Bidirectional Elongation Strategy Using Ambiphilic Radical Linchpin for Modular Access to 1,4-Dicarbonyls via Sequential Photocatalysis.

Organic molecules that can be connected to multiple substrates by sequential C-C bond formations can be utilized as linchpins in multicomponent processes. While they are useful for rapidly increasing molecular complexity, most of the reported linchpin coupling methods rely on the use of organometallic species as strong carbon nucleophiles to form C-C bonds, which narrows the functional group compatibility. Here, we describe a metal-free, radical-mediated coupling approach using a formyl-stabilized phosphonium ylide as a multifunctional linchpin under visible-light photoredox conditions. The present method uses the ambiphilic character of the phosphonium ylide, which serves as both a nucleophilic and an electrophilic carbon-centered radical source. The stepwise and controllable generation of these radical intermediates allows sequential photocatalysis involving two mechanistically distinct radical additions, both of which are initiated by the same photocatalyst in one pot with high functional group tolerance. The methodology enables a bidirectional assembly of the linchpin with two electronically differentiated alkene fragments and thus offers rapid and modular access to 1,4-dicarbonyl compounds as versatile synthetic intermediates.

The histone demethylase Utx controls CD8+ T-cell-dependent antitumor immunity via epigenetic regulation of the effector function.

CD8+ T cells play a central role in antitumor immune responses. Epigenetic gene regulation is essential to acquire the effector function of CD8+ T cells. However, the role of Utx, a demethylase of histone H3K27, in antitumor immunity remains unclear. In this study, we examined the roles of Utx in effector CD8+ T-cell differentiation and the antitumor immune response. In a murine tumor-bearing model, an increased tumor size and decreased survival rate were observed in T-cell-specific Utx KO (Utx KO) mice compared with wild-type (WT) mice. The number of CD8+ T cells in tumor-infiltrating lymphocytes (TILs) was significantly decreased in Utx KO mice. We found that the acquisition of effector function was delayed and attenuated in Utx KO CD8+ T cells. RNA sequencing revealed that the expression of effector signature genes was decreased in Utx KO effector CD8+ T cells, while the expression of naïve or memory signature genes was increased. Furthermore, the expression of Cxcr3, which is required for the migration of effector CD8+ T cells to tumor sites, was substantially decreased in Utx KO CD8+ T cells. These findings suggest that Utx promotes CD8+ T-cell-dependent antitumor immune responses partially through epigenetic regulation of the effector function.

Additional Microvascular Anastomosis to Gastric Conduit During Esophagectomy Reduces Anastomotic Leaks: Propensity Score Weighting Study.

BACKGROUND: Impaired gastric conduit perfusion during esophagectomy and reconstruction is considered a key risk factor of anastomotic leaks. The aim of this study is to evaluate the indication and feasibility of additional microvascular anastomosis (AMA) to the gastric conduit in esophageal cancer surgery. PATIENTS AND METHODS: Patients who received an esophagectomy with gastric conduit reconstruction between July 2008 and July 2021 at a single center were reviewed. Patient characteristics, anastomotic viability index (AVI) of the gastric conduit measured with thermal imaging, and operative outcomes were analyzed using Fisher's exact test and Mann-Whitney U test. Two propensity score weighting methods (inverse probability of treatment weighting and overlap weighting) were applied to investigate whether AMA reduces anastomotic leaks. RESULTS: Of the 293 patients who underwent an esophagectomy over the study period, 26 received AMA. AVI in the AMA group was significantly lower than that in the control group (0.64 vs. 0.74, p = 0.026). Overall anastomotic leak rates were 3.8% in the AMA group and 12.4% in the control group. Using two different propensity score weighting methods, the same conclusion was obtained that AMA significantly reduced anastomotic leaks after esophagectomy (both p < 0.001). The logistic regression model for estimating probability of anastomotic leaks provided AVI criteria for AMA application and revealed that AMA significantly reduced the estimated leak rates by a maximum of 49%. CONCLUSIONS: Additional microvascular anastomosis significantly reduced anastomotic leaks after esophagectomy. The proposed AVI criteria for AMA application can help guide surgeons as to when AMA is needed.

