First-line nivolumab plus ipilimumab with or without chemotherapy for Japanese patients with non-small cell lung cancer: LIGHT-NING study.

OBJECTIVE: As first-line treatment for stage IV or recurrent non-small cell lung cancer, combination immunotherapy with nivolumab and ipilimumab, with or without chemotherapy, had demonstrated survival benefits over chemotherapy; however, data on Japanese patients are limited. METHODS: LIGHT-NING was a multicenter, observational study and retrospectively collected data. In this interim analysis, we analyzed patients who received combination immunotherapy between 27 November 2020 and 31 August 2021 for the treatment status, safety objectives (treatment-related adverse events and immune-related adverse events incidences), and effectiveness objectives (objective response rate and progression-free survival) to determine the characteristics and early safety information. RESULTS: We analyzed 353 patients, with a median follow-up of 7.1 (interquartile range, 5.0-9.7) months. Overall, 60.1 and 39.9% received nivolumab plus ipilimumab with and without chemotherapy, respectively. In these cohorts, the median age was 67 and 72 years; 10.8 and 35.5% were aged ≥75 years; 80.2 and 79.4% were male; 5.2 and 13.5% had a performance score ≥ 2; 32.1 and 27.0% developed grade 3-4 immune-related adverse events; treatment-related deaths were observed in 6 (2.8%) and 5 (3.5%) patients, respectively. Grade 3-4 immune-related adverse event incidence was the highest within the first month of treatment in both cohorts, although the immune-related adverse event risk persisted throughout. No new safety signals were observed at this interim analysis. The median progression-free survival was 6.0 (95% confidence interval, 5.2-7.6) and 5.8 (4.3-7.0) months in nivolumab plus ipilimumab with and without chemotherapy cohorts, respectively. CONCLUSIONS: LIGHT-NING offers valuable insights into combination immunotherapy for untreated patients with stage IV or recurrent non-small cell lung cancer in Japanese real-world settings.

Impact of autonomic symptoms on the clinical course of Parkinson's disease.

PURPOSE: Patients with Parkinson's disease (PD) exhibit various degrees of autonomic symptoms, which may be associated with Lewy body pathology distributed extensively in the autonomic nervous system. We hypothesized that the severity of autonomic symptoms reflects the severity of PD-related pathology, resulting in poor outcomes. The purpose of this study was to evaluate the impact of autonomic symptoms on PD progression. METHODS: We conducted a follow-up study among consecutive patients with PD at Dokkyo Medical University Hospital. Patients underwent comprehensive baseline evaluations and were classified into high and low autonomic symptom groups using the Scale for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT). The Kaplan‒Meier survival curves were used to analyze the time to discontinuation of their visits because of PD-related endpoints and to evaluate the association with high SCOPA-AUT scores. RESULTS: Of the 101 patients, 74 (73%) met the inclusion criteria. During the follow-up period (mean 1654 days), 22/74 patients reached PD-related endpoints (death, 4; hospitalization, 9; nursing home institutionalization, 9). PD patients with high SCOPA-AUT scores reached the endpoints faster than those with low SCOPA-AUT scores. A high SCOPA-AUT score, including gastrointestinal, urinary, and thermoregulation domains; high motor symptom scores; and low specific binding ratios (SBRs) on 123I FP-CIT-SPECT (DAT-SPECT) were associated with reaching PD-related endpoints. A high SCOPA-AUT score was associated with reaching the endpoints even after adjustment for covariates. CONCLUSIONS: Patients with high autonomic symptom scores had a greater risk of reaching PD-related endpoints than patients with low autonomic symptom scores.

A case of meningoencephalitis caused by multisystem inflammatory syndrome in adult SARS-CoV-2 infection.

A 37-year-old woman was hospitalized with fever and consciousness disturbance. She showed systemic inflammation with stress cardiomyopathy. Brain computed tomography showed diffuse brain edema. Cerebrospinal fluid (CSF) findings revealed markedly elevated cerebrospinal fluid pressure with pleocytosis, elevated protein, and elevated interleukin 6. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nicking enzyme amplification reaction test using a nasopharyngeal swab was positive, and the patient was diagnosed with SARS-CoV-2 infection. From the negative result of the CSF SARS-CoV-2 polymerase chain reaction test and no findings of bacterial or viral infection, we diagnosed meningoencephalitis by multisystem inflammation syndrome in adults (MIS-A). Intravenous methylprednisolone pulse therapy improved her symptoms and brain edema. There have been no cases of MIS-A with meningoencephalitis, and no initial treatment strategy has been established, especially in emergency cases of suspected MIS-A. The present case suggested Early intravenous methylprednisolone pulse with anti-coronaviral therapies after the exclusion of bacterial infection would be useful in suspected MIS-A with emergent meningoencephalitis cases.

