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ABSTRACT: Graft-versus-host disease (GVHD) is the major obstacle to performing allogeneic hematopoietic cell transplantation (allo-HCT). We and others have shown that intestinal stem cells are targeted in lower gastrointestinal GVHD. A leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-expressing gastric stem cells (GSCs) reside at the base of the gastric glands in mice. After experimental allo-HCT, Lgr5+ GSCs significantly decreased. Parietal cells, which underwent continuous renewal by GSCs, were injured in gastric GVHD, leading to failure of gastric acidification and aerobic bacterial overgrowth in the duodenum. Fate-mapping analysis demonstrated that administration of R-Spondin1 (R-Spo1) that binds to Lgr5 for 6 days in naïve mice significantly increased proliferating epithelial cells derived from Lgr5+ GSCs. R-Spo1 administered on days -3 to -1 and from days +1 to +3 of allo-HCT protected GSCs, leading to amelioration of gastric GVHD and restoration of gastric acidification, and suppression of aerobic bacterial overgrowth in the duodenum. In conclusion, Lgr5+ GSCs were targeted by gastric GVHD, resulting in disruption of the gastric homeostasis, whereas R-Spo1 protected Lgr5+ GSCs from GVHD and maintained homeostasis in the stomach.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Ratones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , EstómagoRESUMEN
BACKGROUND: The degrees of adverse effects with carboplatin (CBDCA) are influenced by interindividual differences in the area under the curve (AUC), whereas renal function is not considered in the CBDCA dose design for dexamethasone, etoposide, ifosfamide, and CBDCA (DeVIC) therapy. We conducted this study to evaluate the association between the AUC and incidence of severe thrombocytopenia in patients treated with DeVIC with or without rituximab (DeVIC ± R). METHODS: We retrospectively analyzed clinical data for 36 patients with non-Hodgkin's lymphoma who received DeVIC ± R between May 2013 and January 2021 at the National Hospital Organization Hokkaido Cancer Center. The AUC of CBDCA (AUCactual) was calculated backward using a variant of the Calvert formula. RESULTS: The median AUCactual was 4.6 (interquartile range: 4.3-5.3) min mg/mL and AUCactual was negatively correlated with the nadir platelet count (r = -0.45; P < 0.01). Multivariate analysis showed that AUCactual ≥ 4.3 versus < 4.3 was an independent factor predictive of severe thrombocytopenia (odds ratio: 19.3, and 95% confidence interval: 1.45-258; P = 0.02). CONCLUSION: This study suggests that the CBDCA dosing design considering renal function can reduce the risk of severe thrombocytopenia in DeVIC ± R therapy.
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Linfoma no Hodgkin , Trombocitopenia , Humanos , Carboplatino , Incidencia , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Linfoma no Hodgkin/tratamiento farmacológico , Trombocitopenia/inducido químicamente , Trombocitopenia/epidemiología , Etopósido , Área Bajo la CurvaAsunto(s)
Encefalitis Viral , Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 6 , Hiponatremia , Infecciones por Roseolovirus , Humanos , Hiponatremia/diagnóstico , Hiponatremia/etiología , Trasplante Homólogo/efectos adversos , Encefalitis Viral/diagnóstico , Encefalitis Viral/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones por Roseolovirus/diagnóstico , ADN ViralRESUMEN
Granulopoiesis in the bone marrow adjusts cellular output as demand for neutrophils changes. Reactive granulopoiesis is induced by profound neutropenia, but its mechanism remains to be clarified. We herein explored its mechanisms using mouse models of syngeneic hematopoietic stem cell transplantation (SCT) and 5-fluorouracil-induced neutropenia. After SCT, T cell production of IL-17A was up-regulated. Neutrophil recovery was significantly delayed in IL-17A-deficient or T cell-deficient RAG1-/- mice, and adoptive transfer of wild-type (WT) T cells facilitated neutrophil engraftment. Gut decontamination with oral antibiotics suppressed T cell production of IL-17A and impaired neutrophil recovery. Transplantation of fecal microbiota collected from neutropenic, not naive, mice promoted neutrophil recovery in these mice, suggesting that neutropenia-associated microbiota had a potential to stimulate reactive granulopoiesis. Our study uncovered a cross talk between gut microbiota and neutropenia after SCT and chemotherapy.