Postoperative inflammatory markers predict survival in patients after McKeown esophagectomy for esophageal cancer.

BACKGROUND: Preoperative C-reactive protein-to-albumin ratio (CAR) and neutrophil-to-lymphocyte ratio (NLR) are correlated with a poor prognosis of various cancers. The significance of postoperative systemic inflammation markers for prognostic stratification of patients with esophageal cancer (EC) has not been established. Therefore, this study aimed to elucidate the impact of postoperative CAR and NLR on survival in patients with EC for prognostic stratification. METHODS: A total of 235 patients who received curative esophagectomy were analyzed. A Cox proportional hazard model was performed to detect prognostic factors. RESULTS: Multivariate analysis revealed that postoperative CAR ≥ 0.05 (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.01-2.57) and NLR ≥ 3.0 (HR, 2.81; 95% CI, 1.79-4.40) were independent prognostic factors for overall survival. Meanwhile, postoperative CAR ≥ 0.05 (HR, 1.61; 95% CI, 1.07-2.41) and NLR ≥ 3.0 (HR, 1.92; 95% CI, 1.29-2.85) were also significant prognostic factors for relapse-free survival. In addition, the patient group with postoperative CAR ≥ 0.05 and NLR ≥ 3.0 had the worst survival. CONCLUSIONS: Postoperative CAR ≥ 0.05 and NLR ≥ 3.0 can predict the poor survival of patients who received curative esophagectomy for EC.

A Novel Frailty Grade Combined with Cachexia Index and Osteopenia in Esophagectomy.

BACKGROUNDS: The optimal method for evaluating frailty grade in patients with cancer has not been established in patients undergoing esophagectomy for esophageal cancer. This study aimed to clarify the impact of cachexia index (CXI) and osteopenia on survival in esophagectomized patients for esophageal cancer to develop frailty grade for risk stratification of the prognosis. METHODS: A total of 239 patients who underwent esophagectomy were analyzed. CXI was calculated as follows: skeletal muscle index × serum albumin/neutrophil-to-lymphocyte ratio. Meanwhile, osteopenia was defined as below the cutoff value of bone mineral density (BMD) calculated by the receiver operating characteristic curve. We evaluated the average Hounsfield unit within a circle in the lower midvertebral core of the 11th thoracic vertebra on preoperative computed tomography as BMD. RESULTS: Multivariate analysis revealed that low CXI (Hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.25-3.04) and osteopenia (HR, 1.86; 95% CI, 1.19-2.93) were independent prognostic factors for overall survival. Meanwhile, low CXI (HR, 1.58; 95% CI, 1.06-2.34) and osteopenia (HR, 1.57; 95% CI, 1.05-2.36) were also significant prognostic factors for relapse-free survival. A frailty grade combined with CXI and osteopenia stratified into four groups by their prognosis. CONCLUSIONS: Low CXI and osteopenia predict poor survival in patients undergoing esophagectomy for esophageal cancer. Furthermore, a novel frailty grade combined with CXI and osteopenia stratified the patients into four groups according to their prognosis.

Postoperative tegafur-uracil for stage I lung adenocarcinoma: first real-world data with an exploratory subgroup analysis.

PURPOSE: The effect of postoperative tegafur-uracil on overall survival (OS) after resection of stage I adenocarcinoma has been shown in clinical trials. The purpose of this study was to investigate whether findings from randomized trials of adjuvant tegafur-uracil are reproducible in a real-world setting. METHODS: A retrospective cohort study was performed using a multi-institutional database that included all patients who underwent complete resection of pathological stage I adenocarcinoma between 2014 and 2016. Survival outcomes for patients managed with and without tegafur-uracil were analyzed using the Kaplan-Meier method and a Cox proportional hazards model for the whole patient cohort and in a selected cohort based on eligibility criteria of a previous randomized trial. Propensity score matching was used to adjust for confounding effects. RESULTS: After propensity score matching, the hazard ratios for OS were 0.57 (95% confidence interval (CI) 0.29-1.14, P = 0.11) in the whole cohort and 0.69 (95% CI 0.32-1.50, P = 0.35) in the selected cohort. CONCLUSIONS: The effects of tegafur-uracil in this retrospective study appear to be consistent with those found in randomized clinical trials. These effects may be maximized in patients aged from 45 to 75 years.