CGRP-monoclonal antibodies in Japan: insights from an online survey of physician members of the Japanese headache society.

BACKGROUND: Anti-calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) have greatly changed migraine treatment options. In Japan, although CGRPmAb guidelines (≥ 4 monthly migraine days (MMDs) and ≥ 1 previous preventive failure) are well-acknowledged, the actual use of CGRPmAbs and the circumstances of the related headache care are unknown. METHODS: We conducted an online survey of Japanese Headache Society members, inquiring about the physicians' experience with CGRPmAbs and how they make decisions related to their use. RESULTS: Of the 397 respondents, 320 had prescribed CGRPmAbs. The threshold number of previous preventive failures for recommending a CGRPmAb was two for the majority of the respondents (n = 170, 54.5%), followed by one (n = 64, 20.5%). The MMD threshold was ≥ 4 for 71 respondents (22.8%), ≥ 6 for 68 (21.8%), ≥ 8 for 76 (24.4%), and ≥ 10 for 81 (26.0%). The respondents tended to assess treatment efficacy after 3 months (episodic migraine: n = 217, 69.6%, chronic migraine: n = 188, 60.3%). The cost of CGRPmAbs was described by many respondents in two questions: (i) any request for a CGRPmAb (27.7%), and (ii) the most frequently reported reason for responders to discontinue CGRPmAbs (24.4%). CONCLUSIONS: Most of the respondents recommended CGRPmAbs to patients with ≥ 2 preventive failures, followed by ≥ 1. The MMD threshold ranged mostly from ≥ 4 to ≥ 10. The concern for costs was raised as a major limiting factor for prescribing CGRPmAbs.

Effectiveness of three calcitonin gene-related peptide monoclonal antibodies for migraine: A 12-month, single-center, observational real-world study in Japan.

BACKGROUND: Real-world data on the effectiveness of calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) in migraine patients are needed. METHODS: We performed a single-center, real-world study with an observation period of up to 12 months (mean 7.5 ± 3.4 months) after CGRP mAb administration. A total of 228 Japanese patients with episodic or chronic migraine (age, 45.9 ± 13.2 years; 184F; 45 erenumab; 60 galcanezumab; 123 fremanezumab) who were treated with CGRP mAbs for at least three months were ultimately included in this study. RESULTS: In the total cohort, after CGRP mAb treatment, mean monthly migraine days decreased by 7.2 ± 4.8, 8.3 ± 4.7, and 9.5 ± 5.0 at three, six and 12 months, respectively. The ≥50% monthly migraine day reduction rates at three, six and 12 months were 48.2%, 61.0% and 73.7%, respectively. In the logistic regression analysis, the presence of osmophobia and fewer baseline monthly migraine days contributed to ≥50% responders at three, six and 12 months. The ≥50% responders at three or six months were useful in predicting ≥50% responders at 12 months. In subgroups of patients with difficult-to-treat migraine (those with medication overuse headache or psychiatric comorbidities) and previous CGRP mAb users, monthly migraine days were substantially reduced over 12 months. There was no difference in monthly migraine day reduction over 12 months among three different CGRP mAbs. Adverse reactions were observed in 28 (12.3%) patients, with injection site reactions being the most common (n = 22) though generally mild in severity. CONCLUSION: This real-world study confirmed the efficacy and safety of three different CGRP mAbs for prophylactic treatment of patients with migraine.

A retrospective preliminary study of intrapancreatic late enhancement as a noteworthy imaging finding in the early stages of pancreatic adenocarcinoma.

