Search

Abstract There have been several reports of drug‐induced lung injury caused by molecular‐targeted agents. Additionally, medical history of interstitial lung disease and chest irradiation are established risk factors for the development and progression of drug‐induced lung injury. Moreover, the presence of fibrosis on chest computed tomography before treatment is a predictive factor for the appearance of pneumonia induced by anticancer drugs. Accordingly, patients with a history of interstitial lung disease or pneumonitis were excluded from clinical trials of dabrafenib and trametinib combination therapy for patients with previously treated BRAF V600E‐mutant metastatic non‐small‐cell lung cancer. This article presents a case of successful dabrafenib and trametinib combination therapy in a patient with BRAF V600E‐mutant non‐small‐cell lung cancer who had a history of radiation pneumonitis and developed recurrence after conventional chemoradiotherapy.

Abstract A 28‐year‐old man with ankylosing spondylitis (AS) who was treated with a tumour necrosis factor‐alpha (TNF‐α) inhibitor, adalimumab, presented with newly detected multiple bilateral pulmonary nodules on chest computed tomography (CT). We suspected bacterial infection, including those caused by acid‐fast bacilli, or adalimumab‐related condition, such as sarcoidosis. After adalimumab cessation, no resolution of the pulmonary shadows was observed. Moreover, pulmonary cavitation appeared on chest CT at 7 weeks, prompting surgical lung biopsy. Acid‐fast bacteria culture of the lung tissue showed negative results. Pathological examination suggested that confluent granulomas associated with sarcoidosis might have obstructed the blood vessels, causing necrosis and lung cavitation. Consequently, prednisolone was initiated, and these shadows were reduced. After administering anti‐interleukin (IL)‐17A antibody for treatment of AS and prednisolone withdrawal, these shadows were not exacerbated. TNF‐α inhibitor‐induced sarcoidosis could cause cavitary lesions due to vascular invasion of granulomas.

Background: Among international cardiologists it is unclear whether equipoise exists regarding the benefit of diagnosing and managing obstructive sleep apnea (OSA) to improve atrial fibrillation (AF) outcomes and whether clinical practice and equipoise are linked. Methods: Between January 2019 and June 2020 we distributed a web-based 12-question survey regarding OSA and AF management to practicing cardiologists in 16 countries. Results: The United States, Japan, Sweden, and Turkey accounted for two-thirds of responses. 863 cardiologists responded; half were general cardiologists, a quarter electrophysiologists. Responses regarding treating OSA with CPAP to improve AF endpoints were mixed. 33% of respondents referred AF patients for OSA screening. OSA was diagnosed in 48% of referred patients and continuous positive airway pressure (CPAP) was prescribed for 59% of them. Nearly 70% of respondents believed randomized controlled trials (RCTs) of OSA treatment in AF patients were necessary and indicated willingness to contribute to such trials. Conclusions: There was no clinical equipoise among surveyed cardiologists; a majority expressed certainty that combined OSA and AF treatment is superior to AF treatment alone for improving AF outcomes. However, a minority of surveyed cardiologists referred AF patients for OSA testing, and while half of screened AF patients had OSA, CPAP was prescribed in little more than half of them, reflecting the view that better clinical trial evidence is needed to support this practice. Our results underscore the need for larger, multi-national prospective studies of OSA treatment and AF outcomes to inform more uniform society guideline recommendations.

Abstract Nintedanib is a multi‐target receptor tyrosine kinase inhibitor that reduces the decline in forced vital capacity (FVC) and prevents acute exacerbations in idiopathic pulmonary fibrosis (IPF), which is a risk factor for lung cancer. However, it remains unclear whether nintedanib is an effective treatment for lung cancer in patients with IPF. Here, we describe an 82‐year‐old man with non‐small cell lung carcinoma complicated by IPF who was treated with nintedanib. High‐resolution computed tomography (HRCT) showed a subpleural basal‐predominant reticular shadow and traction bronchiectasis with a honeycomb pattern. His FVC decreased over time, and his 6‐min walk test showed oxygen desaturation. Furthermore, an enlarged nodular lesion was detected after 6 months of referral. Biopsy confirmed non‐small cell carcinoma. Because of the risk of acute exacerbation of IPF by chemotherapy, supportive care was selected. Nintedanib was started as treatment for the IPF. Nine months later, HRCT revealed partial remission without exacerbation of IPF. This case indicates the possibility of nintedanib monotherapy in suppressing lung cancer complicated by IPF. Patients with lung cancer complicated by IPF in whom treatment is effective remain unknown. Additional research is needed to identify effective therapy for lung cancer with IPF.

Abstract Background Paravertebral compartment syndrome occurring without trauma is quite rare. We report a case of compartment syndrome that occurred after spinal exercises. Case presentation A 23-year-old Japanese rower developed severe back pain and was unable to move 1 day after performing exercises for the spinal muscles. Initial evaluation at a nearby hospital revealed hematuria and elevated creatine phosphokinase levels. He was transferred to our hospital, where magnetic resonance imaging revealed no hematoma but confirmed edema in the paravertebral muscles. The compartment pressure measurements were elevated bilaterally. Despite his pain being severe, his creatine phosphokinase levels were expected to peak and decline; his urine output was normal; and surgery was undesirable. Therefore, we opted for conservative management. The next day, the patient’s compartment pressure diminished, and his pain levels decreased to 2/10. After 5 days, he was able to walk without medication. Conclusions We present a rare case of compartment syndrome of the paravertebral muscles with good resolution following conservative management. We hope our case findings will help avoid unnecessary surgery in cases of paravertebral compartment syndrome.

Abstract We report an approach to fabricate high conductivity graphite sheets based on a heat-and-current treatment of filtrated, exfoliated graphite flakes. This treatment combines heating (~ 900 °C) and in-plane electrical current flow (550 A·cm−2) to improve electrical conductivity through the reduction of crystalline defects. This process was shown to require only a 1-min treatment time, which resulted in a 2.1-fold increase in electrical conductivity (from 1088 ± 72 to 2275 ± 50 S·cm−1). Structural characterization by Raman spectroscopy and X-ray diffraction indicated that the improvement electrical conductivity originated from a 30-fold improvement in the crystallinity (Raman G/D ratio increase from 2.8 to 85.3) with no other observable structural transformations. Significantly, this treatment was found to act uniformly across a macroscopic (10 mm) sheet surface indicating it is on the development of applications, such as electrodes for energy generation and storage and electromagnetic shielding, as well as on the potential for the development of large-scale treatment technologies.

