Total Synthesis of Keramaphidin B and Ingenamine by Base-Catalyzed Diels-Alder Reaction Using Dynamic Regioselective Crystallization.

The control of the selectivity is a central issue in the total synthesis of complex natural products. In this paper, we report the total synthesis of (±)-keramaphidin B and (±)-ingenamine. The key reaction is a DMAP-catalyzed Diels-Alder reaction in which the regioselectivity is completely controlled by dynamic crystallization. Our synthesis successfully demonstrates that dynamic crystallization can be an alternative when the selectivity is not controlled by either kinetic or thermodynamic approaches in solution.

Drug-induced interstitial lung disease after chemoimmunotherapy for extensive-stage small cell lung cancer.

Objectives: The combination of chemotherapy and immune checkpoint inhibitors (chemo-ICI) has become the new standard of treatment for extensive-stage small cell lung cancer (ES-SCLC). Recently, slight changes in interstitial shadows, defined as interstitial lung abnormalities (ILA), have been identified. In patients with ES-SCLC who received chemo-ICI, there are limited data on the incidence of drug-induced interstitial lung disease (D-ILD) in daily practice and the association between the development of D-ILD and ILA in the baseline computed tomography (CT). Materials and methods: A multicenter, retrospective study was conducted to investigate the incidence of D-ILD, the risk factors for developing D-ILD, progression-free survival (PFS), and overall survival (OS) in patients with ES-SCLC who received chemo-ICI between August 2019 and November 2021. Results: This study enrolled 70 patients (median age, 71 years; including 58 men) from nine institutions in Japan. There were 62 patients (89%) treated with carboplatin/etoposide/atezolizumab and 8 patients treated with carboplatin or cisplatin/etoposide/durvalumab. Twenty-nine patients (41.4%) were found to have ILA at baseline CT. Eleven patients (15.7%) developed D-ILD. The proportion of patients with ILA was significantly higher in the group who developed D-ILD than in the group who did not (9/11 (81.8%) vs. 20/59 (33.9%), respectively, P = 0.0057). In addition, the frequency of ground glass attenuation (GGA) and reticulation was higher in patients who developed D-ILD. There was no significant difference in PFS and OS between patients who developed D-ILD and those who did not (median PFS, 8.0 (95% confidence interval (CI), 5.5-9.5) months vs. 5.0 (95% CI, 4.5-5.6) months, respectively, P = 0.11 and median OS, not reached (NR) (95% CI, 8.7-NR) vs. 18.2 (95% CI, 13.2-NR) months, respectively, P = 0.20). Conclusion: The incidence of D-ILD in patients with ES-SCLC who received chemo-ICI in clinical practice was higher than that in clinical trials. Patients with pre-existing ILA were more likely to develop D-ILD.

Effect of urinary glucose concentration and pH on signal intensity in magnetic resonance images.

PURPOSE: With advances in anti-diabetes drugs, increasing numbers of patients have high urinary glucose concentrations, which may alter magnetic resonance (MR) signal intensity. We sought to elucidate the effect of urinary glucose concentration and pH on transverse relaxation and MR signal intensity. MATERIALS AND METHODS: The transverse relaxation rate (R2) was measured in samples with different glucose concentrations (in vitro) and in the urinary bladder of seven patients with diabetes and nine healthy volunteers (in vivo). The glucose concentration and pH in the in vitro samples and urine were measured. The signal intensity ratio of the bladder to adjacent tissues was obtained on T2-weighted imaging (WI), T1WI, and MR urography (in vivo). To clarify the effect of pH further, the urine of two healthy subjects was adjusted with acid and/or base to obtain various pH values (ex vivo). RESULTS: R2 increased significantly with high glucose concentrations in the in vitro study. In the in vivo study, high glucose concentration (p < 0.001) and low pH (p = 0.005) were significantly associated with high R2. R2 was higher (p = 0.002) and the signal in maximum-intensity projection images of MR urography was lower (p = 0.005) in patients with diabetes than in healthy subjects. Ex vivo study revealed that a decrease in pH in acid portion resulted in increased R2. CONCLUSION: High concentrations of urinary glucose and low pH both enhance transverse relaxation, which, in turn, causes low signal intensity in urinary bladder on long echo time (TE) images, such as MR urography. Radiologists should be aware of this phenomenon when interpreting abnormally low-intensity bladders on long TE images.

Endobronchial metastases 20 years after prostate cancer excision.

