[Fecal microbiota transplantation for refractory Clostridioides difficile infection with Crohn's disease in an allogeneic bone marrow transplant recipient].

We report a case of a 15-year-old girl who developed refractory Clostridioides difficile infection (CDI) after allogeneic bone marrow transplantation (BMT). She was treated successfully with fecal microbiota transplantation (FMT). The patient who had aplastic anemia underwent allogeneic BMT from an HLA 1-locus-mismatched unrelated donor. Four months later, she developed gastrointestinal graft-versus-host disease (GVHD), and immunosuppressive treatment improved the GVHD. However, she developed CDI 5 months after BMT and experienced recurrence after that. Fifteen months after transplant, CDI relapsed despite discontinuation of immunosuppressive treatment; thus, she underwent FMT. Colonoscopy at the time of FMT revealed round aphthae, mainly in the ileocecum, and colonic biopsy revealed inflammatory cell infiltration and noncaseating epithelioid granuloma, which fulfilled the diagnostic criteria for Crohn's disease. Following FMT for CDI, she was treated with enteric budesonide and intravenous methotrexate for Crohn's disease. These interventions resulted in a marked improvement in both CDI and Crohn's disease. Twenty-eight months after FMT, both CDI and Crohn's disease remained in remission with oral mesalamine monotherapy.

Human immune responses elicited by an intranasal inactivated H5 influenza vaccine.

Intranasally administered influenza vaccines could be more effective than injected vaccines, because intranasal vaccination can induce virus-specific immunoglobulin A (IgA) antibodies in the upper respiratory tract, which is the initial site of infection. In this study, immune responses elicited by an intranasal inactivated vaccine of influenza A(H5N1) virus were evaluated in healthy individuals naive for influenza A(H5N1) virus. Three doses of intranasal inactivated whole-virion H5 influenza vaccine induced strong neutralizing nasal IgA and serum IgG antibodies. In addition, a mucoadhesive excipient, carboxy vinyl polymer, had a notable impact on the induction of nasal IgA antibody responses but not on serum IgG antibody responses. The nasal hemagglutinin (HA)-specific IgA antibody responses clearly correlated with mucosal neutralizing antibody responses, indicating that measurement of nasal HA-specific IgA titers could be used as a surrogate for the mucosal antibody response. Furthermore, increased numbers of plasma cells and vaccine antigen-specific Th cells in the peripheral blood were observed after vaccination, suggesting that peripheral blood biomarkers may also be used to evaluate the intranasal vaccine-induced immune response. However, peripheral blood immune cell responses correlated with neutralizing antibody titers in serum samples but not in nasal wash samples. Thus, analysis of the peripheral blood immune response could be a surrogate for the systemic immune response to intranasal vaccination but not for the mucosal immune response. The current study suggests the clinical potential of intranasal inactivated vaccines against influenza A(H5N1) viruses and highlights the need to develop novel means to evaluate intranasal vaccine-induced mucosal immune responses.

Current Challenge: Endoscopic Submucosal Dissection of Superficial Non-ampullary Duodenal Epithelial Tumors.

OPINION STATEMENT: With the widespread use of esophagogastroduodenoscopy in recent years, the detection rate of superficial non-ampullary duodenal epithelial tumors (SNADETs) is increasing. Most SNADETs are early-stage adenocarcinoma or benign conditions, including adenoma. Therefore, endoscopic resection is desirable from the perspective of quality of life. However, endoscopic resection for SNADETs has not yet been established. Endoscopic submucosal dissection (ESD) is the most promising method for the treatment of SNADETs, because ESD provides a high rate of en bloc resection and a low rate of recurrence regardless of the tumor size. However, the difficulty of the procedure and a high rate of severe adverse events including perforation and bleeding have become major problems. Various preventive countermeasures for adverse events, such as use of specific devices, endoscope stabilization methods, and endoscopic closure of the post-ESD ulcer using clips, are reported to reduce the risk of the adverse events of ESD for SNADETs. This article reviews and highlights the current state of ESD for SNADETs and new challenges towards safe and effective ESD.