Human adrenomedullin (AM), a hypotensive peptide, also has anti-colitis activity. We prepared a polyethylene glycol (PEG) ylated form of AM through the conjugation of PEG-AM (1–15) and AM (15–52). Highly pure monomeric 20 kDa PEG-AM (20kPEG-AM) stimulated cyclic adenosine monophosphate production in HEK-293 cells stably expressing the type 1 AM receptor in a dose-dependent manner. The half-life of 20kPEG-AM was 7.4 h following subcutaneous administration in mice. We assessed the anti-colitis effect of subcutaneous 20kPEG-AM administration in the dextran sodium sulfate murine colitis model. Single and double subcutaneous injection of 20kPEG-AM significantly reduced total inflammation scores. These results suggest that 20kPEG-AM is a promising therapeutic candidate for the treatment of human inflammatory bowel diseases.

Abstract Dupilumab, a human monoclonal antibody against interleukin‐4 (IL‐4) and IL‐13, has been approved for treating severe asthma and eosinophilic chronic rhinosinusitis (ECRS). Patients with ECRS are often candidates for endoscopic sinus surgery (ESS). However, a considerable number of patients have recurrent ECRS. ECRS is an important factor influencing asthma control. Here, we present two cases of severe asthma and recurrent ECRS after ESS. Although they had been treated with inhaled corticosteroids and a long‐acting β2‐agonist, they experienced frequent asthma exacerbations. Laboratory examinations revealed increased serum eosinophils and immunoglobulin E (IgE). Furthermore, the Asthma Control Test (ACT) score and forced expiratory volume in 1 sec (FEV1) were indicative of airway obstruction. After treatment with dupilumab, asthma, rhinosinusitis symptoms, and pulmonary function improved remarkably. Dupilumab therapy improved quality of life in these patients with severe asthma and ECRS.

(1) Background: Human adrenomedullin (hAM) is a hypotensive peptide hormone that exerts powerful anti-inflammatory effects. AM also had therapeutic effects in various animal experimental models of disease. However, treatment required continuous administration as the half-life of native AM is short in blood. To resolve this, we developed four human IgG1 and IgG4 Fc-fusion proteins containing full-length hAM or hAM residues 6-52. (2) Methods: We used mammalian cells to produce recombinant Fc-AM derivatives and tested the pharmacokinetics and biological activity of Fc-AM. (3) Results: We developed four Fc-fusion AMs (Fc-AM), which are long-acting AM derivatives in mammalian cells. Fc-AM had a prolonged half-life in blood and retained its ability to bind to the AM1 receptor. Fc-AM (6-52) induced higher cAMP levels for the receptor than Fc-AM. After the administration of IgG1-AM (6-52) or IgG4-AM (6-52) to rats, tissue transfer to the kidney and small intestine was observed. In addition, treatment with IgG4-AM (6-52) inhibited blood pressure increase in spontaneously hypertensive rats. (4) Conclusions: Fc-AM produced from mammalian cells can be easily prepared and might be an effective novel therapeutic agent.

We describe a case of Trousseau's syndrome in a patient with lung carcinoma. A 69-year-old man presented with pleural effusion. Further evaluation revealed EGFR mutation-positive non-small cell carcinoma in the upper lobe with extensive lymph node, bone, and brain metastases. Administration of osimertinib, an EGFR tyrosine kinase inhibitor, resulted in partial tumor response, but caused osimertinib-induced pneumonitis 10 weeks later. Prednisolone restrained lung injury progression and was gradually tapered. However, he presented with impaired consciousness and right hemiplegia. Magnetic resonance imaging revealed a left middle cerebral artery M1 segment occlusion. D-dimer level was elevated to 19.5 μg/mL. In the absence of atherosclerotic or cardiogenic thrombi, these findings led to the diagnosis of Trousseau syndrome. Endovascular therapy, but not tissue plasminogen activator, improved his condition with no recurrences. These treatment strategies are crucial to restore function in patients with potentially disabling cerebral infarction due to Trousseau syndrome.

BACKGROUND:Mouth breathing could induce not only dry throat and eventually upper respiratory tract infection, but also snoring and obstructive sleep apnea, while nasal breathing is protective against those problems. Thus, one may want to explore an approach to modify habitual mouth breathing as preferable to nasal breathing. The aim of this study was to investigate the physiological effects of our newly developed mask on facilitation of nasal breathing. METHODS:Thirty seven healthy male volunteers were enrolled in a double blind, randomized, placebo-controlled crossover trial. Participants wore a newly developed heated humidification mask or non-heated-humidification mask (placebo) for 10-min each. Subjective feelings including dry nose, dry throat, nasal obstruction, ease to breathe, relaxation, calmness, and good feeling were asked before and after wearing each mask. In addition, the effects of masks on nasal resistance, breathing pattern, and heart rate variability were assessed. RESULTS:Compared with the placebo mask, the heated humidification mask improved all components of subjective feelings except for ease to breathe; moreover, decreased nasal resistance and respiratory frequency accompanied a simultaneous increase in a surrogate maker for tidal volume. However, use of the heated humidification mask did not affect heart rate variability. CONCLUSION:Adding heated humidification to the nasopharynx could modulate breathing patterns with improvement of subjective experience and objective nasal resistance.

One aspect of carbon nanotube (CNT) synthesis that remains an obstacle to realize industrial mass production is the growth efficiency. Many approaches have been reported to improve the efficiency, either by lengthening the catalyst lifetime or by increasing the growth rate. We investigated the applicability of dwell time and carbon flux control to optimize yield, growth rate, and catalyst lifetime of water-assisted chemical vapor deposition of single-walled carbon nanotube (SWCNT) forests using acetylene as a carbon feedstock. Our results show that although acetylene is a precursor to CNT synthesis and possesses a high reactivity, the SWCNT forest growth efficiency is highly sensitive to dwell time and carbon flux similar to ethylene. Through a systematic study spanning a wide range of dwell time and carbon flux levels, the relationship of the height, growth rate, and catalyst lifetime is found. Further, for the optimum conditions for 10 min growth, SWCNT forests with ~2500 μm height, ~350 μm/min initial growth rates and extended lifetimes could be achieved by increasing the dwell time to ~5 s, demonstrating the generality of dwell time control to highly reactive gases.

