drugs with antineoplastic activity against selected hematological malignancies by refining and increasing the DPP8 selectivity of tominostat.
Subject(s)
Hematologic Neoplasms , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/metabolism , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Humans , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , PyroptosisABSTRACT
A 46-year-old woman was referred for hypertension and a right adrenal tumor. Primary aldosteronism (PA) was suspected because of the high plasma aldosterone concentration-to-plasma renin activity ratio. However, a subsequent evaluation revealed coexistent PA and pheochromocytoma. We performed laparoscopic right adrenalectomy. Histology of the resected adrenal gland confirmed pheochromocytoma and multiple aldosterone-producing adrenocortical micronodules. Following adrenalectomy, the urinary catecholamine levels normalized, and hyperaldosteronism improved but persisted. Hypertension also improved but persisted and was normalized with spironolactone. The clinical course indicated that the PA lesions were likely bilateral. This was a histologically proven case of coexistent pheochromocytoma and PA due to multiple aldosterone-producing micronodules.
Subject(s)
Adrenal Gland Neoplasms , Hyperaldosteronism , Hypertension , Pheochromocytoma , Female , Humans , Middle Aged , Aldosterone , Pheochromocytoma/complications , Pheochromocytoma/surgery , Adrenal Glands/diagnostic imaging , Adrenal Glands/pathology , Hyperaldosteronism/complications , Hyperaldosteronism/surgery , Adrenalectomy , Adrenal Gland Neoplasms/complications , Adrenal Gland Neoplasms/surgery , Adrenal Gland Neoplasms/pathology , Hypertension/complications , Hypertension/surgeryABSTRACT
Pembrolizumab has been widely used to treat advanced urothelial carcinoma that has progressed after first-line platinum-based chemotherapy. Because its clinical benefits are limited, biomarkers that can predict a good response to pembrolizumab are required. The prognostic nutritional index (PNI), calculated using the serum albumin level and peripheral lymphocyte count, has been evaluated as a predictive biomarker in cancer immunotherapy. The present study investigated the application of PNI as a predictive biomarker for pembrolizumab response in patients with advanced urothelial cancer. A retrospective study was conducted on 34 patients treated with pembrolizumab at Shiga University of Medical Science Hospital between January 2018 and July 2022. The posttreatment PNI (post-PNI) was calculated within 2 months of starting pembrolizumab. The present study investigated the association between post-PNI and objective response, overall survival (OS) and progression-free survival (PFS). The patient cohort was stratified into two categories, high and low post-PNI groups, with a cutoff value of post-PNI at 40. The higher post-PNI group demonstrated a better disease control rate than the lower post-PNI group (complete response + partial response + stable disease, 75 vs. 21%, P=0.004). Regarding median OS, the higher post-PNI group exhibited a significantly longer survival time than the lower post-PNI group (23.1 vs. 2.9 months, P<0.001). Similarly, the higher post-PNI group exhibited a significantly longer PFS than the lower post-PNI group (10.2 vs.1.9 months, P<0.001). Multivariate analysis showed that a higher post-PNI value was an independent predictor for OS (hazard ratio, 0.04; 95% confidence interval, 0.01-0.14; P<0.001) and PFS (hazard ratio, 0.12; 95% confidence interval, 0.04-0.35; P<0.001). The present study indicated that the post-PNI was a predictor of favorable clinical outcomes in patients treated with pembrolizumab for advanced urothelial carcinoma.
ABSTRACT
We report the case of a 76-year-old female with diffuse large B cell lymphoma who developed tumor lysis syndrome (TLS) and subsequent acute kidney injury (AKI) due to massive hyperphosphatemia during the prophylactic use of rasburicase. Our case showed no hyperphosphatemia before chemotherapy but had elevated uric acid and creatinine levels and unilateral hydronephrosis due to paraaortic lymphadenopathy. TLS risk was classified as high risk because of bulky mass, LDH elevation, and renal disturbance. With rasburicase use, uric acid was completely controlled but massive hyperphosphatemia and, subsequently, AKI developed. Immediate kidney replacement therapy led to improvement of hyperphosphatemia and AKI. In the rasburicase era, hyperphosphatemia has been a key target for preventing and treating TLS. Renal replacement therapy is the only effective option for lowering hyperphosphatemia and treating AKI.