Relationship of the quaternary structure of human secretory IgA to neutralization of influenza virus.

Secretory IgA (S-IgA) antibodies, the major contributors to humoral mucosal immunity to influenza virus infection, are polymeric Igs present in many external secretions. In the present study, the quaternary structures of human S-IgA induced in nasal mucosa after administration of intranasal inactivated influenza vaccines were characterized in relation to neutralization potency against influenza A viruses. Human nasal IgA antibodies have been shown to contain at least five quaternary structures. Direct and real-time visualization of S-IgA using high-speed atomic force microscopy (AFM) demonstrated that trimeric and tetrameric S-IgA had six and eight antigen-binding sites, respectively, and that these structures exhibited large-scale asynchronous conformational changes while capturing influenza HA antigens in solution. Furthermore, trimeric, tetrameric, and larger polymeric structures, which are minor fractions in human nasal IgA, displayed increased neutralizing potency against influenza A viruses compared with dimeric S-IgA, suggesting that the larger polymeric than dimeric forms of S-IgA play some important roles in protection against influenza A virus infection in the human upper respiratory tract.

Allogeneic Hematopoietic Cell Transplantation for Dyskeratosis Congenita: A Report of 3 Cases.

Although bone marrow failure in patients with dyskeratosis congenita (DKC) can be successfully treated with allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced intensity conditioning (RIC) regimen, the outcome of nonhematological disorders in patients with DKC treated with allo-HCT using RIC has not been fully elucidated. Here, we describe the clinical course of nonhematological disorders after allo-HCT with RIC in 3 consecutive patients with DKC. Allo-HCT with RIC was feasible in all cases; however, patient 1 developed lethal pulmonary disease and patient 2 experienced progression of hepatic fibrosis. Careful follow-up of patient-specific complications is required after allo-HCT in patients with DKC.

Sorafenib Therapy for Pediatric Acute Myeloid Leukemia with FMS-like Tyrosine Kinase 3-internal Tandem Duplication Mutations: 2 Case Reports.

Sorafenib is a promising agent for treating pediatric refractory acute myeloid leukemia (AML) exhibiting FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD); however, its optimal use needs to be established. We report 2 cases of refractory pediatric FLT3-ITD-positive AML treated with sorafenib. Case 1 underwent stem cell transplantation (SCT) without entering remission, despite the use of chemotherapy. This patient relapsed despite receiving post-SCT sorafenib. Chemotherapy combined with sorafenib successfully achieved complete remission in case 2. This patient received post-SCT sorafenib and remains in complete remission. The combination of pre-SCT and post-SCT sorafenib may thus be effective for pediatric refractory FLT3-ITD-positive AML.

Monitoring of minimal residual disease after HLA-mismatched allogeneic hematopoietic stem cell transplantation using six-color based HLA-Flow method in pediatric acute leukemia.

HLA-Flow is a flow cytometry-based method using anti-HLA antibodies against mismatched HLA alleles combined with the antibodies against antigens expressed on leukemic cells. It is a sensitive assay to determine minimal residual disease (MRD) after HLA mismatched hematopoietic stem cell transplantation (HSCT). In this study, we report the results of our HLA-Flow using six-color based multicolor fluorescence-activated cell sorting for HLA-mismatched HSCT. We performed HLA-Flow monitoring after HLA mismatched HSCT from July 2013 to July 2016 in nine patients (three with acute lymphoblastic leukemia, five with acute myeloid leukemia, and one with therapy-related acute myeloid leukemia) for MRD monitoring. We detected a relapse after HSCT in three of the nine patients, two of them at MRD levels. HLA-Flow is a sensitive, fast, and inexpensive method for the detection of MRD in patients with HLA-mismatched HSCT.

Secondary neuroendocrine tumor after allogeneic bone marrow transplantation.