Block catiomers with flanking hydrolyzable tyrosinate groups enhance in vivo mRNA delivery via π-π stacking-assisted micellar assembly.

Messenger RNA (mRNA) therapeutics have recently demonstrated high clinical potential with the accelerated approval of SARS-CoV-2 vaccines. To fulfill the promise of unprecedented mRNA-based treatments, the development of safe and efficient carriers is still necessary to achieve effective delivery of mRNA. Herein, we prepared mRNA-loaded nanocarriers for enhanced in vivo delivery using biocompatible block copolymers having functional amino acid moieties for tunable interaction with mRNA. The block copolymers were based on flexible poly(ethylene glycol)-poly(glycerol) (PEG-PG) modified with glycine (Gly), leucine (Leu) or tyrosine (Tyr) via ester bonds to generate block catiomers. Moreover, the amino acids can be gradually detached from the block copolymers after ester bond hydrolyzation, avoiding cytotoxic effects. When mixed with mRNA, the block catiomers formed narrowly distributed polymeric micelles with high stability and enhanced delivery efficiency. Particularly, the micelles based on tyrosine-modified PEG-PG (PEG-PGTyr), which formed a polyion complex (PIC) and π-π stacking with mRNA, displayed excellent stability against polyanions and promoted mRNA integrity in serum. PEG-PGTyr-based micelles also increased the cellular uptake and the endosomal escape, promoting high protein expression both in vitro and in vivo. Furthermore, the PEG-PGTyr-based micelles significantly extended the half-life of the loaded mRNA after intravenous injection. Our results highlight the potential of PEG-PGTyr-based micelles as safe and effective carriers for mRNA, expediting the rational design of polymeric materials for enhanced mRNA delivery.

[Coagulative complete remission following early gastric cancer resection in a patient with steroid-resistant acquired hemophilia A and nephrotic syndrome].

During laparoscopic cholecystectomy, an 89-year-old man was discovered to have a prolonged APTT. He was transferred to our hospital for a thorough examination because wound bleeding necessitated a reoperation. Based on coagulation factor VIII activity (FVIII:C) of 3.6% and FVIII inhibitor levels of 48.5 BU/ml, he was diagnosed with acquired hemophilia A (AHA). Due to concerns about his advanced age and postoperative infection, immunosuppressive therapy with prednisolone 0.5 mg/kg/day was initiated. His clinical course was favorable, except hemorrhagic shock caused by intramuscular hemorrhage on the right back, although low FVIII inhibitor levels persisted for more than a month; additionally, lower leg edema and increased urinary protein were also observed. He was diagnosed as with AHA and secondary nephrotic syndrome, possibly because of early gastric cancer. As a result, radical endoscopic submucosal dissection (ESD) was performed while a recombinant coagulation factor VIIa preparation was administered. AHA improved rapidly following ESD, and coagulative remission was achieved. Simultaneously, the nephrotic syndrome improved. Because the control of malignant tumors may improve the status of AHA, the timing of malignant tumor intervention must be considered considering the risk of bleeding and infection associated with immunosuppression.

[Acquired hemophilia A that developed after BNT162b2 mRNA COVID-19 vaccination and worsened following re-vaccination].