ABSTRACT
BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy, the mechanism of which is involved in oxidative stress, can be lethal due to hemorrhage. Thus, we aimed to investigate the effect of hydrogen-rich water (HRW), in terms of oxidative stress, on intestinal mucosal damage as well as changes in the gut microbiome and the short-chain fatty acids (SCFAs) content in feces. METHODS: Hydrogen-rich water was orally administered for 5 days to investigate the effectiveness of indomethacin-induced enteropathy in mice. Small intestinal damage and luminal reactive oxygen species (ROS) were evaluated to investigate the ameliorating effects of hydrogen. Then, components of the gut microbiome were analyzed; fecal microbiota transplantation (FMT) was performed using the cecal contents obtained from mice drinking HRW. The cecal contents were analyzed for the SCFAs content. Finally, cells from the macrophage cell line RAW264 were co-cultured with the supernatants of cecal contents. RESULTS: Hydrogen-rich water significantly ameliorated IND-induced enteropathy histologically and reduced the expression of IND-induced inflammatory cytokines. Microscopic evaluation revealed that luminal ROS was significantly reduced and that HRW did not change the gut microbiota; however, FMT from HRW-treated animals ameliorated IND-induced enteropathy. The SCFA content in the cecal contents of HRW-treated animals was significantly higher than that in control animals. The supernatant had significantly increased interleukin-10 expression in RAW264 cells in vitro. CONCLUSION: Hydrogen-rich water ameliorated NSAID-induced enteropathy, not only via direct antioxidant effects but also via anti-inflammatory effects by increasing luminal SCFAs. These results suggest that hydrogen may have therapeutic potential in small intestinal inflammatory diseases.
Subject(s)
Intestinal Diseases , Mice , Animals , Reactive Oxygen Species , Intestinal Diseases/chemically induced , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents/adverse effects , Fatty Acids, Volatile , Hydrogen/pharmacology , Hydrogen/therapeutic use , WaterABSTRACT
Prostate cancer is the most common genitourinary cancer in men. Population-based serum prostate-specific antigen (PSA) testing is used to screen men for the early detection of asymptomatic prostate cancer. The present study compared the features of patients with prostate cancer in Kusatsu City, the only municipality in Shiga Prefecture of Japan to implement organized PSA screening, with those in other municipalities. The target population for organized PSA screening by mail invitation was men ≥50 years. Patients were pathologically diagnosed via prostate biopsy because of elevated serum PSA. This multicenter observational study was subsequently conducted in 14 hospitals. The following information was extracted from patient records: age, reason for PSA testing, initial PSA level, Gleason score, clinical stage, and place of residence. Risk classification was defined as low, intermediate, high, and advanced. Each patient was stratified according to their city/town. A total of 984 patients diagnosed with prostate cancer in Shiga in 2012 and 2017 were analyzed, of which 955 (97%) were opportunistically tested, with the remaining 29 (3%) assessed by organized screening. In Kusatsu, 93 patients were diagnosed, of whom 26 (28%) were detected by organized screening. By contrast, only three of 891 patients (0.3%) were detected by organized screening in other municipalities. Of patients in Kusatsu, cases identified by opportunistic testing had a higher initial PSA value (P=0.010) than those identified by organized screening. However, patients detected through opportunistic testing in Kusatsu City were younger (P=0.034), had a lower PSA value (P=0.001), and improved risk classification (P<0.001) than those in other municipalities. It was concluded that more patients were diagnosed with early-stage cancer by organized PSA screening. Furthermore, population-based PSA screening in Kusatsu City may have indirectly affected early detection, even by opportunistic testing.
ABSTRACT
The present study aimed to use real-world Japanese data to compare the treatment outcome of conventional hormonal therapy to that of using androgen receptor axis-targeted (ARAT) agents for patients with metastatic castration-resistant prostate cancer. The overall survival between the conventional hormonal therapy group and the ARAT agent therapy group was compared using a group of 75 Japanese patients who were treated for metastatic castration-resistant prostate cancer. A subgroup analysis was carried out and the risk factors that affected overall survival (OS) were determined. The median OS from the time of prostate-specific antigen recurrence was 73.1 months in the ARAT group and 45.2 months in the conventional treatment group (P=0.414). Although OS tended to be slightly longer in the ARAT group, the difference between the groups was not significant. Subgroup analysis suggested that the therapeutic outcome of using ARAT agents tended to be less beneficial in patients who were older, and in those with a higher tumor volume or low Gleason grade. In conclusion, use of ARAT agents did not impart a significant survival benefit to patients with metastatic castration-resistant prostate cancer when compared with survival rates in response to conventional therapy. However, there was some clinical benefit when ARAT agents were used after patients developed castration-resistant prostate cancer. These findings suggest that up-front therapy using ARAT agents at the time of the initial hormone therapy can impart clinical benefit in Japanese patients with metastatic prostate cancer.