Sleep apnea syndrome (SAS) is a very common disease involving intermittent hypoxia (IH), recurrent symptoms of deoxygenation during sleep, strong daytime sleepiness, and significant loss of quality of life. A number of epidemiological researches have shown that SAS is an important risk factor for insulin resistance and type 2 diabetes mellitus (DM), which is associated with SAS regardless of age, gender, or body habitus. IH, hallmark of SAS, plays an important role in the pathogenesis of SAS and experimental studies with animal and cellular models indicate that IH leads to attenuation of glucose-induced insulin secretion from pancreatic β cells and to enhancement of insulin resistance in peripheral tissues and cells, such as liver (hepatocytes), adipose tissue (adipocytes), and skeletal muscles (myocytes). In this review, we focus on IH-induced dysfunction in glucose metabolism and its underlying molecular mechanisms in several cells and tissues related to glucose homeostasis.

Understanding the fundamental mechanisms and limiting processes of the growth of single-walled carbon nanotube (SWCNT) would serve as a guide to achieve further control on structural parameters of SWCNT. In this paper, we have studied the growth kinetics of a series of SWCNT forests continuously spanning a wide range of diameters (1.9–3.2 nm), and have revealed an additional fundamental growth limiting process where the mass of the individual SWCNT is determined by the individual catalyst volume. Calculation of the conversion rate of carbon atoms into CNTs per Fe atom is 2 × 102 atoms per second. This rate limiting process provides an important understanding where the larger diameter SWCNT would grow faster, and thus be more suited for mass production.

Electron density of single wall carbon nanotubes (SWCNT) is effectively modified by hexaiodobenzene (HIB) molecules using liquid-phase adsorption. UV-Vis-NIR absorption spectra of the HIB-adsorbed SWCNT, especially in the NIR region, showed a disappearance of S11 transitions between the V1 valance band and the C1 conduction band of van Hove singularities which can be attributed to the effective charge transfer between HIB and the SWCNT. The adsorption of HIB also caused significant peak-shifts (lower frequency shift around 170 cm−1 and higher shift around 186 cm‑1) and an intensity change (around 100–150 cm−1 and 270–290 cm−1) in the radial breathing mode of Raman spectra. The charge transfer from SWCNT to HIB was further confirmed by the change in the C1s peak of X-ray photoelectron spectrum, revealing the oxidation of carbon in SWCNT upon HIB adsorption.

Cardiomyocyte dysfunction and cardiovascular diseases (CVDs) can be classified as ischemic or non-ischemic. We consider the induction of cardiac tissue dysfunction by intracellular advanced glycation end-products (AGEs) in cardiomyocytes as a novel type of non-ischemic CVD. Various types of AGEs can be generated from saccharides (glucose and fructose) and their intermediate/non-enzymatic reaction byproducts. Recently, certain types of AGEs ( N ε -carboxymethyl-lycine [CML], 2-ammnonio-6-[4-(hydroxymetyl)-3-oxidopyridinium-1-yl]-hexanoate-lysine [4-hydroxymethyl-OP-lysine, hydroxymethyl-OP-lysine], and N δ -(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine [MG-H1]) were identified and quantified in the ryanodine receptor 2 (RyR2) and F-actin-tropomyosin filament in the cardiomyocytes of mice or patients with diabetes and/or heart failure. Under these conditions, the excessive leakage of Ca 2+ from glycated RyR2 and reduced contractile force from glycated F-actin-tropomyosin filaments induce cardiomyocyte dysfunction. CVDs are included in lifestyle-related diseases (LSRDs), which ancient people recognized and prevented using traditional medicines (e.g., Kampo medicines). Various natural compounds, such as quercetin, curcumin, and epigallocatechin-3-gallate, in these drugs can inhibit the generation of intracellular AGEs through mechanisms such as the carbonyl trap effect and glyoxalase 1 activation, potentially preventing CVDs caused by intracellular AGEs, such as CML, hydroxymethyl-OP, and MG-H1. These investigations showed that bioactive herbal extracts obtained from traditional medicine treatments may contain compounds that prevent CVDs.

Lifestyle-related diseases (LSRDs), such as diabetes mellitus, cardiovascular disease, and nonalcoholic steatohepatitis, are a global crisis. Advanced glycation end-products (AGEs) have been extensively researched because they trigger or promote LSRDs. Recently, techniques such as fluorimetry, immunostaining, Western blotting, slot blotting, enzyme-linked immunosorbent assay, gas chromatography-mass spectrometry, matrix-assisted laser desorption-mass spectrometry (MALDI-MS), and electrospray ionization-mass spectrometry (ESI-MS) have helped prove the existence of intra/extracellular AGEs and revealed novel AGE structures and their modifications against peptide sequences. Therefore, we propose modifications to the existing categorization of AGEs, which was based on the original compounds identified by researchers in the 20th century. In this investigation, we introduce the (i) crude, (ii) diverse, and (iii) multiple AGE patterns. The crude AGE pattern is based on the fact that one type of saccharide or its metabolites or derivatives can generate various AGEs. Diverse and multiple AGE patterns were introduced based on the possibility of combining various AGE structures and proteins and were proven through mass analysis technologies such as MALDI-MS and ESI-MS. Kampo medicines are typically used to treat LSRDs. Because various compounds are contained in Kampo medicines and metabolized to exert effects on various organs or tissues, they may be suitable against various AGEs.