Here we report a case of aggressive neuroendocrine tumor (NET), which is an extremely rare secondary solid tumor that occurs after allogeneic hematopoietic cell transplantation (allo-HSCT). A patient with chronic active Epstein-Barr virus infection received allo-HSCT from an HLA-DR two allele-mismatched unrelated donor. Four years later, he developed NET with multiple metastases. He received thoraco-abdominal irradiation as a conditioning regimen, and developed repeated episodes of intestinal graft-versus-host disease, for which he received long-term immunosuppressive therapy. Although these factors may be potential contributing factors to the development of secondary NET, the exact pathogenesis remains unclear.

MRD detection of leukemia relapse using HLA typing by FACS in combination with FISH after mismatched allogeneic stem cell transplantation.

Loss of mismatched HLA is a cause of relapse following HLA-mismatched allo-SCT. We directly detected the loss of mismatched HLA alleles in relapsed leukemic cells at a MRD level using HLA typing by multicolor FACS (HLA-Flow) in combination with FISH in the BM of two patients with MLL-AF9-positive AML, at 6 and 10 months after mismatched allo-SCT. HLA-Flow with FISH analysis detected relapsed leukemic cells not expressing a mismatched HLA allele and harboring the MLL rearrangement. Simultaneously, real-time quantitative RT-PCR detected a low copy number of MLL-AF9 transcripts, consistent with MRD detection. HLA-Flow with FISH is a powerful method for detecting molecular relapse after mismatched allo-SCT and provides important information on the HLA expression status of the relapsed leukemic cells to help determine the next intervention.

Efficacy and histologic frequencies of endoscopic ultrasonography-guided tissue acquisition using conventional fine-needle aspiration needles for gastric subepithelial hypoechoic mass.

Introduction/Purpose: For gastric subepithelial lesions (GSELs) showing a hypoechoic mass (HM) on endoscopic ultrasonography (EUS) imaging, the utility of EUS-guided tissue acquisition using conventional fine-needle aspiration needles (EUS-TA-CFNAN) and the frequency of histological types remain unclear. This study aimed to examine this issue. Methods: This prospective observational study enrolled 291 consecutive patients who underwent EUS-TA-CFNAN for GSELs showing an HM (GSELHM) on EUS imaging. Immunohistochemical analysis was performed for all EUS-TA-CFNAN and surgically resected specimens. The main outcome measures were the technical results of EUS-TA-CFNAN and the frequency of histological types in GSELHM. Results: The endoscopic ultrasound-guided tissue acquisition using conventional fine-needle aspiration needle diagnosis rate for GSELHM was 80.1% (95% confidence interval [CI]: 75.0-84.5, 233/291). It was significantly lower for antrum (P = 0.004) and lesions smaller than 2 cm (P = 0.003). There were no adverse events. The immunohistochemical diagnoses of EUS-TA-CFNAN included 149 cases of gastrointestinal stromal tumour (GIST) (51.2%), 48 cases of leiomyoma (16.5%), 11 cases of schwannoma (3.8%), 8 cases of the ectopic pancreas (2.7%), 5 cases of subepithelial lesion like cancer (1.7%), 12 cases of other lesions (4.1%), and 58 cases of undiagnosable lesions (19.9%). The frequency of malignant or potentially malignant tumour in GSELHM was 55.0% (95% CI: 49.1-60.8, 160/291). Surgery was performed in 149 patients according to the conclusive EUS-TA-CFNAN results, in which the diagnostic accuracy of EUS-TA-CFNAN was 97.3% (95% CI: 94.7-99.9, 145/149). Conclusion: The use of EUS-TA-CFNAN for GSELHMs is safe and accurate. Gastric subepithelial lesions showing a hypoechoic mass have a reasonably high possibility of containing malignant or potentially malignant tumours, including GISTs.

A photostable bi-luminophore pressure-sensitive paint measurement system developed with mesoporous silica nanoparticles.