ABSTRACT
BACKGROUND AND AIM: The functions of basophils have not been elucidated until recently because of their rarity. However, with recent developments in basophil-specific antibodies and basophil-deficient animals, the roles of basophils in various diseases related to chronic inflammation have been clarified. In this study, we aimed to investigate the roles of basophils in human ulcerative colitis (UC) and oxazolone (OXA) colitis using genetically engineered Mcpt8DTR mice. METHODS: Immunohistochemical staining of human colon specimens was performed to examine the involvement of basophils in the pathogenesis of UC. We examined the correlation between the number of infiltrating basophils and the UC endoscopic index of severity (UCEIS), Mayo score, and Matts score. We also examined the correlation between eosinophil count and basophil infiltration. In murine experiments, we examined whether basophil infiltration was involved in OXA-induced colitis and whether basophil depletion improved inflammation in Mcpt8DTR mice. RESULTS: Colonic basophil infiltration was significantly increased in patients with UC. There were significant correlations between UCEIS, Mayo score, Matts score, and the number of infiltrating basophils. In murine OXA-induced colitis, a significant increase in basophil infiltration was observed. When basophils were depleted by diphtheria toxin in Mcpt8DTR mice, inflammation improved significantly and mRNA expression of some proinflammatory cytokines, including Tnf-α and Ifn-γ decreased significantly. CONCLUSION: Basophil infiltration correlated with endoscopic, clinical, and pathological scores in human UC independently of eosinophil infiltration, and depletion of basophils ameliorated mucosal inflammation in murine OXA-induced colitis, collectively suggesting that basophils exert a proinflammatory role in chronic intestinal inflammation such as UC.
Subject(s)
Colitis, Ulcerative , Colitis , Animals , Basophils/metabolism , Basophils/pathology , Colitis/chemically induced , Colitis/pathology , Colitis, Ulcerative/pathology , Humans , Inflammation/pathology , Intestines/pathology , Mice , OxazoloneABSTRACT
Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a systemic condition associated with fibroinflammatory lesions and is characterized by elevated serum IgG4 levels and IgG4-positive cell infiltration into the affected tissues. It has been reported that IgG4-RD affects a variety of organs but uncommonly affects the gastrointestinal tract. In particular, there are few cases of lesions in the small intestine, except for sclerosing mesenteritis, which were mostly diagnosed from surgical specimens. Herein, we describe the case of a 70-year-old man who initially presented with abdominal pain, headache, later cognitive decline, and gait disturbance caused by IgG4-RD. Colonoscopy revealed irregular ulcers in the terminal ileum, and computed tomography of the head showed hypertrophic pachymeningitis. Numerous IgG4-positive cells were detected in the ileal and dural biopsies. We diagnosed the patient with IgG4-RD and started steroid pulse therapy. After initiation of treatment, the symptoms quickly improved. The patient was discharged from the hospital after starting oral prednisolone treatment (30 mg). The dosage was gradually reduced to 10 mg. A follow-up colonoscopy revealed scarring of the ileal ulcers. This case may provide valuable information regarding the endoscopic findings of small intestinal lesions in IgG4-RD.
ABSTRACT
A 78-year-old man presented to our hospital with a history of 10 kg weight loss within 6 months previously and general fatigue and fever for 2 and 1 months, respectively. On hospitalisation, the patient was diagnosed with polyarteritis nodosa after multiple microaneurysms were observed in the liver, kidney, pancreas, and mesenteries. He achieved remission with the administration of 1000 mg methylprednisolone for 3 days, followed by prednisolone (55 mg/day). Steroids were successfully tapered with no re-elevation in inflammation. Two months after the administration of steroids, the patient complained of acute abdominal pain and developed severe acute pancreatitis. During treatment for pancreatitis, the patient died due to septic shock and disseminated intravascular coagulation. An autopsy revealed necrotising vasculitis in the intrapancreatic arteries and ischaemia of the downstream arterioles resulting in acute pancreatitis.