OBJECTIVE: To characterize intrapancreatic late enhancement (ILE) observed in the early stages of pancreatic adenocarcinoma (PAC). METHODS: Among 203 patients pathologically diagnosed with PAC between October 2011 and February 2021, 32 patients with pre-diagnostic abdominal contrast-enhanced CT performed from 6 months to 5 years before the diagnosis were enrolled in this study. Indirect findings (IFs) on pre-diagnostic CT, including ILE, were evaluated and examined for various clinical data and time intervals to diagnosis (TIDs). The detected ILE was quantitatively evaluated, and the effect of ILE awareness on lesion detection by two radiologists and their interobserver agreement were assessed. RESULTS: Among the 32 patients, 23 showed IFs. ILE was observed in 14 patients (63%), with a median TID of 17 months (interquartile ratio [IQR]: 9.3-42.3). ILE alone was observed in eight patients (35%), ILE with focal pancreatic parenchymal atrophy (FPPA) was observed in five patients (22%), and ILE with main pancreatic duct abnormalities (MPDA) was observed in one patient (4%). Pancreatic head lesions were significantly more frequent in patients with ILE alone than in patients with FPPA or MPDA (p = 0.026). The median long-axis diameters of the region with ILE and ILE-to-pancreas contrast were 10 (IQR: 5-11) mm and 24 (IQR: 17-33) HU, respectively. Awareness of ILE led observers to detect two or three more pancreatic head lesions, and interobserver agreement increased from poor agreement (k = 0.17) to moderate agreement (k = 0.55). CONCLUSION: ILE is a significant IF for early PAC detection. KEY POINTS: • Intrapancreatic late enhancement (ILE) is a significant indirect finding in the early detection of pancreatic adenocarcinoma. • ILE without other indirect findings is expected to help detect pancreatic head lesions. • Image evaluation focusing on ILE can increase lesion detection and improve the interobserver agreement.

Biomarkers in the Rat Hippocampus and Peripheral Blood for an Early Stage of Mental Disorders Induced by Water Immersion Stress.

It is difficult to evaluate the pre-symptomatic state of mental disorders and prevent its onset. Since stress could be a trigger of mental disorders, it may be helpful to identify stress-responsive biomarkers (stress markers) for the evaluation of stress levels. We have so far performed omics analyses of the rat brain and peripheral blood after various kinds of stress and have found numerous factors that respond to stress. In this study, we investigated the effects of relatively moderate stress on these factors in the rat to identify stress marker candidates. Adult male Wistar rats underwent water immersion stress for 12 h, 24 h, or 48 h. Stress caused weight loss and elevated serum corticosterone levels, and alterations regarded as anxiety and/or fear-like behaviors. Reverse-transcription PCR and Western blot analyses revealed significant alterations in the expressions of hippocampal genes and proteins by the stress for no longer than 24 h, such as mitogen-activated protein kinase phosphatase 1 (MKP-1), CCAAT/enhancer-binding protein delta (CEBPD), small ubiquitin-like modifier proteins 1/sentrin-specific peptidase 5 (SENP5), matrix metalloproteinase-8 (MMP-8), kinase suppressor of Ras 1 (KSR1), and MKP-1, MMP-8, nerve growth factor receptor (NGFR). Similar alterations were observed in three genes (MKP-1, CEBPD, MMP-8) in the peripheral blood. The present results strongly suggest that these factors may serve as stress markers. The correlation of these factors in the blood and brain may enable the evaluation of stress-induced changes in the brain by blood analysis, which will contribute to preventing the onset of mental disorders.

Effect of PACAP on Heat Exposure.

Heat stroke is a life-threatening illness caused by exposure to high ambient temperatures and relative humidity. The incidence of heat stroke is expected to increase due to climate change. Although pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in thermoregulation, the role of PACAP on heat stress remains unclear. PACAP knockout (KO) and wild-type ICR mice were subjected to heat exposure at an ambient temperature of 36 °C and relative humidity of 99% for 30-150 min. After heat exposure, the PACAP KO mice had a greater survival rate and maintained a lower body temperature than the wild-type mice. Moreover, the gene expression and immunoreaction of c-Fos in the ventromedially preoptic area of the hypothalamus, which is known to harbor temperature-sensitive neurons, were significantly lower in PACAP KO mice than those in wild-type mice. In addition, differences were observed in the brown adipose tissue, the primary site of heat production, between PACAP KO and wild-type mice. These results suggest that PACAP KO mice are resistant to heat exposure. The heat production mechanism differs between PACAP KO and wild-type mice.