The accurate and high-resolution measurement of surface pressure is achieved by a pressure/ temperature-sensitive composite paint (bi-PSP), whereas the pressure-sensitive dye photodegraded the temperature sensitive dye in close arrangement of both dyes. In the present study, an attempt was made to synthesize a homogeneous bi-PSP membrane without light-induced degradation of the dye using mesoporous silica. Mesoporous silica as a molecular sieve was the separation of pressure- and temperature-sensitive dyes. Both achievement of control of photodegradation in temperature-sensitive paints with molecule-screening capacity and macroscopically uniform placement of insoluble pigments in the respective solvent, was accomplished using the mesoporous silica nanoparticles in a compound PSP.

Multi-Label Local to Global Learning: A Novel Learning Paradigm for Chest X-Ray Abnormality Classification.

Deep neural network (DNN) approaches have shown remarkable progress in automatic Chest X-rays classification. However, existing methods use a training scheme that simultaneously trains all abnormalities without considering their learning priority. Inspired by the clinical practice of radiologists progressively recognizing more abnormalities and the observation that existing curriculum learning (CL) methods based on image difficulty may not be suitable for disease diagnosis, we propose a novel CL paradigm, named multi-label local to global (ML-LGL). This approach iteratively trains DNN models on gradually increasing abnormalities within the dataset, i,e, from fewer abnormalities (local) to more ones (global). At each iteration, we first build the local category by adding high-priority abnormalities for training, and the abnormality's priority is determined by our three proposed clinical knowledge-leveraged selection functions. Then, images containing abnormalities in the local category are gathered to form a new training set. The model is lastly trained on this set using a dynamic loss. Additionally, we demonstrate the superiority of ML-LGL from the perspective of the model's initial stability during training. Experimental results on three open-source datasets, PLCO, ChestX-ray14 and CheXpert show that our proposed learning paradigm outperforms baselines and achieves comparable results to state-of-the-art methods. The improved performance promises potential applications in multi-label Chest X-ray classification.

Masked image modeling-based boundary reconstruction for 3D medical image segmentation.

Accurate segmentation of 3D medical images is vital for computer-aided diagnosis. However, the complexity of target morphological variations and a scarcity of labeled data make segmentation more challenging. Furthermore, existing models make it difficult to fully and efficiently integrate global and local information, which hinders structured knowledge acquisition. To overcome these challenges, we introduce the TNT Masking Network (TNT-MNet), a groundbreaking transformer-based 3D model that utilizes a transformer-in-transformer (TNT) encoder. For the first time, we present masked image modeling (MIM) in supervised learning, utilizing target boundary regions as masked prediction targets to enhance structured knowledge acquisition. We execute multiscale random masking on inner and outer tokens in online branch to tackle the challenge of segmenting organs and lesion regions with varying structures at multiple scales and to enhance modeling capabilities. In contrast, the target branch utilizes all tokens to guide the online branch to reconstruct the masked tokens. Our experiments suggest that TNT-MNet's performance is comparable, or even better, than state-of-the-art models in three medical image datasets (BTCV, LiTS2017, and BraTS2020) and effectively reduces the dependence on labeled data. The code and models are publicly available at https://github.com/changliu-work/TNT_MNet.

Multi-scale attention and deep supervision-based 3D UNet for automatic liver segmentation from CT.