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Microbioma Gastrointestinal , Neutropenia , Ratones , Animales , Interleucina-17 , Linfocitos T , Ratones NoqueadosRESUMEN
Evans syndrome presents as concurrent autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Systemic lupus erythematosus (SLE) is the most frequent autoimmune disorder associated with Evans syndrome. We herein report a case of new-onset Evans syndrome associated with SLE after BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccination in a 53-year-old woman. Blood examination at diagnosis showed hemolytic anemia with a positive Coombs test and thrombocytopenia. Hypocomplementemia and the presence of lupus anticoagulant indicated a strong association with SLE. Prednisolone administration rapidly restored hemoglobin level and platelet count. This case suggests that mRNA COVID-19 vaccination may cause an autoimmune disorder. Physicians should be aware of this adverse reaction by mRNA COVID-19 vaccination and should consider the benefits and risks of vaccination for each recipient.
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Anemia Hemolítica Autoinmune/etiología , Vacuna BNT162/efectos adversos , Lupus Eritematoso Sistémico/etiología , Trombocitopenia/etiología , Vacunación/efectos adversos , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/tratamiento farmacológico , Femenino , Pruebas Hematológicas/métodos , Hemoglobinas , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Persona de Mediana Edad , Recuento de Plaquetas , Prednisolona/administración & dosificación , Púrpura Trombocitopénica Idiopática , Medición de Riesgo , Trombocitopenia/diagnóstico , Trombocitopenia/tratamiento farmacológicoRESUMEN
BACKGROUND: In patients with hepatitis C virus (HCV) and malignant lymphoma, hepatitis C flare during R-CHOP can result in discontinuation of treatment. However, appropriate therapeutic strategies for managing hepatitis C flare during R-CHOP have not been established, and this issue is complicated by conflicting results regarding the use of direct-acting antivirals in patients with uncontrolled malignancies. CASE PRESENTATION: We report the first case of effective and safe treatment with on-demand 8-week glecaprevir and pibrentasvir for hepatitis C flare during R-CHOP in a patient with diffuse large B-cell lymphoma (DLBCL). The patient completed five additional courses of R-CHOP without hepatic toxicity. A complete response of DLBCL and a sustained virological response were observed at 24 weeks after glecaprevir and pibrentasvir completion. CONCLUSION: On-demand, direct-acting antivirals could be a novel strategy for managing hepatitis C flare during R-CHOP.
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Ácidos Aminoisobutíricos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Ciclopropanos/administración & dosificación , Hepacivirus/genética , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Lactamas Macrocíclicas/administración & dosificación , Leucina/análogos & derivados , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Prolina/análogos & derivados , Quinoxalinas/administración & dosificación , Sulfonamidas/administración & dosificación , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Genotipo , Humanos , Leucina/administración & dosificación , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Prolina/administración & dosificación , Pirrolidinas , ARN Viral/sangre , ARN Viral/genética , Rituximab/uso terapéutico , Respuesta Virológica Sostenida , Vincristina/uso terapéutico , Carga Viral/efectos de los fármacosRESUMEN
Graft-versus-host disease (GVHD) and infection are major obstacles to successful allogeneic hematopoietic stem cell transplantation (HSCT). Intestinal goblet cells form the mucus layers, which spatially segregate gut microbiota from host tissues. Although it is well known that goblet cell loss is one of the histologic features of GVHD, effects of their loss in pathophysiology of GVHD remain to be elucidated. In mouse models of allogeneic HSCT, goblet cells in the colon were significantly reduced, resulting in disruption of the inner mucus layer of the colon and increased bacterial translocation into colonic mucosa. Pretransplant administration of interleukin-25 (IL-25), a growth factor for goblet cells, protected goblet cells against GVHD, prevented bacterial translocation, reduced plasma concentrations of interferon-γ (IFN-γ) and IL-6, and ameliorated GVHD. The protective role of IL-25 was dependent on Lypd8, an antimicrobial molecule produced by enterocytes in the colon that suppresses motility of flagellated bacteria. In clinical colon biopsies, low numbers of goblet cells were significantly associated with severe intestinal GVHD, increased transplant-related mortality, and poor survival after HSCT. Goblet cell loss is associated with poor transplant outcome, and administration of IL-25 represents an adjunct therapeutic strategy for GVHD by protecting goblet cells.
