Antiplatelet drugs may increase the risk for checkpoint inhibitor-related pneumonitis in advanced cancer patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are indicated for various cancers and are the mainstay of cancer immunotherapy. They are often associated with ICI-related pneumonitis (CIP), however, hindering a favorable clinical course. Recently, non-oncology concomitant drugs have been reported to affect the efficacy and toxicity of ICIs; however, the association between these drugs and the risk for CIP is uncertain. The aim of this study was to assess the impact of baseline concomitant drugs on CIP incidence in ICI-treated advanced cancer patients. PATIENTS AND METHODS: This was a single-center retrospective study that included a cohort of 511 patients with advanced cancer (melanoma and non-small-cell lung, head and neck, genitourinary, and other types of cancer) treated with ICIs. Univariable analysis was conducted to identify baseline co-medications associated with CIP incidence. A propensity score matching analysis was used to adjust for potential CIP risk factors, and multivariable analysis was carried out to assess the impact of the identified co-medications on CIP risk. RESULTS: Forty-seven (9.2%) patients developed CIP. In these patients, the organizing pneumonia pattern was the dominant radiological phenotype, and 42.6% had grade ≥3 CIP, including one patient with grade 5. Of the investigated baseline co-medications, the proportion of antiplatelet drugs (n = 50, 9.8%) was higher in patients with CIP (23.4% versus 8.4%). After propensity score matching, the CIP incidence was higher in patients with baseline antiplatelet drugs (22% versus 6%). Finally, baseline antiplatelet drug use was demonstrated to increase the risk for CIP incidence regardless of cancer type (hazard ratio, 3.46; 95% confidence interval 1.21-9.86). CONCLUSIONS: An association between concomitant antiplatelet drug use at baseline and an increased risk for CIP was seen in our database. This implies the importance of assessing concomitant medications for CIP risk management.

Resveratrol suppresses the alveolar bone resorption induced by artificial trauma from occlusion in mice.

OBJECTIVE: Besides inflammatory bone loss, trauma from occlusion (TO)-induced alveolar bone loss increases the risk of future tooth loss. We have shown that resveratrol, a polyphenol, possesses anti-inflammatory characteristics and a suppressive effect on osteoclastogenesis. Therefore, we investigated the effects of resveratrol on TO-induced bone loss in mice. MATERIAL AND METHODS: Trauma from occlusion was induced by overlaying composite resin onto the maxillary first molar of C57BL/6 mice. TO-induced mice were administered either resveratrol or vehicle for 15 days from 5 days before TO induction. The mice administered vehicle only served as controls. The effect of resveratrol on bone resorption was assessed histologically. Gene expression in gingival and periodontal ligament tissues was analyzed. In vitro effect of resveratrol on the differentiation of RAW 264.7 cells and bone marrow-derived macrophages into osteoclastic cells was analyzed. RESULTS: Resveratrol administration significantly decreased the bone loss and suppressed the elevated expression of osteoclastogenesis-related gene in periodontal ligament tissue by TO. Resveratrol treatment also suppressed the differentiation of both RAW 264.7 cells and bone marrow-derived macrophages into osteoclastic cells. CONCLUSION: Resveratrol administration suppressed the TO-induced alveolar bone loss by suppressing osteoclast differentiation, suggesting that resveratrol is effective in preventing both inflammation and mechanical stress-induced alveolar bone resorption.

Ligature-induced periodontitis in mice induces elevated levels of circulating interleukin-6 but shows only weak effects on adipose and liver tissues.