Kampo is a Japanese traditional medicine modified from traditional Chinese medicine. Kampo medicines contain various traditional crude drugs with unknown compositions due to the presence of low-molecular-weight compounds and proteins. However, the proteins are generally rare and extracted with high-polarity solvents such as water, making their identification and quantification difficult. To develop methods for identifying and quantifying the proteins in Kampo medicines, in the current study we employ previous technology (e.g., column chromatography, electrophoresis, and membrane chromatography), focusing on membrane chromatography with a polyvinylidene difluoride (PVDF) membrane. Moreover, we consider slot blot analysis based on the principle of membrane chromatography, which is beneficial for analyzing the proteins in Kampo medicines as the volume of the samples is not limited. In this article, we assess a novel slot blot method developed in 2017 and using a PVDF membrane and special lysis buffer to quantify advanced glycation end products-modified proteins against other slot blots. We consider our slot blot analysis superior for identifying and quantifying proteins in Kampo medicines compared with other methods as the data obtained with our novel slot blot can be shown with both error bars and the statistically significant difference, and our operation step is simpler than those of other methods.

Kampo medicines are Japanese traditional medicines developed from Chinese traditional medicines. The action mechanisms of the numerous known compounds have been studied for approximately 100 years; however, many remain unclear. While components are normally affected through digestion, absorption, and metabolism, in vitro oral, esophageal, and gastric epithelial cell models avoid these influences and, thus, represent superior assay systems for Kampo medicines. We focused on two areas of the strong performance of this assay system: intracellular and extracellular advanced glycation end-products (AGEs). AGEs are generated from glucose, fructose, and their metabolites, and promote lifestyle-related diseases such as diabetes and cancer. While current technology cannot analyze whole intracellular AGEs in cells in some organs, some AGEs can be generated for 1-2 days, and the turnover time of oral and gastric epithelial cells is 7-14 days. Therefore, we hypothesized that we could detect these rapidly generated intracellular AGEs in such cells. Extracellular AEGs (e.g., dietary or in the saliva) bind to the receptor for AGEs (RAGE) and the toll-like receptor 4 (TLR4) on the surface of the epithelial cells and can induce cytotoxicity such as inflammation. The analysis of Kampo medicine effects against intra/extracellular AGEs in vitro is a novel model.

The purpose of this study was to assess the burden of caregiving among family caregivers of cancer survivors aged 75 years or older in Japan. We included family caregivers of cancer survivors aged 75 years or older who were attending two hospitals in Ishikawa Prefecture, Japan, or receiving treatment during home visits. A self-administered questionnaire was developed based on previous studies. We obtained 37 responses from 37 respondents. Excluding those with incomplete responses, we had data from 35 respondents for analysis. The factor that significantly influenced the burden of caregiving for cancer survivors aged 75 years or older and family caregivers living together was the provision of full-time care ( p = 0.041). Helping cancer survivors manage money ( p = 0.055) was also associated with a higher burden. For family caregivers living separately, a more detailed examination of the association between the sense of caregiving burden and distance of travel to provide home-visit care is necessary, along with more support to attend hospitals with cancer survivors., Competing Interests: The authors declare no conflict of interest.

Aims: In Japan, the use of comprehensive genomic profiling (CGP) is only available for cancer patients who have no standard of care (SoC), or those who have completed SoC. This may lead to missed treatment opportunities for patients with druggable alterations. In this study, we evaluated the potential impact of CGP testing before SoC on medical costs and clinical outcome in untreated patients with advanced or recurrent biliary tract cancer (BTC), non-squamous non-small cell lung cancer (NSQ-NSCLC), or colorectal cancer (CRC) in Japan between 2022 and 2026., Materials and Methods: We constructed a decision-tree model reflecting the healthcare environment of Japan, to estimate the clinical outcome and medical costs impact of CGP testing by comparing two groups (with vs without CGP testing before SoC). The epidemiological parameters, detection rates of druggable alterations, and overall survival were collected from literature and claims databases in Japan. Treatment options selected based on druggable alterations were set in the model based on clinical experts' opinions., Results: In 2026, the number of untreated patients with advanced or recurrent BTC, NSQ-NSCLC, and CRC was estimated to be 8600, 32,103, and 24,896, respectively. Compared with the group without CGP testing before SoC, CGP testing before SoC increased druggable alteration detection and treatment rate with matched therapies in all three cancer types. The medical costs per patient per month were estimated to increase with CGP testing before SoC in the three cancer types by 19,600, 2900, and 2200 JPY (145, 21, and 16 USD), respectively., Limitations: Only those druggable alterations with matched therapies were considered in the analysis model, while the potential impact of other genomic alterations provided by CGP testing was not considered., Conclusions: The present study suggested that CGP testing before SoC may improve patient outcomes in various cancer types with a limited and controllable increase in medical costs.

Life satisfaction is increasingly important for older cancer survivors as the global population ages and the life expectancy 29 of cancer survivors increases. This study sought to identify factors associated with physical symptoms, quality of life under treatment, and current life satisfaction in cancer survivors aged 75 years and older receiving outpatient chemotherapy. Information about treatment for cancer survivors was collected from electronic medical records, and interviews were conducted to assess life satisfaction under treatment. Participants were older cancer survivors in Ishikawa, Japan. Of the participants, 80% lived on the Noto Peninsula. The average linear distance traveled for treatment was 40.7 km. The factors associated with patients' dissatisfaction with their current lives included general malaise (odds ratio: 9.61; 95% confidence interval: 1.28-72.22) and being less happy now than when they were younger (odds ratio: 10.559; 95% confidence interval: 1.50-74.24). In outpatient cancer treatment for survivors aged 75 years and older, support should consider the distance to the hospital. As in past studies, general malaise was shown to have a negative impact on the lives of cancer survivors aged 75 years or older. Support providers should pay attention to patients' general malaise when providing support.