An 86-year-old Japanese male patient visited a nearby hospital with painful swelling in his left upper and lower limbs 35 days after the second dose of the BNT162b2 mRNA coronavirus disease-2019 (COVID-19) vaccine. He was referred to our hematological department due to a prolonged activated partial thromboplastin time and was urgently admitted. He was diagnosed with acquired hemophilia A (AHA) based on factor VIII (FVIII) activity of 1.7%, FVIII inhibitor of 152.3 BU/ml, and FVIII-binding antibodies detected by enzyme-linked immunosorbent assay. Immunosuppressive therapy with prednisolone (PSL) at 0.5 mg/kg/day was started owing to the risk of infection due to old age and poor activities of daily living. Hemostasis treatment with bypass hemostatic preparations (rFVIIa preparation, FVIIa/FX) was administered for each bleeding event, such as intramuscular and knee joint bleeding, resulting in good hemostatic effects. Coagulative complete remission was achieved on day 69 with PSL treatment; however, FVIII activity decreased with PSL tapering. AHA relapse with rectus abdominis muscle hematoma was observed after the third vaccination. This is the first Japanese report of AHA after COVID-19 vaccination and the world's first case, in which the presence of anti-FVIII-binding antibodies were observed.

Microscopic venous invasion is a predictor of prognosis in patients with esophageal squamous cell carcinoma undergoing ineffective neoadjuvant chemotherapy and surgery.

BACKGROUND: Neoadjuvant chemotherapy followed by surgery is Japan's most effective treatment modality for advanced thoracic esophageal squamous cell carcinoma. However, the prognosis is not as expected. This study aimed to examine prognostic factors in patients with pathologically ineffective neoadjuvant chemotherapy followed by surgery for esophageal squamous cell carcinoma. METHODS: We retrospectively analyzed patients who underwent neoadjuvant chemotherapy followed by curative esophagectomy for esophageal squamous cell carcinoma between December 2008 and July 2021. The patients were divided into the neoadjuvant chemotherapy effective group and the neoadjuvant chemotherapy ineffective group according to the pathological diagnosis. Clinicopathological data, prognosis, and recurrence were analyzed. RESULTS: A total of 143 patients (121 males, 22 females; median age, 67 years) were included in this study. Of these, 34 patients were classified into the effective group and the remaining 109 patients were assigned to the ineffective group. The ineffective group had significantly worse overall survival and recurrence-free survival than the effective group (p = 0.0192 and p = 0.0070, respectively). In the ineffective group, multivariate analysis demonstrated that microscopic venous invasion was an independent prognostic factor for overall survival (hazard ratio 2.44; 95% confidence interval 1.13-5.30) and recurrence-free survival (hazard ratio 2.43; 95% confidence interval 1.24-4.73). CONCLUSIONS: Microscopic venous invasion was associated with poor survival and cancer recurrence in the neoadjuvant chemotherapy ineffective group of patients who underwent esophagectomy for esophageal squamous cell carcinoma.

Risk factors for rectal bleeding after volumetric-modulated arc radiotherapy of prostate cancer.

Background: It is crucially important to understand the risk factors for rectal bleeding after volumetric-modulated arc radiotherapy (VMAT) for prostate cancer to prevent subsequent rectal bleeding. We assayed clinical and dosimetric data to investigate the risk factors for rectal bleeding after VMAT of prostate cancer. Materials and methods: This study included 149 patients with prostate cancer who received VMAT from February, 2012 to June, 2020. Irradiated total doses were 78 Gy/39 fractions in 33 patients (22.1%), 76 Gy/38 fractions in 89 (59.7%), 74 Gy/37 fractions in 4 (2.7%), and 72 Gy/36 fractions in 23 (15.4%). We investigated multiple clinical and dosimetric factors with reference to rectal bleeding. Results: The median observation period was 38 months. Fourteen patients (9.4%) experienced rectal bleeding: five (3.4%) were classified as Grade 2, and nine (6.0%) as Grade 1. There were significant differences between Grade ≥ 1 and Grade 0 patients in the overlap region of the planning target volume (PTV) and the rectum, the rectal V30-75, and the mean rectal dose (p < 0.05). There were significant differences between Grade 2 and Grade 0-1 patients in rectal V30-65 and mean rectal dose (p < 0.05). Conclusions: Rectal bleeding occurred, but its grades and rate of occurrence were permissible. Higher rectal doses were shown to be related to rectal bleeding, and reduction of low/intermediate and mean rectal doses will be important for preventing rectal bleeding.