BACKGROUND AND OBJECTIVES: Our previous study demonstrated using an oral gavage model that Porphyromonas gingivalis could induce various inflammatory changes linked to periodontitis-associated systemic diseases by altering gut microbiota. A ligature-induced periodontitis model is similar to human periodontitis in various aspects: in both cases, alveolar bone resorption depends on oral bacterial load, and gingival tissue becomes infiltrated with inflammatory cells. Therefore, this model may be suitable for the analysis of bacterial burden and gingival tissue inflammation with changes related to systemic diseases. MATERIAL AND METHODS: Periodontal tissue destruction was induced by a 2 wk ligature placement around the bilateral maxillary second molar. We analyzed the expression profile of various genes in several tissues, levels of systemic inflammatory markers and induction of insulin resistance. In addition, we studied changes in gut microbiota composition and bacterial load in the oral cavity. RESULTS: Two weeks after ligature placement gingival inflammation was significantly induced with a disrupted gingival epithelial barrier and alveolar bone resorption accompanied by increased bacterial burden in the oral cavity. Gene expression analysis of the gingival tissue of ligated mice demonstrated that interleukin (Il)1b was significantly elevated and Il6 and Il17a tended to be higher in ligated mice than in untreated mice. Although serum IL-6 was significantly elevated and serum amyloid A tended to be higher in ligated compared to untreated mice, endotoxin levels did not differ between the two groups. Among the genes whose expressions are closely related to glucose and lipid metabolisms, only phosphoenolpyruvate carboxykinase 1 (Pck1) and acetyl-coenzyme A carboxylase alpha (Acaca) showed significant changes following ligature placement in the liver, with the former upregulated and the latter downregulated. However, insulin sensitivity did not change following ligature placement. Furthermore, ligature placement weakly affected the composition of gut microbiota and gene expression in the intestines. CONCLUSION: The results suggest that increased oral commensals and gingival inflammation have limited roles in the pathological changes to adipose and liver tissues, which are important organs whose dysfunctions contribute to the development of periodontitis-related systemic diseases.

Resveratrol suppresses the inflammatory responses of human gingival epithelial cells in a SIRT1 independent manner.

BACKGROUND AND OBJECTIVE: In periodontitis, chronic infection by periodontopathic bacteria induces uncontrolled inflammation, which leads to periodontal tissue destruction. Human gingival epithelial cells (HGECs) constitute a critical first line of defense against periodontopathic bacteria, both as a physical barrier and as regulators of inflammation. Resveratrol, a polyphenol found in grapes and red wine, reportedly has anti-inflammatory properties. Therefore, we investigated the effects of resveratrol on the Porphyromonas gingivalis-induced inflammatory responses of HGECs and their mechanism. MATERIAL AND METHODS: We stimulated the HGEC line, epi 4, with live or heat-killed P. gingivalis in the presence of resveratrol, and analyzed expressions of the interleukin-8, monocyte chemoattractant protein-1 and interleukin-1ß genes. We determined the involvement of SIRT1 in the effect of resveratrol using sirtinol (a SIRT1 inhibitor) or SIRT1 knockdown. We also examined whether the effects were mediated by activation of AMP-activated kinase, suppression of reactive oxygen species, or inhibition of nuclear factor-κB (NF-κB). RESULTS: Resveratrol treatment decreased the expression of inflammatory cytokines and slightly increased the expression of SIRT1. However, neither SIRT1 inhibition nor SIRT1 knockdown counteracted its anti-inflammatory effects. Although resveratrol did not affect AMP-activated kinase activation or reactive oxygen species production, it slightly suppressed NF-κB translocation when cells were stimulated with heat-killed P. gingivalis. CONCLUSION: Resveratrol suppressed the inflammatory responses of P. gingivalis-stimulated HGECs, probably by inhibiting NF-κB signaling but independent of SIRT1.

[Experience of long term survival in a case with surgery for cancer metastasis to brain and mediastinal lymph node from unknown primary site].

We report a rare case of metastatic brain and lymph node carcinoma of unknown primary origin. A 68-year-old man had been followed up after resection of brain metastasis in right parietooccipital region without suspicious primary site. Seventy-eight months after the resection, a mediastinal lymph node (#2R) of 15 mm in diameter was detected by computed tomography (CT) and was surgically removed. The histological diagnosis was poorly differentiated adenocarcinoma resembling lymphoepithelial carcinoma, which was similar to the histology of the previously resected brain tumor. This patient is alive without recurrence and apparent primary site at 24 months after lymph node resection.

[Aortic root replacement for aortic dissection and aortic regurgitation due to aortitis syndrome].

Aortic aneurysms and aortic regurgitation (AR) with aortitis syndrome are occasionally reported in young women. We report a case of aortic dissection with severe AR in an 8-year-old girl. The patient underwent aortic root replacement with a composite graft. Pathological report revealed aortitis syndrome and steroid therapy was continued to suppress further inflammatory vascular reaction.

[Aortic valve replacement through right thoracotomy; report of a case].