Background: Kampo medicines, which are standardized traditional Japanese herbal medicines, have been tried to support patients with cancer., Methods: Randomized controlled trials on the use of Kampo medicines for cancer supportive care and the descriptions of Kampo medicines in clinical practice guidelines were reviewed., Results: Kampo medicines potentially ameliorate refractory symptoms in cancer patients. For example, hochuekkito, juzentaihoto, and ninjin'yoeito seem to be efficacious for fatigue/general malaise. Potential use of rikkunshito for anorexia/cancer cachexia and goshajinkigan for peripheral neuropathy is proposed from small numbers of randomized controlled trials in addition to basic research. The number of clinical practice guidelines which contain descriptions of Kampo medicines is increasing in general, but only a few in the area of cancer supportive care., Conclusion: Kampo medicines potentially play some roles in preventing or ameliorating side effects of anticancer agents. Supportive care with Kampo medicines for patients with cancer might lead to physical, mental, and nutritional improvement., Competing Interests: YM received honoraria from Tsumura & Co. The authors declare that this review was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. YM is an editorial board member of the journal but the editorial board membership had no bearing on the editorial process or decision., (© 2022 Korea Institute of Oriental Medicine. Published by Elsevier B.V.)

Kampo Medicine is a traditional Japanese medicine and is well integrated with modern medicine. Anticancer agents are highly developed, and evidence regarding standard treatment has accumulated. Kampo Medicine helps support patients with cancer who lack vital energy and feel cold. Cancer chemotherapy is associated with adverse reactions that are refractory to modern therapy, such as anorexia, general malaise/fatigue, and peripheral neuropathy. Recently, evidence of the effectiveness of Kampo Medicines for these symptoms has been reported in randomized controlled trials (RCTs). The Japan Society for Oriental Medicine celebrated the first 20 years of its evidence-based medicine (EBM) committee in June 2021. The activities of this committee include publication of the Evidence Reports of Kampo Treatment, which contains RCTs and meta-analyses, including RCTs on cancer supportive care. Evidence is accumulating for hangeshashinto for mucositis, rikkunshito for anorexia, goshajinkigan and ninjin'yoeito for peripheral neuropathy, hochuekkito for general malaise/fatigue, and shakuyakukanzoto for myalgia/arthralgia. However, additional evidence and further clinical trials are needed. Supportive care with Kampo Medicine increases the likelihood of completing standard treatment for cancer.

Background: Pharmacists guide patients in their use of traditional, complementary, and integrative medicine (TCIM). The present study aimed to evaluate the opinions of Japanese pharmacists regarding TCIM, and to evaluate the usability of the evidence-based Japanese Integrative Medicine (eJIM) website from the pharmacists' point of view., Methods: We conducted a two-stage, mixed-method study using interviews and an internet-based survey. In-person interviews were conducted with 20 pharmacists working in hospitals, dispensing pharmacies, or retail pharmacies. We analyzed their perspectives on TCIM and the usability of the eJIM. Based on the interviews, questionnaires for an internet survey conducted in February 2019 were developed., Results: In the interviews, 55% of pharmacists acknowledged TCIM as a supportive measure for modern medicine, and 45% responded that TCIM was efficacious. However, pharmacists' evaluation levels of Kampo medicine were high, whereas pharmacists' attitudes towards dietary supplements were primarily negative. There have been various proposals to improve the eJIM, such as highlighting important information and providing more specific information on TCIM in Japan. An internet survey of 365 pharmacists showed that 67.4% were consulted by patients regarding TCIM. Of these TCIM, pharmacists' evaluation levels of Kampo medicines were high. Only 5% of the respondents had visited the eJIM website prior to the survey, and the overall usability score of each web page was high., Conclusions: Kampo medicines and dietary supplements are common TCIMs that pharmacists use or advise on in Japan. Pharmacists' evaluation levels of Kampo medicine were high, whereas pharmacists' attitudes towards dietary supplements were generally negative., (© 2022. The Author(s).)

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases with no approved treatment. Zonarol, an extract from brown algae, has been proven to have anti-inflammatory and antioxidant effects. In this study, we investigated the role of zonarol in the progression of methionine- and choline-deficiency (MCD) diet-induced NAFLD in mice. After oral treatment with zonarol, a lighter body weight was observed in zonarol group (ZG) mice in comparison to control group (CG) mice. The NAFLD scores of ZG mice were lower than those of CG mice. Hepatic and serum lipid levels were also lower in ZG mice with the reduced expression of lipid metabolism-related factors. Furthermore, ZG mice showed less lipid deposition, less inflammatory cell infiltration and lower inflammatory cytokine levels in comparison to CG mice. Moreover, the numbers of 8-hydroxy-20-deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic and serum thiobarbituric acid reactive substances (TBARS) were significantly lower in comparison to CG mice. The expression levels of nuclear factor erythroid 2 related factor 2 (Nrf2), as well as its upstream and downstream molecules, changed in ZG mice. Zonarol could prevent the progression of NAFLD by decreasing inflammatory responses, oxidative stress and improving lipid metabolism. Meanwhile the Nrf2 pathway may play an important role in these effects.

Background: The evidence-based Japanese integrative medicine (eJIM) website was launched by the Japanese government in 2014 to provide information on integrative medicine to the general public and physicians. While Japanese physicians discourage the use of traditional, complementary, and integrative medicine (TCIM), there are very few reports that explore this issue. We aimed to understand the attitudes of Japanese physicians towards TCIM and evaluate the usability of the eJIM website according to physicians., Methods: We conducted a two-staged, mixed-method study with interviews and an internet-based survey. Face-to-face interviews were conducted with 12 physicians who worked for large-scale hospitals in two different areas of Japan. We assessed their understanding of TCIM and the usability of the eJIM website. Based on the interviews, the internet survey was developed and was conducted in February 2019., Results: In the interviews, 12 physicians provided their opinion on TCIM and highlighted important areas, such as increasing the resources available for patients, and ensuring more information on TCIM is available. The internet survey of 231 physicians showed that 35% of the physicians used or advised on TCIM in clinical practice. Kampo medicines (87.8%) and dietary supplements (24.7%) were common. The physicians did not use TCIM primarily because of concerns regarding its efficacy, safety, and cost. Most physicians were not aware of which TCIM their patients used., Conclusion: Physicians in Japan may not have comprehensively understood TCIM and do not actively use TCIM. The eJIM website could help physicians to gain a better understanding of TCIM if improvements are made., (© 2020 Korea Institute of Oriental Medicine. Publishing services by Elsevier B.V.)