BACKGROUND: Automatic liver segmentation is a prerequisite for hepatoma treatment; however, the low accuracy and stability hinder its clinical application. To alleviate this limitation, we deeply mine the context information of different scales and combine it with deep supervision to improve the accuracy of liver segmentation in this paper. METHODS: We proposed a new network called MAD-UNet for automatic liver segmentation from CT. It is grounded in the 3D UNet and leverages multi-scale attention and deep supervision mechanisms. In the encoder, the downsampling pooling in 3D UNet is replaced by convolution to alleviate the loss of feature information. Meanwhile, the residual module is introduced to avoid gradient vanishment. Besides, we use the long-short skip connections (LSSC) to replace the ordinary skip connections to preserve more edge detail. In the decoder, the features of different scales are aggregated, and the attention module is employed to capture the spatial context information. Moreover, we utilized the deep supervision mechanism to improve the learning ability on deep and shallow information. RESULTS: We evaluated the proposed method on three public datasets, including, LiTS17, SLiver07, and 3DIRCADb, and obtained Dice scores of 0.9727, 0.9752, and 0.9691 for liver segmentation, respectively, which outperform the other state-of-the-art (SOTA) methods. CONCLUSIONS: Both qualitative and quantitative experimental results demonstrate that the proposed method can make full use of the feature information of different stages while enhancing spatial data's learning ability, thereby achieving high liver segmentation accuracy. Thus, it proved to be a promising tool for automatic liver segmentation in clinical assistance.

Endoscopic Ultrasonography-Guided Fine-Needle Aspiration for Duodenal Subepithelial Lesions Showing a Hypoechoic Mass on Endoscopic Ultrasound Imaging.

BACKGROUND/AIMS: For duodenal subepithelial lesions showing a hypoechoic mass on endoscopic ultrasound imaging, the utility of endoscopic ultrasound-guided fine-needle aspiration and the frequency of histological types have not been the focus of previous literature. This study aimed to clarify this. MATERIALS AND METHODS: This prospective observational study enrolled 22 consecutive patients who underwent endoscopic ultrasoundguided fine-needle aspiration for duodenal subepithelial lesions with hypoechoic mass on endoscopic ultrasound. Immunohistochemical analysis was performed for all endoscopic ultrasound-guided fine-needle aspiration and surgically resected specimens. The main outcome measures were the technical results of endoscopic ultrasound-guided fine-needle aspiration and the frequency of histological types of duodenal subepithelial lesions with hypoechoic mass. RESULTS: Thirteen fine-needle aspiration specimens were obtained from the duodenal bulb and eight from the descending duodenal region. The puncture was not performed because of intervening vessels in one patient. The diagnostic rate was 81% (95% confidence interval: 58.1-94.6, 17/21 patients). In 12 patients receiving surgical resection (excluding one cancellation of endoscopic ultrasoundguided fine-needle aspiration), the diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration was 75% (95% confidence interval: 42.8-94.5, 9/12 patients). No complications were observed. The histopathological diagnoses included 11 cases of gastrointestinal stromal tumor (50%), 2 cases of leiomyoma (9%), 2 cases of metastatic cancer (9%), 2 cases of benign inconclusive, and 1 case each of carcinoid, malignant lymphoma, leiomyosarcoma, gauzeoma, and aberrant pancreas (4.5% each). The frequency of malignant tumors in the duodenal subepithelial lesions with hypoechoic mass group was 73% (16/22 patients). CONCLUSIONS: Endoscopic ultrasound-guided fine-needle aspiration for duodenal subepithelial lesions with hypoechoic mass was safe and accurate. As duodenal subepithelial lesion with hypoechoic mass has a reasonably high possibility of containing malignant tumors, it is desirable to perform endoscopic ultrasound-guided fine-needle aspiration.

Characterization of neutralizing antibodies in adults after intranasal vaccination with an inactivated influenza vaccine.

The levels and properties of neutralizing antibodies in nasal wash and serum collected from five healthy adults were examined after intranasal administration of an A/Uruguay/716/2007 (H3N2) split vaccine (45 µg hemagglutinin (HA) per dose; five doses, with an interval of 3 weeks between each dose). Prior to the assays, nasal wash samples were concentrated so that the total amount of antibodies was equivalent to about 1/10 of that found in the natural nasal mucus. Vaccination induced virus-specific neutralizing antibody responses, which increased with the number of vaccine doses given. Neutralizing antibodies were produced more efficiently in the nasal passages than in the serum: A ≥4-fold increase in nasal neutralization titres was observed after the second vaccination in four out of five subjects, whereas a rise in serum neutralization titres was observed only after the fifth vaccination. Nasal and serum neutralizing antibodies were mainly found in the polymeric IgA and monomeric IgG fractions, respectively, after gel filtration. Taken together, these results suggest that intranasal administration of an inactivated split vaccine induces high levels of nasal neutralizing antibodies (primarily polymeric IgA) and low levels of serum neutralizing antibodies (primarily monomeric IgG).