A 78-year-old female was admitted to our hospital with a diagnosis of severe aortic valve regurgitation. She had had dyspnea on effort and syncope twice in 5 months. She had also suffered from right pneumonia 8 years before, and her respiratory function was severely constrictive. Chest X-ray showed her mediastinum significantly shifted toward the right side. Chest computed tomography (CT) revealed the main pulmonary artery, right atrium (RA) and right pulmonary veins also shifted toward the right. We planned right thoracotomy at 4th intercostals space to obtain a good surgical field. A cardiopulmonary bypass was established by RA appendage drainage and femoral artery perfusion. Aortic valve replacement(AVR) was performed successfully after aortic clamp. Though defibrillator pads were placed on her back and the anterior wall of the left chest during operation, no ventricular fibrillation occurred. AVR via right thoracotomy is considered to be a good option for such a mediastinum shifted case.

[Multiple recurrent cardiac myxomas].

A 49-year-old male had undergone resection of biatrial multiple myxomas 4 years previously in another hospital. Echocardiography revealed new masses in the left atrium and the right ventricle. Both tumors were removed surgically and subsequently treated with adjuvant chemotherapy. There was no further recurrence during the following 4 years. It was considered that the multiple recurrences in our case were due to multicentricity of the tumor.

[Beating heart surgery for the patient of severe mitral regurgitation with a episode of ventricular fibrillation; report of a case].

A 77-year-old female was admitted to our hospital with a diagnosis of severe mitral regurgitation. Cardiopulmonary revival was done by an emergent resuscitation for the ventricular fibrillation before admission. She had mild anoxic brain damage and brain magnetic resonance imaging (MRI) revealed severe brain atrophy. Chest X-ray showed severe cardiomegaly and congestion. Beating heart mitral valve replacement was planned for the prevention of reperfusion injury. A cardiopulmonary bypass was established by bicaval drainage and aortic return. The prolapse of anterior leaflet was recognized through transeptal approach after aortic clamp. We selected continuous infusion of antegrade cardioplegia for intraoperative coronary perfusion. Mitral valve replacement was done successfully. During intraoperation and postoperation, ventricular fibrillation did not occur. On-pump beating mitral valve replacement is a good procedure to prevent perioperative ventricular arrhythmia especially such the case with a decompressed myocardial function and with a preoperative episode of lethal ventricular arrhythmia necessary for cardiopulmonary resuscitation.

[Aggressively metastatic neuroendocrine carcinoma in the middle mediastinum].

A 50-year-old male patient with no symptoms was admitted to our hospital for further evaluation of a right superior mediastinal mass shadow found in chest radiographs during a health examination. Computed tomographic (CT) scans demonstrated a middle mediastinal mass of 4 cm in diameter surrounded by the SVC, the ascending aorta and the trachea at the subaortic level. Routine examination disclosed no metastatic or primary lesion elsewhere. A surgical biopsy resulted in a diagnosis of neuroendocrine carcinoma of unknown primary organ. The patient was given 1 course of chemotherapy with CAV-PE, but little effect was seen. However, when a PE regimen combined with thoracic radiation was used, the tumor shrank to half of its size. After the patient subsequently received high-dose treatment with Etoposide, CT imaging and cytologic analysis revealed multiple metastases to the subcutaneous tissue, both adrenal glands and the liver. Lung lesions also spread aggressively, and the patient died of metastasis. Although neuroendocrine carcinomas can arise from the systemic neuroendocrine cells including those in the mediastinum, their appearance in the middle mediastinum is rarely reported.

Risk stratification using serum concentrations of cardiac troponin T in patients with end-stage renal disease on chronic maintenance dialysis.

BACKGROUND: It has been recently suggested that cardiac troponin T (cTnT) may be more sensitive than troponin I (cTnI) for subclinical myocardial cell injury in patients on chronic dialysis. METHODS: We prospectively compared the predictive value of cTnT with cTnI, atrial (ANP) and brain natriuretic peptide (BNP) in 100 consecutive outpatients on chronic dialysis without acute coronary syndromes over a period of 3 months, and assessed whether the combination of cTnT with clinical information including age, duration of dialysis, and medical histories was useful for risk stratification of these patients. During the 2-year follow-up period, 19 patients died, mostly due to cardiac causes (53%). RESULTS: The area under the receiver operator characteristic (ROC) curve for the cTnT as predictor of both overall and cardiac death was significantly greater than the area under the cTnI curve (p < 0.0001 and p = 0.01), the BNP curve (p < 0.001 and p < 0.01) or the ANP curve (p < 0.0001 and p < 0.005). In a stepwise multivariate Cox regression analysis, only cTnT (p < 0.05 and p < 0.01) and a history of heart failure requiring hospitalization (p < 0.05 and p < 0.005) were independent predictors of both all cause and cardiac mortality. Using parameters of cTnT > or =0.1 microg/l and/or history of heart failure, the overall and cardiac mortality rate for the low risk group (n=66) were 4.5% and 1.5%, respectively, 40% and 16% for the intermediate risk group (n=25), and 67% and 56% for the high risk group (n=9). CONCLUSION: cTnT concentrations offer a higher prognostic accuracy than cTnI, ANP and BNP in patients on chronic dialysis. The combination of elevated cTnT and a history of heart failure may be a highly effective means of risk stratification of these patients.