Background: Non-alcoholic fatty liver disease (NAFLD), in which abnormal lipid metabolism plays an important role in disease progression, has become a pandemic. Abnormal lipid metabolism, for example an increased fat intake, has been thought to be an initial factor leading to NAFLD. The small intestine is the main site of dietary lipid absorption. A number of clinical trials have shown that acupuncture has positive effects in the regulation of lipid metabolism, which is closely associated with the progression of NAFLD. We therefore hypothesized that, acupuncture can improve the conditions of NAFLD by regulating intestinal absorption of lipid., Aim: To study the role of acupuncture treatment in the improvement of metabolic syndrome secondary to NAFLD by mouse model., Methods: 8-wk-old male C57BL/6J mice were fed a methionine- and choline-deficient diet for 3 wk. Then, all mice were separated randomly into acupoints group (AG) or non-acupoints group (NG) with high fat diet feeding. Needling treatment was performed at Zu san li, Guan yuan and Yong quan acupoints as acupuncture treatment to AG mice while non-acupoints place to NG mice. Finally, mice were anesthetized with an injection of ketamine-medetomidine and euthanized by exsanguination., Results: An apparent improvement of obesity was found in AG mice after acupuncture treatment. In AG mice, the body weight was much lower (22.6 ± 1.2 g vs 28.1 ± 1.0 g, P < 0.005) in comparison to NG mice. The length of small intestine in AG mice was significantly shorter (26.7 ± 2.3 cm vs 32.7 ± 2.7 cm, P < 0.005). A large amount of chyme was observed in the lumen of the AG small intestine. The expression of microsomal triglyceride transfer protein, apolipoprotein B and apolipoprotein C2 was downregulated. Triacylglycerols (TGs), total cholesterol and nonesterified fatty acid (NEFA) levels of the small intestinal tissue were significantly higher in AG mice, but the serum TGs and NEFA levels were reduced in AG mice., Conclusion: These results indicate that acupuncture at Zu san li, Guan yuan and Yong quan suppressed lipid absorption by downregulating the expression of apolipoproteins in the small intestine., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest in association with the present study., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Ninjin'yoeito (NYT), a traditional Japanese (Kampo) medicine that originates from China, has been used to treat qi and blood deficiency based on its original concept. Kampo medicine has been widely used to treat many conditions and disorders combined with western medicine or Kampo medicine alone in modern situation., Aims: We reviewed randomized controlled trials (RCTs) of NYT and discussed various standpoints regarding its use in modern situation., Methods: We searched PubMed, Cochrane Library, and Evidence Reports of Kampo Treatment (EKAT) for articles written in English, and Ichushi, J-Stage, and EKAT for those written in Japanese. Articles published before January 1, 2019, were retrieved using the keywords "ninjinyoeito" and "ninjin'yoeito," and RCTs were selected from these extracted articles., Result: Of 734 articles, 13 were RCTs, 46 were non-RCTs or studies of other designs, 15 were case reports, and 36 were experimental studies using NYT. NYT was evaluated for its use as a treatment for cancer and related conditions, refractory blood diseases and conditions, and otorhinolaryngologic symptom in 13 RCTs. Based on the use of Kampo medicine in modern situation called as Yasui's classification, 10 of 13 RCTs were categorized as "the side effects of Western medicinal treatment are mitigated when combined with Kampo treatment" and the remaining 3 were categorized as "treatment effect of Kampo medicine is increased in combination with standard Western medicinal treatment." Conclusion . Several studies demonstrated the efficacy of NYT in refractory diseases and other conditions, and the accompanied side effects of treatment with western medicine., Competing Interests: S. T., M. O., and T. I. belong to the Department of Kampo and Integrative Medicine, Tohoku University School of Medicine. The department received a grant from Tsumura & Co, a Japanese manufacturer of Kampo medicine which was used as per Tohoku University rules. T. M. received a research grant support from Tsumura & Co. and JPS Pharmaceuticals., (Copyright © 2019 Shin Takayama et al.)

Background: In Taiwan, numerous studies have been conducted to investigate the use of complementary and alternative medicine (CAM). However, most of them focused on specific diseases or the use of particular methods. Therefore, the results of those studies were quite different and difficult to compare with those of studies from other countries. The International CAM Questionnaire (I-CAM-Q), meanwhile, is a unified tool that can provide comparable results for studies conducted worldwide. Thus, the aim of this study was to discover the proportions of people in Taiwan receiving CAM treatments from different types of health care providers by using an adapted version of I-CAM-Q (I-CAM-QT)., Methods: I-CAM-QT was developed by translating the Korean version of I-CAM-Q (I-CAM-QK) into traditional Chinese language because of the similarity of CAM usage and doctor licensing system. This study had two stages: the first was a pretest survey used to adjust the questionnaire, while the second was an internet-based survey used to collect data from the community., Results: Of the 1200 survey respondents, 37% and 37.7% were prescribed or advised to use Chinese herbal medicine (CHM) by Western medicine (WM) physicians and traditional Chinese medicine (TCM) doctors, respectively. Other than CHM, dietary supplements and massage were the forms of CAM most commonly prescribed or recommended by WM physicians or TCM doctors. Overall, walking and relaxation techniques were the most commonly used self-help practices (used by 61.9% and 40.4% of the respondents, respectively). Additionally, 70.3% of the respondents had used at least one kind of dietary supplement in the past 12 months., Conclusion: Regarding the utilization of CAM in Taiwan, this internet-based survey revealed that CHM, dietary supplements, and massage were the types of CAM most commonly prescribed or recommended by WM physicians or TCM doctors.

Introduction: Although there have been several national survey studies on complementary and alternative medicine (CAM) use in Japan, previous studies have not been compared with investigations conducted in other countries. An international CAM questionnaire known as I-CAM-Q was developed through a two-day international workshop in 2006. The purpose of this study was to investigate the use of CAM by the general Japanese population using a modified version of the I-CAM-Q for the Japanese (I-CAM-QJ)., Methods: We developed the I-CAM-QJ to conduct an internet survey of 3,208 participants from the general population of Japan in February 2016. The respondents included 1,592 males (49.6%), 1,348 university graduates (38.8%), 1,105 individuals in good health (34.4%), and 1,028 individuals with long-term illness or disability (32.0%)., Results: Of the 3,208 respondents, 411 participants reported CAM use during the past 12 months (12.8%). The following therapies and products were used: Kampo medicines (over-the-counter Kampo medicines: 15.7%; prescribed Kampo medicines: 15.4%), dietary supplements 11.8%, massage services 3.9%, and physical therapy 3.5%. Regarding the use of self-care methods during the last 12 months, the following methods and products were used: bath salts 25.8% and walking 25.3%., Conclusions: An internet survey on CAM use by the general Japanese population with a modified I-CAM-Q (I-CAM-QJ) revealed that Kampo medicines and dietary supplements were the most commonly used CAMs in Japan., Competing Interests: None, (Copyright © Japan Medical Association.)