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Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Células Caliciformes , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Mucosa Intestinal , RatonesRESUMEN
Several studies have demonstrated increased pericardial effusion during anti-PD-1 immunotherapy, and treatment in patients who have developed pericardial tamponade is controversial. In this study, we describe a 63-year-old woman with stage IVA lung adenocarcinoma given pembrolizumab as a first-line therapy. After four cycles of pembrolizumab treatment, the patient suddenly developed a pericardial tamponade. Although pericardial effusion was increased, her tumor lesions were reduced. After an emergency pericardiocentesis, she continued the pembrolizumab therapy without recurrent pericardial effusions for three months until the primary tumor and lymph node metastasis progressed. Nine months after the pericardiocentesis, the patient died of progressive lung cancer, but pericardial effusion did not recur throughout the treatment course. This case study suggests that pembrolizumab therapy can be continued with a strict follow-up in some patients with pembrolizumab-induced pericardial tamponade. KEY POINTS: ⢠Significant findings of the study Our patient developed pericardial tamponade during pembrolizumab treatment but continued pembrolizumab treatment after emergency pericardiocentesis without recurrent pericardial effusions. ⢠What this study adds Pembrolizumab treatments may be resumed with a strict follow-up in some patients with treatment-related pericardial tamponade.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Taponamiento Cardíaco/patología , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Taponamiento Cardíaco/inducido químicamente , Femenino , Humanos , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , PronósticoRESUMEN
STUDY DESIGN: Retrospective study. PURPOSE: To evaluate the efficacy of the Spinal Instability Neoplastic Score (SINS) in predicting surgical outcomes and survival. Patients were categorized into two groups according to the SINS, and their surgical outcomes and survival following decompression and stabilization were assessed. OVERVIEW OF LITERATURE: Palliative surgery in patients with a life expectancy ≥3 months may effectively improve their overall condition in the long term. Currently, the effectiveness of the SINS for predicting surgical results and survival remains controversial. METHODS: This study included 44 patients who underwent decompression and stabilization for spinal metastases at Yokosuka Kyosai Hospital between 2008 and 2017. The patients were divided into two groups: stable (SINS ≤12) and unstable (SINS ≥13). Changes in the Frankel score and Eastern Cooperative Oncology Group Performance Status (ECOG-PS) were compared between the two groups, and patient survival was evaluated according to the SINS, Tokuhashi score, and Katagiri score. RESULTS: The stable group (SINS range, 7-12) included 24 patients while the unstable group (SINS range, 13-16) included 20 patients. The Frankel score significantly improved from 2.8 to 3.6 in the stable group (p <0.001) and from 2.7 to 3.9 in the unstable group (p <0.001). The ECOG-PS significantly improved from 3.2 to 2.1 in the stable group (p <0.001) and from 3.0 to 1.8 in the unstable group (p <0.001). There was a statistically significant difference in median survival between the two groups. CONCLUSIONS: All patients treated with palliative surgery showed favorable outcomes, as indicated by improved the Frankel score and ECOG-PS following surgery. However, median survival was significantly better in the stable group. The results of this study indicate that the SINS is appropriate for surgical decision making and may be used to predict survival.
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The R-Spondin (R-Spo) family regulates WNT signaling and stimulates the proliferation and differentiation of intestinal stem cells (ISCs). R-Spo plays a critical role in maintaining intestinal homeostasis, but endogenous producers of R-Spo in the intestine remain to be investigated. We found that R-Spo3 was the major R-Spo family member produced in the intestine and it was predominantly produced by CD45-CD90+CD31+ lymphatic endothelial cells (LECs) in the lamina propria of the intestinal mucosa. Transcriptome analysis demonstrated that LECs highly expressed R-Spo receptor, Lgr5, suggesting an autocrine stimulatory loop in LECs. LECs were significantly reduced in number, and their R-Spo3 production was impaired in intestinal graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. The impaired production of R-Spo3 in the intestine may be a novel mechanism of delayed tissue repair and defective mucosal defense in intestinal GVHD. We demonstrate a novel role of intestinal LECs in producing R-Spondin3 to maintain intestinal homeostasis.