A 78-year-old Japanese man who had undergone total prostatectomy for prostate cancer (pT3cN1M0, Gleason score 3 + 3) 20 years previously was referred to the Respiratory Medicine Department of our institution because of a 1-week history of chest pain and cough. Computed tomography showed multiple small nodules and mediastinal lymph node enlargement. Bronchoscopy revealed multiple soft polypoid masses and obstruction of the lingular segment. Prostate-specific antigen (PSA) concentrations had increased markedly from 0.48 ng/mL in 2014 to 741 ng/mL in 2018. The diagnosis of prostatic cancer metastases was confirmed by revealing the presence of PSA via immunohistological staining of a bronchoscopically obtained biopsy of one of the masses. The patient had not been attending scheduled follow-up visits for the past 4 years. Treatment with degarelix (a gonadotropin-releasing hormone) was started, and the PSA concentration decreased dramatically (29 ng/mL). Metastases from prostate cancer are rarely first diagnosed two decades after radical prostatectomy. This patient illustrates the importance of obtaining a complete medical history.

Nivolumab-induced acute-onset type 1 diabetes mellitus as an immune-related adverse event: A case report.

A 60-year-old Japanese man, with no medical or family history of diabetes, presented with acute-onset type 1 diabetes following nivolumab treatment for advanced non-small-cell lung cancer. During cycle 35 of nivolumab therapy, his glycated hemoglobin level increased from 7.6% to 9.1% in one month. Test results for islet-related and anti-thyroid peroxidase antibodies were negative. A glucagon tolerance test showed insulin dependency. Type 1 diabetes after anti-programmed death-ligand 1 antibody administration is an immune-related adverse event, and numerous reports suggest that fulminant type 1 diabetes can develop in these patients. However, there are few reports of acute-onset type 1 diabetes mellitus.

The sensitivities and prognostic values of the Wells and revised Geneva scores in diagnosis of pulmonary embolism in the Japanese population.

OBJECTIVE: To assess the sensitivities of the Wells score (WS) and the revised Geneva score (RGS) and their prognostic values in the diagnosis of pulmonary embolism (PE) in the Japanese population. METHODS: We conducted a retrospective chart review of patients with PE aged 16 years or older who were assessed between December 2008 and August 2014. Patients were divided into the PE unlikely and PE likely groups according to the WS and PE unlikely and PE likely groups according to the RGS. We also described the characteristics and three-month mortality of the patients. Univariate predictors with p < 0.05 were included in the multiple regression model. Fisher׳s exact test and Student׳s t-test were used for categorical and continuous variables, respectively. RESULTS: PE was confirmed in 53 patients, and seven (13%) patients died within 3 months. The mean age was 66.0 ± 14.4 years. There were 32 female patients (60.4%). The RGS had a higher sensitivity than the WS (20.8% vs. 15.1%, P <0.01), although both scores had low yields. Mortality rate was significantly higher in patients with syncope than in those without (33.3% vs. 7.3%, respectively; P = 0.039). After age and sex adjustments, the presence of syncope showed a statistically significant association with mortality. The mortality rate did not significantly differ between the two groups categorized according to the WS (17.4% vs. 0%; P = 0.58) and RGS (21.7% vs. 14.3%; P = 1.00). CONCLUSION: WS and RGS had low sensitivity in the diagnosis of PE and had limited prognostic values in a Japanese community hospital setting. Promoting awareness about the risk of mortality in patients with PE, especially those with syncope, is necessary.

Microscopic polyangiitis presented with biopsy-confirmed pleuritis.

We describe a case of microscopic polyangiitis manifested as pleuritis confirmed by thoracoscopic biopsy. An 80-year-old man presented with a three-day history of shortness of breath and cough. Chest radiography revealed patchy opacities in the lower fields of the bilateral lung and right-sided pleural effusion. Thoracentesis revealed lymphocytic pleural exudates. Thoracoscopic biopsy specimens were compatible with fibrotic pleuritis. He developed rapidly progressive glomerulonephritis with elevated myeloperoxidase anti-neutrophil cytoplasmic antibody titer in blood and pleural effusion. Although the patient was resistant to two weekly courses of pulse steroid therapy, he was successfully treated with a five-day course of intravenous immunoglobulin.

[Retropharyngeal abscess with cervical discitis and vertebral osteomyelitis caused by Escherichia coli in a patient with liver cirrhosis].