Background: The information site for evidence-based Japanese Integrative Medicine (eJIM) was launched by the Japanese Ministry of Health, Labour and Welfare to enable patients, medical staff, and others to obtain appropriate information, but it has not been objectively evaluated by users. The present study aimed to assess the usability of the eJIM website from the viewpoint of the general population., Methods: We held a focus group discussion with 12 persons in November 2016, conducted an Internet survey of 1107 people (general population) in February 2017, and assessed their understanding of basic concepts of complementary and alternative medicine and usefulness of the contents after browsing the eJIM website. Levels of functional, communicative, and critical health literacy were also assessed., Results: Most patients had never visited the eJIM website, because basic terms such as "integrative medicine" and "evidence" were not fully understood. Most overseas information in English was difficult to understand for the general Japanese population, although approximately 50% of the information was translated into Japanese. The degree of appropriate responses depended on health literacy level., Conclusion: The usability of eJIM website was low, because the currently available information did not meet the needs of the general population. Moreover, simpler expressions and visual tools would help the general population to understand the website contents more easily. A further survey that considers cultural and quantitative perspectives is warranted.

Background: In Korea, there are two types of medical doctors: one practises conventional medicine (hereafter called a physician), and the other practises traditional medicine (hereafter called a Korean medical doctor). This study aimed to compare the provision of complementary and alternative medicine (CAM) by these providers to CAM use per self-judgement in Korea., Methods: We analysed 1668 Korean people via an internet survey with the Korean adopted version of the I-CAM-Q, namely, the International Questionnaire to measure use of CAM, to understand whether respondents used CAM based either on a prescription or advice from a physician or a Korean medical doctor or on self-judgement., Results: In the previous 12 months, the proportions of respondents who were treated by a physician, who were treated by a Korean medical doctor and who were not treated by anyone were 67.9, 20.7 and 14.2%, respectively. Among the respondents who received CAM based on a prescription or advice from a physician, traditional Korean medicine practices and dietary supplements were commonly used; only a small percentage used other CAM therapies. Respondents who received CAM based on a prescription or advice from a Korean medical doctor showed similar results. Acupuncture and moxibustion, traditional Korean medicines (decoction), or cupping were more commonly used. Korean traditional medicines as over-the-counter (OTC) drugs were more commonly used by respondents who received CAM therapy based on a prescription or advice from a physician than by those who received CAM therapy based on a prescription or advice from a Korean medical doctor. A total of 74% of the responders used any CAM by self-judgement in the previous 12 months., Conclusions: For the use of CAM in Korea, in addition to the Korean traditional medical care provided by Korean medical doctors, general physicians advised people regarding Korean traditional medical care and dietary supplements.

Molecular-targeted drugs are generally effective against tumors containing driver oncogenes, such as EGFR, ALK, and NTRK1. However, patients harboring these oncogenes frequently experience a progression of brain metastases during treatment. Here, we present an in vivo imaging model for brain tumors using human cancer cell lines, including the EGFR-L858R/T790M-positive H1975 lung adenocarcinoma cells, the NUGC4 hepatocyte growth factor (HGF)-dependent gastric cancer cells, and the KM12SM colorectal cancer cells containing the TPM3-NTRK1 gene fusion. We investigated the efficacy of targeted drugs by comparison with their effect in extracranial models. In vitro, H1975 cells were sensitive to the third-generation epidermal growth factor receptor inhibitor osimertinib. Moreover, HGF stimulated the proliferation of NUGC4 cells, that was inhibited by crizotinib, which has anti-MET activity. KM12SM cells were sensitive to the tropomyosin-related kinase-A inhibitors crizotinib and entrectinib. In in vivo H1975 cell models, osimertinib inhibited the progression of both brain and subcutaneous tumors. Furthermore, in in vivo NUGC4 cell models, crizotinib remarkably delayed the progression of brain tumors, and that of peritoneal carcinomatosis. Interestingly, in in vivo KM12SM cell models, treatment with crizotinib delayed the progression of liver metastases, but not that of brain tumors. Conversely, treatment with entrectinib discernibly delayed the progression of both tumor types. Thus, the effect of targeted drugs against brain tumors can differ from the one reported in extracranial tumors. Moreover, the same multikinase inhibitory drug can display different efficacies in brain tumor models containing different drivers. Therefore, our in vivo imaging model for brain tumors may prove useful for preclinical drug screening against brain metastases., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The Committee for Evidence-based Medicine (EBM) of the Japan Society for Oriental Medicine started compiling Evidence Reports of Kampo Treatment (EKAT) in 2007. EKAT is a compilation of structured abstracts of randomized controlled trials (RCTs), along with comments by a third party reviewer. As of 31 December, 2012, there were 378 RCTs of Kampo medicines in Japan. The primary research question of this study is "How frequently is Kampo diagnosis used in RCTs of Kampo medicines?" The secondary research question is "When is Kampo diagnosis used in RCTs?", Materials and Methods: The structured abstract (SA) of each RCT article was reviewed to examine how Kampo diagnosis was used in RCTs, especially how Kampo diagnosis was used in the randomization process., Results: Kampo diagnosis was used before randomization in 27 RCTs (7.1%), after randomization in 31 RCTs (8.2%), and not used in 320 RCTs (84.7%). Before randomization, Kampo diagnosis was used as a criterion for inclusion in 10 RCTs, criterion for exclusion in 9 RCTs, and criteria for both inclusion and exclusion in 2 RCTs. Kampo formulas were determined according to Kampo diagnosis in 7 RCTs. After randomization, subgroup analyses according to Kampo diagnosis were done in 27 RCTs, and grade of disease severity at Kampo diagnosis was used for analysis as an endpoint in 4 RCTs., Conclusions: Kampo diagnosis was used before randomization only in approximately 15% of RCTs, and the number of RCT articles using Kampo diagnosis after randomization was almost the same as that before randomization. Further studies to determine the good RCTs conforming to CONSORT requirements and good systematic reviews conforming to PRISMA requirements are needed to clarify the significance of Kampo diagnosis.