Glucocorticoid imprints a low glucose metabolism onto CD8 T cells and induces the persistent suppression of the immune response.

Glucocorticoids (GCs), immunosuppressive, and anti-inflammatory agents have various effects on T cells. However, the long-term influence of GCs on the T cell-mediated immune response remain to be elucidated. We demonstrated that the administration of GC during the TCR-mediated activation phase induced long-lasting suppression of glycolysis, even after the withdrawal of GC. The acquisition of the effector functions was inhibited, while the expression of PD-1 was increased in CD8 T cells activated in the presence of GC. Furthermore, adoptive transfer experiments revealed that GC-treated CD8 T cells reduced memory T cell formation and anti-tumor activity. These findings reveal that GCs have long-lasting influence on the T cell-mediated immune response via modulation of T cell metabolism.

Molecular hydrogen suppresses Porphyromonas gingivalis lipopolysaccharide-induced increases in interleukin-1 alpha and interleukin-6 secretion in human gingival cells.

Periodontitis is defined as a multifactorial polymicrobial infection accompanied by inflammatory reactions. Porphyromonas gingivalis (Pg) is known as a major pathogen in the initiation and progression of periodontitis, and a major virulence factor is Pg lipopolysaccharide (LPS). Molecular hydrogen (H2) has been reported to act as a gaseous antioxidant, which suppresses periodontitis progression by decreasing gingival oxidative stress. However, no human periodontitis model has examined the anti-inflammatory effects of H2. In this study, we examined the effects of H2 on Pg LPS-induced secretion of 8 types of inflammation markers in a human periodontitis model using human gingival cells with enzyme-linked immunosorbent assays. Our results demonstrated that Pg LPS increased interleukin (IL) 1 alpha (IL-1α) and IL-6 secretion, but H2 significantly suppressed the secretion of both cytokines without cytotoxicity. H2 can suppress the production of IL-1α and IL-6, which are identified as cytokines involved in inflammatory reactions in periodontal disease. Thus, H2 may provide therapeutic applications for periodontitis.

Determination of intracellular ascorbic acid using tandem mass spectrometry.

Ascorbic acid is involved in a variety of biological events. Nevertheless, its detailed intracellular behavior remains unexplored due to a lack of sensitive analytical methods. Here we report a method using HPLC-ESI-MS/MS achieving the lowest detection limit ever reported (1 pg), to provide mechanistic insight into the intracellular ascorbic acid physiology.

Intraoperative nerve monitoring during esophagectomy reduces the risk of recurrent laryngeal nerve palsy.

BACKGROUND: Despite the risk of recurrent laryngeal nerve (RLN) palsy during esophagectomy, no established method of monitoring RLN injury is currently available. METHODS: This study included 187 patients who underwent esophagectomy between 2011 and 2018. Among these, intraoperative nerve monitoring (IONM) was done in 142 patients (IONM group), while the remaining 45 patients underwent conventional surgery without IONM (control group). We investigated the incidence of postoperative complications with regard to the use of IONM. RESULTS: The overall incidence of postoperative RLN palsy was 28% (52/187). The IONM group showed a significantly lower incidence of postoperative RLN palsy as compared to that in the control group (p = 0.004). The overall incidence of postoperative pneumonia was 22% (41/187) in those with Clavien-Dindo (CD) classification beyond grade 2. There were no significant differences between the incidence of any grade of postoperative pneumonia and the use of IONM (p = 0.195 and 0.333; CD > 2 and > 3, respectively). Multivariate analysis demonstrated that tumors in the upper third [odds ratio (OR) 3.12; 95% confidence interval (CI) 1.04-9.29] and lack of IONM use (OR 2.51; 95% CI 1.17-5.38) were independent factors causing postoperative RLN palsy after esophagectomy. CONCLUSION: IONM helps to reduce the risk of postoperative RLN palsy after esophageal cancer surgery.