Enantioselective Total Syntheses of Preussomerins: Control of Spiroacetal Stereogenicity by Photochemical Reaction of a Naphthoquinone through 1,6-Hydrogen Atom Transfer.

We report the enantioselective total syntheses of preussomerins EG1 , EG2 , and EG3 . The key transformation is a stereospecific photochemical reaction involving 1,6-hydrogen atom transfer to achieve retentive replacement of a C-H with a C-O bond, enabling otherwise-difficult control of the spiroacetal stereogenic center.

Estimating the longitudinal trajectory of cognitive function measurement using short-term data with different disease stages: Application in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by a gradual decline in cognitive function over a few decades. The Mini-Mental State Examination (MMSE) is a widely used measure for evaluating global cognitive functioning. Characterizing the longitudinal trajectory of the MMSE in the population of interest is important to detect AD onset for preventive intervention. In this study, we formulate a new class of longitudinal trajectory modeling for MMSE from short-term individual data based on an ordinary differential equation. The proposed method models the relationship between individual decline speed of MMSE and the average MMSE using the fractional polynomial function model and subsequently estimates the longitudinal trajectory of MMSE by solving the ordinary differential equation for the estimated model. The appropriate model for trajectory estimation is selected based on the proposed criterion for quantifying the goodness of trajectory fit. The accuracy of the trajectory estimation of the proposed method was demonstrated via simulation studies. The proposed method was successfully applied to MMSE data from the Japanese Alzheimer's Disease Neuroimaging Initiative study.

Anti-LGI1 encephalitis recurring 3 years after the first episode: a case report.

BACKGROUND: Patients with antibodies against leucine-rich glioma-inactivated 1 (LGI1) present with limbic encephalitis, which is clinically characterized by a subacute disturbance of memory and behavior, often experience seizures. Most patients have a monophasic course, often with hyponatremia. CASE PRESENTATION: Herein, we report a 67-year-old Japanese male presenting with involuntary neck movement, abnormal behavior and apraxia. He was disoriented to time and place and occasionally unable to follow directions. Laboratory tests revealed the patient had hyponatremia (131 mEq/L). Cerebrospinal fluid (CSF) analysis showed that the cell count (1/µL) and protein content (33 mg/dL) were in the normal ranges. Electroencephalography showed transient theta bursts in the right frontal lobe. Magnetic resonance imaging (MRI) of the brain demonstrated hyperintensities in the medial temporal lobe and basal forebrain on fluid-attenuated inversion recovery (FLAIR) without gadolinium enhancement. Anti-voltage-gated potassium channel (Anti-VGKC) complex antibodies were below the reference level for limbic encephalitis. Although the diagnosis was unknown, intravenous methylprednisolone therapy was effective. Three years later, the patient began to speak incoherently and became disoriented to time. FLAIR MRI of the brain revealed recurrence in the left medial temporal lobe. The patient's serum sodium level was 131 mEq/L. After intravenous methylprednisolone therapy, he regained alertness. A CSF sample stored at the time of the first attack was assayed and the patient was found to be LGI1-positive and CASPR-2-negative, and the diagnosis of anti-LGI1 encephalitis was made. CONCLUSIONS: Monitoring serum sodium levels and the preserved samples from the first episode were useful for diagnosis.

Sick sinus syndrome as the initial manifestation of neuromyelitis optica spectrum disorder: a case report.

BACKGROUND: Sick sinus syndrome (SSS) is known to occur due to lesions in the medulla oblongata. Although medullary lesions have occurred in patients with neuromyelitis optica spectrum disorder (NMOSD), there are few reports of SSS associated with NMOSD. We report a patient with NMOSD who developed refractory nausea, vomiting and SSS as the initial manifestation. CASE PRESENTATION: A 77-year-old female developed refractory nausea and frequent episodes of syncope. The patient was diagnosed with SSS because sinus pauses lasting five to six seconds were observed, and pacemaker implantation was performed. Two months later, she was referred to our hospital because of limb weakness and sensory impairment that progressed over a month. The patient was confirmed to have muscle weakness; manual muscle testing revealed grade 4 in the upper extremities and grade 3 in the lower extremities. Tendon reflexes were diminished, while no pathological reflexes were present. Thermal and pain sensations were impaired in the upper and lower extremities, and vibration sensation was impaired in both lower extremities. Bladder and rectal disturbances were also noted. Optic neuritis was not detected. T2-weighted magnetic resonance imaging (MRI) showed high-intensity lesions in the dorsal part of the medulla oblongata and C3-6 cervical cord. Her serum was positive for antibodies against aquaporin 4, and a diagnosis of NMOSD was made. She was treated with two courses of an intravenous methylprednisolone pulse and one course of plasma exchange. Then, she was transferred to another hospital for rehabilitation. CONCLUSIONS: Because SSS is a life-threatening complication, clinicians should be aware of the possibility that medullary lesions in NMOSD can cause SSS as the initial manifestation.

Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study.

BACKGROUND: Levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. METHODS: This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30-84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300-400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. DISCUSSION: This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031180248 ; registered 12 March 2019.

De novo synthesis of dimerization-ready flavan unit via intramolecular Pummerer/Friedel-Crafts cascade.

We describe the de novo synthesis of a dimerization-ready flavan derivative via the Pummerer/Friedel-Crafts cascade. This method allowed facile access to oligomeric proanthocyanidin natural products. The total synthesis of procyanidin B4 was achieved by this strategy.

Impact of nocturnal hypoxemia on the recurrence of atrial tachyarrhythmia after catheter ablation of atrial fibrillation.

Factors causing atrial tachyarrhythmia recurrence after catheter ablation (CA) of atrial fibrillation (AF) remain undetermined. This study aimed to investigate the effect of nocturnal hypoxemia on the recurrence of atrial tachyarrhythmia after CA of AF. Among 594 patients with AF who underwent an ambulatory sleep study at the National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (2014-2019), 365 underwent CA of AF; 290 patients who underwent CA were followed up for > 3 months. Multivariate Cox regression analysis was used to calculate hazard ratios (HRs) using clinical variables, to identify the independent predictors of atrial tachyarrhythmia recurrence after the final CA. Atrial tachyarrhythmia recurred in 45 of 290 (15.5%) patients during the median follow-up period of 479 days (interquartile range 225-1002). On the performing multivariate analysis of the data of patients who did not receive continuous positive airway pressure (CPAP), severe nocturnal hypoxemia [defined as the percentage of sleep time spent with SaO2 of < 90% (T90) over 20%] [HR 8.53, 95% confidence interval (CI) 1.872-38.814; P < 0.01] and an 1 mL/m2 increase in the left atrial volume index (HR 1.02, 95% CI 1.004-1.044; P = 0.02) were found to be independently associated with the recurrence of atrial tachyarrhythmia. In addition, the rates of freedom from atrial tachyarrhythmia after the final AF ablation with CPAP were significantly lower in the group with more severe nocturnal hypoxemia (Log-rank P = 0.03). In conclusion, it is necessary to consider both, AHI and nocturnal hypoxia while performing an ambulatory sleep apnea study. CA may be less effective in patients with more severe nocturnal hypoxia, despite the administration of CPAP.

Effects of In-Hospital Rehabilitation on Preventing Hospital Readmissions in Patients With Cirrhosis: A Retrospective Cohort Study.

OBJECTIVES: To investigate the effect of rehabilitation on hospital readmissions in patients with cirrhosis. DESIGN: A retrospective cohort study. SETTING: Acute hospitals. PARTICIPANTS: Patients hospitalized due to cirrhosis (N=6485). INTERVENTIONS: We defined rehabilitation as any type and intensity of rehabilitation administered by physical, occupational, or speech therapists. MAIN OUTCOME MEASURES: Readmission within 30 days after discharge. RESULTS: Rehabilitation was provided to 1177 patients (19.0%). After propensity score matching, rehabilitation was associated with 30- and 90-day readmissions. CONCLUSIONS: The present study demonstrated that rehabilitation is associated with lower proportions of 30- and 90-day readmissions in patients with cirrhosis. Therefore, rehabilitation may be one way to reduce the risk of readmission in patients hospitalized for cirrhosis.

Guillain-Barré syndrome diagnosed as central cervical spinal cord injury after hyperextension injury.