Quantitative RT-PCR analysis of the MOZ-CBP fusion transcript in therapy-related acute myeloid leukemia with t(8;16)(p11;p13).

We developed a real time reverse transcriptase polymerase chain reaction (RT-PCR) assay system for detecting the MOZ-CBP fusion transcript and used it to monitor minimal residual disease (MRD) status in a patient with therapy related acute myeloid leukemia (t-AML) harboring t(8;16)(p11;p13). Expression of the MOZ-CBP fusion transcript was determined by RT-PCR analysis of the patient's bone marrow at the time of diagnosis. Thereafter, real time RT-PCR was used to evaluate MRD levels throughout the entire course of treatment. The sensitivity of quantitative RT-PCR for the MOZ-CBP fusion transcript was 10(-5). Below this level, MRD was classified as negative. Real time RT-PCR of the bone marrow after induction therapy showed the reduction of MOZ-CBP transcript to approximately 10(-3) level when compared to the diagnostic sample. MRD was classified as negative (< 10(-5) compared with that in the bone marrow at diagnosis) after 5 courses of chemotherapy, a level that was maintained post-allo-hematopoietic stem cell transplantation. Real time RT-PCR of the MOZ-CBP transcript is a useful tool for assessing MRD status for a patient with therapy related acute myeloid leukemia who was initially predicted to have a poor prognosis.

GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B- and NK-cell (DCML) deficiency, and myelodysplasia.

A Japanese patient presented with lymphedema, severe Varicella zoster, and Salmonella infection, recurrent respiratory infections, panniculitis, monocytopenia, B- and NK-cell lymphopenia, and myelodysplasia. The phenotype was a mixture of the monocytopenia and mycobacterial infection (MonoMAC) and Emberger syndromes. Sequencing of the GATA-2 cDNA revealed the heterozygous missense mutation 1187 G > A. This mutation resulted in the amino acid mutation Arg396Gln in the zinc fingers-2 domain, which is predicted to cause significant structural change and prevent a critical interaction with DNA. Functional analysis of the patient's GATA-2 mutation is required to understand the relationship between these distinctive syndromes.

[Effective infliximab treatment for a recurrent type of acute intestinal graft-versus-host disease accompanied by steroid-induced depression].

A 22-year-old man with chronic active Epstein-Barr virus infection underwent allogeneic bone marrow transplantation (allo-BMT) from an HLA two allele-mismatched unrelated donor. Ten months after allo-BMT, he developed protein-losing enteropathy following a respiratory syncytial virus infection. A diagnosis of a recurrent type of acute graft-versus-host disease (GVHD) was made based on the histopathological findings, such as the infiltration of T lymphocytes into the superficial epithelium and crypts, and apoptotic bodies in crypts. Although methylprednisolone (mPSL: 10 mg/kg) administration for two consecutive days improved gastrointestinal symptoms, acute pancreatitis and severe depression developed in association with corticosteroid treatment. Reduction of mPSL and administration of infliximab (5 mg/kg/dose, 3 times) resulted in rapid improvement of depression and pancreatitis without aggravating intestinal GVHD. Recent studies have demonstrated that tumor-necrosis-factor (TNF)-α is associated with not only GVHD but also depression and acute pancreatitis. In the present case, anti-TNF-α treatment enabled us to reduce corticosteroid dose without aggravating GVHD, which suggests that this approach might be effective for the treatment of depression and acute pancreatitis.