We describe the case of a 67-year-old male with liver cirrhosis who presented with fever and neck pain. Magnetic resonance imaging of the spine detected cervical vertebral osteomyelitis, and enhanced CT of the neck and spine revealed retropharyngeal abscess. The patient was treated with empirical antimicrobial therapy and surgical drainage due to significant airway involvement. Escherichia coli was cultured from the blood and pus in inferior cervical vertebrae which was a rare pathogen. Haematogenous spread may have resulted in cervical vertebral osteomyelitis and retropharyngeal abscess. With high mortality rates, early diagnosis of retropharyngeal abscess is required to avoid debilitating complications such as airway obstruction.

Renal embolism as a primary manifestation of Streptococcus dysgalactiae subspecies equisimilis endocarditis in a patient with chronic aortic dissection.

We report a case of renal embolism as an initial manifestation of Streptococcus dysgalactiae subspecies equisimilis (SDSE) endocarditis in a patient with chronic aortic dissection. A 37-year-old man who underwent total aortic arch replacement owing to aortic dissection, presented with a 3-h history of fever, chills, and acute right-sided flank pain. The endocarditis affected the native aortic valve and was complicated by a renal embolism. Blood culture results were positive for SDSE. Intravenous penicillin resulted in satisfactory clinical and echocardiographic recovery.

A case of granulomatosis with polyangiitis (Wegener's granulomatosis) presenting with marked inflamed tracheobronchial mucosa.

A 70-year-old man was admitted to our hospital because of weight loss and persistent dry cough. Chest radiograph and CT showed multiple infiltrates in the bilateral upper lobes and the remarkably thickened bronchial walls. Bronchoscopy revealed diffuse erythema and edema of the tracheobronchial mucosa without any ulcerous legions. Serum MPO-ANCA was positive (155 EU). Transbronchial biopsy was performed and revealed necrotic granulomas with multinucleated giant cells in the bronchial/bronchiolar and parenchymal lesions. Thus, we diagnosed it as a localized form of granulomatosis with polyangiitis (GPA, Wegener's granulomatosis). After treatment with corticosteroid and cyclophosphamide, the bronchial findings were entirely resolved. We report here a rare case of GPA presenting with markedly inflamed tracheobronchial mucosa.

Antithyroid drug-induced agranulocytosis complicated by pneumococcal sepsis and upper airway obstruction.

Streptococcus pneumoniae is a rare pathogen of sepsis in patients with antithyroid drug-induced agranulocytosis. We herein describe a case of antithyroid drug-induced agranulocytosis complicated by pneumococcal sepsis and upper airway obstruction. A 27-year-old woman who was previously prescribed methimazole for nine months presented with a four-day history of a sore throat. She nearly choked and was diagnosed with febrile agranulocytosis. She was successfully treated with intubation, intravenous antibiotics and granulocyte colony-stimulating factor. Her blood cultures yielded S. pneumoniae. Emergency airway management, treatment of sepsis and the administration of granulocyte colony-stimulating factor can improve the clinical course of antithyroid drug-induced pneumococcal sepsis in patients with airway obstruction.

Evaluation of simple aspiration therapy in the initial treatment for primary spontaneous pneumothorax.

OBJECTIVE: A retrospective evaluation of the effectiveness of simple aspiration therapy in primary spontaneous pneumothorax was carried out. METHODS: We enrolled 143 patients with mild and moderate primary spontaneous pneumothorax between June 2006 and October 2010. Clinical backgrounds and therapeutic results from 92 patients that underwent simple aspiration therapy were assessed. RESULTS: All patients were treated safely without any serious complications. With the exception of one patient with an unknown result, the initial success rate after three days was 72.5% (66 out of 91 patients). Chest X-ray analysis at the first medical examination showed that the success rate was significantly low in patients with a larger vertical rim between the apex and top of the lung and a higher collapsed area ratio; in particular, the success rate was markedly decreased in cases that exceeded 8 cm and 50%, respectively. No significant difference was observed in the aspiration volume, however, the success rate was lower when the aspiration volume was more than 1,500 mL. The recurrence rate at one year was 36.4% (24 out of 66 successfully treated patients). CONCLUSION: Our results are nearly identical to previous reports from other countries and show that simple aspiration has proved to be a safe and effective therapy.

Randomized phase II study of two different schedules of gemcitabine and oral S-1 in chemo-naïve patients with advanced non-small cell lung cancer.