The clinical features of Guillain-Barré syndrome (GBS) are progressive, fairly symmetric muscle weakness, and patients present a few days to a week after onset of symptoms. A 63-y-old man strongly hit his forehead, and next day felt paresthesia in both upper limbs, with difficulty in walking. Spinal cord injury (SCI) was suspected; the cervical cord was severely compressed at the C4 level. He was diagnosed with central cervical SCI and transferred to a community hospital. Three days after the injury, oxygenation worsened, and the patient was transferred to our hospital for laminoplasty. After admission, we noticed bilateral ptosis-an atypical finding for SCI. Under analgesic sedation, he could only move his fingertips. Severe respiratory muscle weakness and absence of reflexes were observed. Moreover, albuminocytologic dissociation and decreased motor nerve conduction were observed, and GBS was suspected. Intravenous immunoglobulin was administered; thereby, the muscle weakness gradually improved, and the patient returned to work. Muscle weakness usually starts in the legs in GBS; however, in 10% of patients, it starts in the arms. In our patient, the symptoms started with paresthesia, followed by severe respiratory muscle weakness in a short period. Furthermore, intubation made history-taking and neurological examination difficult. The degree of inflammation in the acute GBS phase correlates with the severity of nerve injury. Therefore, early diagnosis and treatment of GBS is important. We should perform detailed history-taking and consider GBS as a differential diagnosis, especially when neurological examination cannot be performed at the emergency department.

Who tailors the blanket?

The gap between the Markov blanket and ontological boundaries arises from the former's inability to capture the dynamic process through which biological and cognitive agents actively generate their own boundaries with the environment. Active inference in the free-energy principle (FEP) framework presupposes the existence of a Markov blanket, but it is not a process that actively generates the latter.

Ossifying fibrous epulis as an IgG4-related disease of the oral cavity: a case report and literature review.

BACKGROUND: Fibrous sclerosing tumours and hypertrophic lesions in IgG4-related disease (IgG4-RD) are formed in various organs throughout the body, but disease in the oral region is not included among individual organ manifestations. We report a case of ossifying fibrous epulis that developed from the gingiva, as an instance of IgG4-RD. CASE PRESENTATION: A 60-year-old Japanese man visited the Department of Oral and Maxillofacial Surgery, Gunma University Hospital, with a chief complaint of swelling of the left mandibular gingiva. A 65 mm × 45 mm pedunculated tumour was observed. The bilateral submandibular lymph nodes were enlarged. The intraoperative pathological diagnosis of the enlarged cervical lymph nodes was inflammation. Based on this diagnosis, surgical excision was limited to the intraoral tumour, which was subsequently pathologically diagnosed as ossifying fibrous epulis. Histopathologically, the ossifying fibrous epulis exhibited increased levels of fibroblasts and collagen fibres, as well as infiltration by numerous plasma cells. The IgG4/IgG cell ratio was > 40%. Serologic analysis revealed hyper-IgG4-emia (> 135 mg/dL). The patient met the comprehensive clinical diagnosis criteria and the American College of Rheumatology and European League Against Rheumatism classification criteria for IgG4-RD. Based on these criteria, we diagnosed the ossifying fibrous epulis in our patient as an IgG4-related disease. A pathological diagnosis of IgG4-related lymphadenopathy was established for the cervical lymph nodes. Concomitant clinical findings were consistent with type II IgG4-related lymphadenopathy. CONCLUSIONS: A routine serological test may be needed in cases with marked fibrous changes (such as epulis) in the oral cavity and plasma cells, accompanied by tumour formation, to determine the possibility of individual-organ manifestations of IgG4-related disease.

Total Synthesis of Parameritannin†A2, a Branched Epicatechin Tetramer with Two Double Linkages.

The first total synthesis of parameritannin A2 (1), a branched epicatechin (EC) tetramer is reported. The "phloroglucinol trick" was used to circumvent two synthetic issues encountered when assembling four EC units, namely, the steric constraint and the formation of the C4-C6 interflavan linkage. As a substructure of the middle EC unit, phloroglucinol enabled the single-step assembly of two EC units (top and side) through A-type linkages. The middle EC unit was constructed by conducting a newly developed three-carbon flavan annulation via a Pummerer/Friedel-Crafts cascade reaction to furnish a trimeric intermediate bearing a thio-leaving group at C4 position, which allowed the final installation of the bottom EC unit.