Effect of the postural transition in minimally invasive esophagectomy: a propensity score matching analysis.

BACKGROUND: The advantages of prone position in minimally invasive esophagectomy have not been well studied. This study aimed to investigate the safety and feasibility of a transition from the left lateral decubitus position to the prone position for thoracic procedures in minimally invasive esophagectomy. METHODS: We retrospectively analyzed patients with thoracic esophageal carcinomas who underwent thoracoscopic esophagectomy and laparoscopic gastric mobilization between January 2015 and December 2019. The left decubitus and prone positions were analyzed using propensity score-matched pairs for the baseline characteristics, morbidity, and survival. RESULTS: A total of 114 consecutive patients were included in this study; 90 (78.9%) were male and the median age was 67.2 years old. Of these patients, 39 and 75 underwent left decubitus and prone esophagectomy, respectively. Prone esophagectomy was associated with a lower incidence of pneumonia than that performed in the decubitus position (12.5% vs. 37.5%, p = 0.0187). With respect to the long-term outcomes, there were no significant differences between the 2 groups. The 4-year overall and relapse-free survival rates for prone and decubitus esophagectomy were 73.8% and 73.2%, and 84.4% and 71.8%, respectively (p = 0.9899 and 0.6751, respectively). Prone esophagectomy yielded a shorter operative time (total: 528 [485-579] min vs. 581 [555-610] min, p < 0.0022; thoracic section: 243 [229-271] min vs. 292 [274-309] min, p < 0.0001), less bleeding in the thoracic procedures (0 [0-10] mL vs. 70 [20-138] mL, p < 0.0001), a shorter length of postoperative hospital stay (19 [15-23] vs. 30 [21-46] days, p = 0.0002), and a lower total hospital charge (30,046 [28,175-32,660] US dollars vs. 36,396 [31,533-41,180] US dollars, p < 0.0001). CONCLUSIONS: Transition into the prone position in minimally invasive esophagectomy is feasible with adequate postoperative and oncological safety and economical in esophageal cancer surgery.

Risk stratification of anastomotic stricture using early postoperative endoscopic and computed tomography findings in patients undergoing esophagectomy with cervical esophagogastric anastomosis for esophageal cancer.

Anastomotic stricture (AS) is one of the major complications after esophagectomy for esophageal cancer. We have previously reported that severe mucosal degeneration (MD) of the anastomotic site was associated with the incidence of AS. Meanwhile, there are few reports to correlate anastomotic internal circumference (AIC) with computed tomography (CT) with the incidence of AS. Therefore, this study was conducted to clarify the correlation of early postoperative endoscopic and CT findings with the incidence of AS. We assessed 205 patients who underwent esophagectomy. We then divided them into the non-AS group (n = 164) and the AS group (n = 41) and compared their background data and intraoperative and postoperative outcomes. We also evaluated the risk factors for AS using logistic regression model. Multivariate analysis revealed small AIC (P = 0.003; OR = 4.400; 95% CI = 1.650-11.700) and severe MD (P < 0.001; OR = 7.200; 95% CI = 2.650-19.600) as the independent risk factors for AS development. We also stratified the patients into the following four groups according to the incidence of AS: low-risk (normal AIC and intact or mild MD, 6.2%), intermediate-risk (small AIC and intact or mild MD, 29.4%), high-risk (normal AIC and severe MD, 42.9%), and very high-risk (small AIC and severe MD, 61.1%). Early postoperative endoscopic and CT findings were useful in predicting the development of AS after esophagectomy.

Sialic acid biosensing by post-printing modification of PEDOT:PSS with pyridylboronic acid.

A poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)-based conducting polymer, which has biorecognition capabilities, has promising biosensing applications. Previously, we developed a facile method for post-printing chemical modification of PEDOT:PSS thin films from commercial sources. Molecular recognition elements were directly introduced into the PSS side chain by a two-step chemical reaction: introduction of an ethylenediamine linker via an acid chloride reaction of the sulfonate moiety, and subsequent receptor attachment to the linker via amine coupling. In this study, the same method was used to introduce 6-carboxypyridine-3-boronic acid (carboxy-PyBA) into the linker for specifically detecting N-acetylneuraminic acid (sialic acid, SA), as a cancer biomarker. The surface-modified PEDOT:PSS films were characterized by X-ray photoelectron spectroscopy, attenuated total reflection Fourier-transform infrared spectroscopy, and static water contact angle and conductivity measurements. The specific interaction between PyBA and SA was detected by label-free reagent-free potentiometry. The SA-specific negative potential responses of modified PEDOT:PSS electrodes, which was ascribed to an SA carboxyl anion, were observed in a physiologically relevant SA range (1.6-2.9 mM) at pH 5, in a concentration-dependent manner even in the presence of 10% fetal bovine serum. The sensitivity was -2.9 mV/mM in 1-5 mM SA with a limit of detection of 0.7 mM. The sensing performances were almost equivalent to those of existing graphene-based electrical SA sensors. These results show that our chemical derivatization method for printing PEDOT:PSS thin films will have applications in SA clinical diagnostics.

[Refractory thrombotic thrombocytopenic purpura complicated with multiple cerebral infarction].

Neuropsychiatric symptoms comprise one of the five classic symptoms of autoimmune thrombotic thrombocytopenic purpura (aTTP). Although aTTP is typically transient, it is sometimes complicated by cerebral infarction with residual disability. This report presents the case of an 87-year-old man previously admitted to a different hospital with fever and transient consciousness loss. After receiving platelet transfusion with diagnosis of Evans syndrome, he was transferred to our hospital with worsening consciousness disturbance. He was subsequently diagnosed with aTTP with a PLASMIC score of 6 points, ADAMTS13 activity of less than 0.5%, and its inhibitor of 7.4 BU/ml. Platelet count and consciousness were rapidly improved with plasmapheresis and steroids, but motor aphasia emerged. MRI showed multiple cerebral infarctions, including a large infarction in the left frontal lobe. Thus, unfractionated heparin was administered. When his platelet count dropped once again on the 20th day, rituximab was added. The treatment eventually proved to be successful, and his aTTP remained in remission one year after the onset. Treatment for cerebral infarctions was switched to DOAC, and rehabilitation was continued. However, his ADL has not yet recovered. Advances in aTTP treatment have cured many similar cases. Thus, rituximab is now considered a treatment option for refractory cases. However, ischemic organ damage in acute phase and sequelae are observed. Therefore, early diagnosis and novel therapy are required.

[Spontaneous disappearance of the inhibitor during emicizumab therapy in a patient with mild hemophilia A].

From a young age, a 63-year-old Japanese man had experienced difficulties with hemostasis during tooth extraction and epistaxis and swelling of bruised areas. He had previously been diagnosed with mild hemophilia (FVIII:C 8.5%) at age of 60 due to swelling of a right hip bruise and was administered FVIII concentrate for the first time. He had frequent bleeding around his shoulder joints and was given FVIII concentrates every time, but his hemostasis was poor. He was referred to our hospital because his FVIII activity decreased to<1% and a low-titer inhibitor (2.0 BU/ml) was detected. Because of a shoulder hematoma and new subcutaneous bleeding on both forearms, recombinant FVIIa was used to perform the hemostatic treatment. Following hemostasis, emicizumab was administered subcutaneously every 2 weeks at a dose of 3.0 mg/kg. Approximately 2 months after starting emicizumab, inhibitors were no longer detected, and FVIII activity increased to 8% after 9 months. We encountered a case of mild hemophilia A with an inhibitor that was first diagnosed in old age. The incidence of inhibitors in non-severe hemophilia A is about 10%, and about 70% of those resolves spontaneously. In this case, suppression of bleeding by emicizumab may have contributed to the spontaneous disappearance of the inhibitor.