INTRODUCTION: This study was conducted to evaluate the efficacy and safety and to compare dosing schedules of gemcitabine combined with S-1 in chemo-naïve non-small cell lung cancer patients. METHODS: Patients with chemo-naïve stage IIIB/IV non-small cell lung cancer were randomized into two treatment arms. Patients were given oral S-1 (60 mg/m/d, twice a day) from days 1 to 14 with gemcitabine (1000 mg/m/d) on days 1 and 8 (arm A) or on days 8 and 15 (arm B). This cycle was repeated every 21 days. RESULTS: A total of 80 patients were entered in this trial. The primary end point of this study was response rate. The response rates of arm A and arm B were 22.0 and 28.9%, respectively (p = 0.606). Median time to treatment failure in arm A was 3.6 months and 4.8 months in arm B. Median time to progression in arm A was 4.1 months and 5.5 months in arm B. Median survival time in arm A and arm B was 15.5 months and 18.8 months, respectively. The toxicity profile was relatively mild and did not differ very much between two arms. CONCLUSION: The combination of gemcitabine and S-1 was determined to be feasible and effective for advanced non-small cell lung cancer. We selected arm B for further studies because of its higher response rate and survival data.

Prolonged survival of a patient with lung cancer after treatment with S-1, a new oral fluoropyrimidine anticancer drug.

A 36-yr-old woman complaining of cough and body weight loss at a health checkup and referred to us after an abnormality was noted on the chest X-ray was diagnosed with clinical stage IV (cT2N3Ml) non-small-cell lung cancer (adenocarcinoma). She received three courses of chemotherapy. The response to treatment was stable disease. She was subsequently enrolled in a clinical trial of S-1, a new oral fluoropyrimidine anticancer drug, and received a total of 22 courses of S-1 over a period of 2 yr 5 mo. At the end of treatment, she was classified as having a partial response. A bronchoscopic biopsy disclosed no cancer cells. Remission continued for 1 yr 7 mo after treatment. The patient died of primary disease 8 yr after the initiation of treatment with oral S-1. Non-small-cell lung cancer was approved as a new indication of S-1 in 2004 in Japan, but the number of patients receiving it for this indication remains limited. Here, we describe our experience with a patient with adenocarcinoma of the lung who survived for a prolonged period after treatment with S-1. Our findings suggest that S-1 is effective for the treatment of non-small-cell lung cancer.

Overexpression of nitric oxide synthase by the endothelium attenuates bleomycin-induced lung fibrosis and impairs MMP-9/TIMP-1 balance.

BACKGROUND: Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is thought to effect an anti-inflammatory response, but its mechanism is still unknown. METHODS: eNOS transgenic (eNOS-TG) mice and their littermate controls (C57/BL6) were used to clarify the role of NO derived from eNOS. Bleomycin hydrochloride (1 U/body/day) or PBS was injected intraperitoneally. RESULTS: Subpleural fibrotic changes and hydroxyproline content in the eNOS-TG mice were significantly reduced compared with those of the wild-type (WT) mice by day 56. Administration of N(omega)-nitro-L-arginine methyl ester, a potent inhibitor of NO synthase, worsened the fibrotic response in bleomycin-treated eNOS-TG mice. Gelatinolytic activity in lung homogenates, corresponding to metalloproteinase-9 (MMP-9), was significantly increased in bleomycin-injured WT mice on day 14. In contrast, the level of tissue inhibitor of metalloproteinases-1 (TIMP-1), an endogenous MMP-9 inhibitor, was increased in the bleomycin-treated eNOS-TG mice compared with WT. Immunohistochemical analysis demonstrated that MMP-9 and TIMP-1 were strongly expressed in inflammatory cells, including subpleural fibrotic lesions. CONCLUSION: These data suggested that eNOS overexpression attenuates bleomycin-induced lung injury by ameliorating the MMP-9/TIMP-1 balance.

Usefulness of the oximetry test for the diagnosis of sleep apnea syndrome in Japan.

We evaluated the usefulness of oximetry tests that are frequently used as screening tools for sleep apnea syndrome (SAS) by determining the level of agreement between oximetry test results and polysomnography test (PSG) results. We retrospectively examined 135 patients suspected of having SAS. Although the oximetry desaturation index (DSI) seemed better than the oximetry apnea index in the agreement with the polysomnography respiratory disturbance index (RDI), the criteria of DSI greater than or equal to 15 was not sensitive enough to screen for moderate SAS (PSG-RDI >or= 20). Multivariate analyses revealing that body mass index (BMI) as well as DSI correlated well with PSG-RDI, we established a new criterion by adding the BMI score (DSI >or= 15 or BMI >or= 25), which remarkably improved the sensitivity. This criterion may be useful not only in clinical practice but also in medical checkups for asymptomatic patients, and also suggests that obese patients with sleep disturbance should undergo PSGs, irrespective of the DSI score.