Distinct phosphoinositide binding specificity of the GAP1 family proteins: characterization of the pleckstrin homology domains of MRASAL and KIAA0538.

GAP1, one of the Ras GTPase-activating protein families, includes four distinct genes (GAP1(m), GAP1(IP4BP), MRASAL (murine Ras GTPase-activating-like), and KIAA0538). It contains an amino-terminal tandem C2 domain, a GAP-related domain, and a carboxyl-terminal pleckstrin homology (PH) domain. Although the PH domains of GAP1(m) and GAP1(IP4BP) have been shown to be essential for membrane targeting via binding of specific phospholipids, little is known about the functions of the PH domains of MRASAL and KIAA0538. Herein, we show that the PH domain of MRASAL has binding activity toward PI(4,5)P(2) and PI(3,4,5)P(3), while the PH domain of KIAA0538 does not bind these phospholipids due to an amino acid substitution at position 592 (Leu-592). Mutation of the corresponding position of MRASAL (Arg-to-Leu substitution at position 591) resulted in loss of the phospholipid binding activity. MRASAL proteins were localized at the plasma membrane in NIH3T3 cells, and this plasma membrane association was unchanged even after cytochalasin B or wortmannin treatment. By contrast, KIAA0538 and MRASAL (R591L) proteins were present in the cytosol. Our data indicate that the distinct phosphoinositide binding specificity of the PH domain is attributable to the distinct subcellular localization of the GAP1 family.

Identification and characterization of a sac domain-containing phosphoinositide 5-phosphatase.

We have characterized a novel Sac domain-containing inositol phosphatase, hSac2. It was ubiquitously expressed but especially abundant in the brain, heart, skeletal muscle, and kidney. Unlike other Sac domain-containing proteins, hSac2 protein exhibited 5-phosphatase activity specific for phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. This is the first time that the Sac domain has been reported to possess 5-phosphatase activity. Its 5-phosphatase activity for phosphatidylinositol 4,5-bisphosphate (K(m) = 14.3 microm) was comparable with those of Type II 5-phosphatases. These results imply that hSac2 functions as an inositol polyphosphate 5-phosphatase.

Uptake by vascular smooth muscle cells plays an important role in targeting of lipid microspheres incorporating prostaglandin E1 into a thickened intima.

A study was done to determine how lipid microspheres (LM) containing prostaglandin E1 (lipo PGE1) accumulate in injured arterial tissue. After administration of lipo PGE1 labeled with a fluorescence probe, 1,1'-dioctadecyl-3, 3, 3',3'-tetramethyl-indocarbocyanine perchlorate (DiI-lipo PGE1) to rats 14 of days after balloon injury of the carotid artery, localization into the injured site was examined using a fluorescence confocal laser scanning microscope (CLSM). In contrast with the normal carotid artery, DiI-lipo PGE1 accumulated remarkably in neointima of the injured site which was occupied mainly by the migration of the proliferating and quiescent vascular smooth muscle cells (SMC). In vitro cellular uptake of DiI-lipo PGE1 was semi-quantitatively measured using CLSM, regarding differentiated and proliferative phenotypes of human vascular SMC, compared with the human endothelial cells (EC) and mouse fibroblasts. The differentiated SMC incorporated DiI-lipo PGE1 to equal or a higher level of the proliferative phenotype, and was significantly higher than EC and fibroblasts. The uptake of DiI-lipo PGE1 by both SMC and EC was inhibited at 4 degrees C, by dansylcadaverine and excessive LM, but was unaffected by cytochalasin B. These results suggest that the uptake of DiI-lipo PGE1 by SMC plays an important role in localization of DiI-lipo PGE1 at the injured site, and that the uptake seems to be a receptor mediated endocytosis.