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Células Endoteliales/patología , Endotelio Linfático/metabolismo , Enfermedad Injerto contra Huésped/patología , Mucosa Intestinal/patología , Trombospondinas/metabolismo , Animales , Comunicación Autocrina , Modelos Animales de Enfermedad , Endotelio Linfático/citología , Femenino , Perfilación de la Expresión Génica , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Mucosa Intestinal/citología , Ratones , Receptores Acoplados a Proteínas G/metabolismo , Trasplante Homólogo/efectos adversosRESUMEN
Graft-versus-host disease (GVHD) is the major complication after allogeneic stem cell transplantation (SCT). Emerging evidence indicates that GVHD leads to injury of intestinal stem cells. However, it remains to be investigated whether skin stem cells could be targeted in skin GVHD. Lgr5+ hair follicle stem cells (HFSCs) contribute to folliculogenesis and have a multipotent capacity to regenerate all epithelial cells in repair. We studied the fate of Lgr5+ HFSCs after SCT and explored the novel treatment to protect Lgr5+ HFSCs against GVHD using murine models of SCT. We found that GVHD reduced Lgr5+ HFSCs in association with impaired hair regeneration and wound healing in the skin after SCT. Topical corticosteroids, a standard of care for a wide range of skin disorders including GVHD, damaged HFSCs and failed to improve skin homeostasis, despite of their anti-inflammatory effects. In contrast, JAK1/2 inhibitor ruxolitinib significantly ameliorated skin GVHD, protected Lgr5+ HFSCs, and restored hair regeneration and wound healing after SCT. We, for the first time, found that GVHD targets Lgr5+ HFSCs and that topical ruxolitinib represents a novel strategy to protect skin stem cells and maintain skin homeostasis in GVHD.
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Enfermedad Injerto contra Huésped/etiología , Homeostasis , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Fenómenos Fisiológicos de la Piel , Células Madre/citología , Células Madre/metabolismo , Corticoesteroides/administración & dosificación , Animales , Biopsia , Epitelio/efectos de los fármacos , Epitelio/metabolismo , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/prevención & control , Folículo Piloso/citología , Ratones , Nitrilos , Pirimidinas , Trasplante de Células Madre/efectos adversos , Células Madre/efectos de los fármacosRESUMEN
The intestinal microbial ecosystem is actively regulated by Paneth cell-derived antimicrobial peptides such as α-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant α-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of α-defensins. Administration of R-Spo1 or recombinant α-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host-microbiota cross talk toward therapeutic benefits.
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Disbiosis/etiología , Disbiosis/prevención & control , Enfermedad Injerto contra Huésped/complicaciones , Células de Paneth/patología , Trombospondinas/farmacología , Trombospondinas/uso terapéutico , Administración Oral , Animales , Bacterias/metabolismo , Diferenciación Celular/efectos de los fármacos , Citoprotección/efectos de los fármacos , Disbiosis/patología , Femenino , Enfermedad Injerto contra Huésped/patología , Humanos , Intestinos/patología , Ratones Endogámicos C57BL , Células de Paneth/efectos de los fármacos , Células de Paneth/metabolismo , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Trasplante de Células Madre , Células Madre/efectos de los fármacos , Células Madre/metabolismo , alfa-Defensinas/metabolismoRESUMEN
A 22-year-old woman presented with high fever, chest tightness and cough in January 20XX. Since CT scans revealed an anterior mediastinal mass, percutaneous needle biopsies of the mass were performed and she was diagnosed with T-cell lymphoblastic lymphoma (T-LBL). After the immunophenotype of lymphocytes in her pleural effusion had been identified, she received CHOP therapy because her dyspnea worsened, and induction therapy for acute lymphoblastic leukemia was subsequently performed after confirmation of her diagnosis as T-LBL. During this induction therapy, she developed paralytic ileus. One week thereafter, she suddenly exhibited visual disturbance, headache and nausea. Her cerebrospinal fluid was normal. Magnetic resonance imaging showed symmetrical high signal intensities on T2-weighted and fluid-attenuated inversion recovery images, and low signal intensities on T1-weighted images in the cortical and subcortical white matter of the posterior parietal and occipital lobes. Based on these findings, she was diagnosed as having posterior reversible encephalopathy syndrome (PRES). During chemotherapy for hematologic malignancies, some patients with PRES reportedly develop paralytic ileus or tumor lysis syndrome. PRES should be considered in patients with neurological abnormalities following such complications during chemotherapy.