Effect of continuous positive airway pressure on soluble CD40 ligand in patients with obstructive sleep apnea syndrome.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for atherosclerosis. CD40-CD40 ligand interaction promotes several proinflammatory mediators and plays a pivotal role in the various stages of atherosclerotic diseases. The present study examines whether CD40 ligation contributes to outcomes in patients with OSAS. METHODS: The study population comprised OSAS patients with an apnea hypopnea index (AHI) > or = 30 (n = 35) and control subjects (AHI < 5; n = 16). We measured serum levels of soluble CD40 ligand (sCD40L), tumor necrosis factor (TNF)-alpha, and hypersensitive C-reactive protein (hsCRP) before and after nasal continuous positive airway pressure (nCPAP) therapy for 3 months. RESULTS: Baseline levels of sCD40L were significantly higher in patients with OSAS (6.93 +/- 4.64 ng/mL) [mean +/- SD] than in control subjects (3.43 +/- 2.11 ng/mL, p < 0.01). Baseline levels of sCD40L positively correlated with TNF-alpha but not with hsCRP. The elevation of sCD40L was improved for 1 night after nCPAP therapy (3.83 +/- 2.78 ng/mL, p < 0.001). Even though patients with severe OSAS did not receive any other medication to control atherosclerotic risk factors for 3 months, nCPAP was continued to reduce the levels of sCD40L. CONCLUSION: The present study suggested that sCD40L is a key factor that links OSAS and atherosclerotic progression.

[Pulmonary thromboembolism associated with familial protein C deficiency type I].

A 66-year-old man was admitted to our hospital because of progressive dyspnea on effort. Arterial blood gas analysis showed severe hypoxemia, and a chest radiograph revealed reticular shadows in both lower lungs and an increase of the cardiothoracic ratio. Echocardiography demonstrated mild indentation of the interventricular septum toward the left ventricle, moderate pericardial effusion and pulmonary hypertension. From these data, we diagnosed pulmonary thromboembolism and started anticoagulation therapy. After the addition of the administration of warfarin and oxygen therapy, his symptoms disappeared. However, we could not obtain more supporting evidence of thromboembolization by methods of ventilation-perfusion scanning, digital subtraction angiography of the pulmonary artery, or venography. Blood coagulation analysis demonstrated that the patient's plasma protein C antigen levels and its activity were depleted. The patient's son had a history of thrombophlebitis and pulmonary embolization, and his data of protein C antigen levels was also decreased. Therefore, this patient was found to have a character of familial protein C deficiency type I. We could not get the conclusive proof of pulmonary thromboembolism, but we considered that the presence of familial protein C deficiency may cause exacerbation of pulmonary hypertension.

Airway remodeling of murine chronic antigen exposure model.

Airway remodeling is one of the most important features of bronchial asthma. However, there are few studies that have used repeated antigen exposure in murine models. We designed a murine chronic antigen exposure model necessary for studying airway remodeling. Two different strains of mice, BALB/c mice and C57BL/6 mice, were sensitized and challenged for 3-7 weeks with ovalbumin (OVA). Bronchoalveolar lavage (BAL) and histology study were conducted in each phase. Morphometry was performed, and the epithelial area ratio (Ae ratio) and subepithelial area ratio (As ratio) were calculated. The Ae ratio and As ratio of BALB/c mice were significantly increased in sensitized mice compared with non-sensitized mice at 3 and 5 weeks, but not at 7 weeks. In C57BL/6 mice, the Ae ratio showed no significant changes, whereas the As ratio maintained high from 3 to 7 weeks. This thickening of the subepithelial layer consisted of collagen fibers with elastica van-Gieson (EVG) stain. Lymphocytes of the BAL showed a significant increase at 3 and 7 weeks in C57BL/6 mice, but not in BALB/c mice. A murine chronic OVA exposure model in C57BL/6 mice revealed subepithelial layer thickening consisting of collagen fibers and increased lymphocytes until 7 weeks. C57BL/6 mice are useful to elucidate the mechanism of airway remodeling.