Integration of a wet analysis system on a glass chip: determination of Co(ii) as 2-nitroso-1-naphthol chelates by solvent extraction and thermal lens microscopy.

The integration of a wet analysis system on a glass chip was demonstrated and determination of Co(II) was performed using this system. The Co(II) was extracted into m-xylene from aqueous solution as 2-nitroso-1-naphthol chelates, and colorimetric determination of the m-xylene phase was applied by a thermal lens microscope. The integration of the chemical operation procedures shown here leads to a considerable reduction in analyzing time. The time for extraction in the integrated system, 10 min, was about tenfold shorter than a conventional system using a separatory funnel and mechanical shaker. Moreover, troublesome operations such as phase separation necessary for the conventional system could be omitted. The determination of Co(II) in the range 2 x 10(-7)-1 x 10(-8) M, which was estimated to be 0.072-1.44 zmol, was achieved.

Integration of a microextraction system solvent extraction of a Co-2-nitroso-5-dimethylaminophenol complex on a microchip.

A newly designed microchannel for solvent extraction was fabricated in a quartz glass chip and applied to solvent extraction of a Co-2-nitroso-5-dimethylaminophenol complex. The aqueous solution of Co complex and toluene were introduced into the microchannel, and the Co complex extracted in toluene was detected by thermal lens microscopy (TLM). The Co complex was quickly extracted into toluene when the flow was stopped. The observed extraction time, ca. 50 s, was almost equivalent to the value calculated using the diffusion distance and diffusion coefficient. The dependence of the TLM signal on the concentration of the Co complex showed good linearity in the range of 1 x 10(-7) - 1 x 10(-6) M.

Integration of a microextraction system on a glass chip: ion-pair solvent extraction of Fe(II) with 4,7-diphenyl-1,10-phenanthrolinedisulfonic acid and tri-n-octylmethylammonium chloride

An ion-pair solvent extraction was performed in a microchannel fabricated in a quartz glass chip. the aqueous solution of Fe-bathophenanthrolinedisulfonic acid complex and the chloroform solution of tri-n-octylmethylammonium chloride were introduced into the microchannel, and a parallel two-phase laminar flow was formed. The ion-pair product extracted in chloroform was monitored by the thermal lens microscope. The ion-pair product was gradually extracted from aqueous solution into chloroform when the flow was very slow or stopped, while nothing was extracted into chloroform when the flow was fast. The time for extraction in the present 250 microns microchannel, 45 s, roughly coincided with the molecular diffusion time, and the extraction time was at least 1 order shorter compared with the ordinary extraction time using a separatory funnel and mechanical shaking. The microspace in the microchannel was characterized by the large specific interface area and short diffusion distance, and these characteristics may contribute to highly efficient extraction without mechanical shaking. The success of this molecular transport may lead to the integration of more complicated separation and chemical operations on a microchip and more applications.

Vasodilating effect and tissue accumulation of prostaglandin E1 incorporated in lipid microspheres on the rat ductus arteriosus.

Prostaglandin E1 incorporated in lipid microspheres (lipo PGE1) was administered to the umbilical vein of neonatal rats. Morphological measurement and quantitative autoradioluminography assessed the relationship between the vasodilating effect and tissue accumulation of lipo PGE1 in the ductus arteriosus. In the morphological measurement under microscopy, the inner diameter ratio of the ductus arteriosus to the main pulmonary artery after infusion of 3H-labeled lipo PGE1 (3H-lipo PGE1) continued to remain significantly higher than that of free 3H-PGE1. Autoradioluminography of the frozen frontal section of neonates after intravenous infusion of 3H-lipo PGE1 for 2 h revealed that the ductus levels of radioactivity were higher than those of free 3H-PGE1 in saline solution, although the blood levels were almost equal. Localization of lipo PGE1 labeled with a lipophilic fluorescent probe, 1,1'-dioctadecyl-3,3,3',3-tetramethyl-indocarbocyanine perchlorate (diI), in the endothelial cells of the ductus arteriosus was confirmed by confocal laser scanning microscopy. These findings suggest that the incorporation of lipid microspheres by the endothelial cells is one of the mechanisms that enables lipo PGE1 to accumulate to higher levels in the ductus tissue and to act more efficiently than free PGE1 in neonatal rats.