Background and Purpose: The major obstacles to treatment of pancreatic cancer are the highly invasive capacity and resistance to chemo- and radiotherapy. Glycogen synthase kinase 3β (GSK3β) regulates multiple cellular pathways and is implicated in various diseases including cancer. Here we investigate a pathological role for GSK3β in the invasive and treatment resistant phenotype of pancreatic cancer., Methods: Pancreatic cancer cells were examined for GSK3β expression, phosphorylation and activity using Western blotting and in vitro kinase assay. The effects of GSK3β inhibition on cancer cell survival, proliferation, invasive ability and susceptibility to gemcitabine and radiation were examined following treatment with a pharmacological inhibitor or by RNA interference. Effects of GSK3β inhibition on cancer cell xenografts were also examined., Results: Pancreatic cancer cells showed higher expression and activity of GSK3β than non-neoplastic cells, which were associated with changes in its differential phosphorylation. Inhibition of GSK3β significantly reduced the proliferation and survival of cancer cells, sensitized them to gemcitabine and ionizing radiation, and attenuated their migration and invasion. These effects were associated with decreases in cyclin D1 expression and Rb phosphorylation. Inhibition of GSK3β also altered the subcellular localization of Rac1 and F-actin and the cellular microarchitecture, including lamellipodia. Coincident with these changes were the reduced secretion of matrix metalloproteinase-2 (MMP-2) and decreased phosphorylation of focal adhesion kinase (FAK). The effects of GSK3β inhibition on tumor invasion, susceptibility to gemcitabine, MMP-2 expression and FAK phosphorylation were observed in tumor xenografts., Conclusion: The targeting of GSK3β represents an effective strategy to overcome the dual challenges of invasiveness and treatment resistance in pancreatic cancer.

The current standard treatment for cancer is a multidisciplinary therapy whereby various types of treatment are properly combined. Chemotherapy with multiple anticancer drugs is now common, and traditional, complementary, and alternative therapies are adopted as supportive measures. Medical care in Japan is distinguished by the ability for patients to access both Western and Kampo medical cares at the same time. There is a high degree of trust in the safety of Kampo therapies because they are practiced by medical doctors who are educated with fundamental diagnosis of Western medicine. Highly reliable clinical studies are being published, demonstrating that palliative or supportive care for cancer patients using Kampo preparations alleviates adverse effects of chemotherapy or radiotherapy. This paper reports the circumstances around cancer care in Japan where traditional therapeutic Kampo formulas are used for patients undergoing cancer treatment with cutting-edge chemotherapy, specifically to alleviate adverse effects of anticancer drugs.

Stress proteins of the pancreas, such as tumor protein 53-induced nuclear protein 1 (TP53INP1), are important factors in the invasion and metastasis of pancreatic cancer. TP53INP1 is a pro-apoptotic factor and is transcriptionally regulated in p53-dependent and -independent manners. A previous study proved that gemcitabine induces TP53INP1 expression in pancreatic cancer cells and the pancreatic cancer cell line (PANC-1). The present study aimed to clarify the association between TP53INP1 and gemcitabine sensitivity. The expression of TP53INP1 and its related factors, such as cell growth and cell cycle status in TP53INP1-knockout mouse embryonic fibroblasts [TP53INP1 -/- -mouse embryonic fibroblasts (MEFs)] to those in wild-type counterparts (TP53INP1 +/+ -MEFs) were compared. Flow cytometric analysis demonstrated no difference of the checkpoint function in TP53INP1 -/- -MEFs and TP53INP1 +/+ -MEFs when exposed to 10 ng/ml of gemcitabine. No significant difference was found in the level of p53 expression in the cell types, although the base level and gemcitabine-induced expression of p21 were significantly decreased in TP53INP1 -/- -MEFs, compared to those in wild-type counterparts. Results showed that gemcitabine induced the p21 expression in TP53INP1 +/+ -MEFs, although not in TP53INP1 -/- -MEFs. However, their respective cell-cycle checkpoints were not different. Therefore, TP53INP1 was found to be associated with drug sensitivity through control of the cell cycle.

Clinical trials to date demonstrate that standard cancer treatments are currently the most efficient treatments for large numbers of cancer patients. Cancer treatments will increasingly require approaches that allow patients to live with cancer, by increasing their natural healing power and tumor immunity, as well as attenuating the progression of their cancers, instead of only attacking the cancer cells directly. Complementary and alternative medicine, including Kampo medicine, compensates for the drawbacks of western medicine by increasing patients' self-defense mechanisms. In Japan, clinicians who have studied both western medicine and Kampo treat cancer patients by fusing the two medical systems into a unitary one. The goal of the system is to assist the functional maintenance and recovery of the living body complex with the physical, mental, social, and spiritual balance, rather than addressing direct antitumor effects. In this review, we describe the usefulness of Kampo medicine, especially juzentaihoto, and outline the reports on evidence, in addition to the report on an attitudinal survey about the use of Kampo medicine in cancer treatment in Japan.

The cause of obesity includes genetic and environmental factors, including cytokines derived from adipocytes (adipo-cytokines). Although drug therapy is available for obesity, it is highly risky. Our main focus in this review is on the traditional form of Japanese medicine, Kampo, in the treated of obesity. Two Kampo formulas, that is, bofutsushosan () and boiogito (), are covered by the national health insurance in Japan for the treatment of obesity. Various issues related to their action mechanisms remain unsolved. Considering these, we described the results of basic experiments and presented clinical evidence and case reports on osteoarthritis as examples of clinical application of their two Kampo medicine. Traditional medicine is used not only for treatment but also for prevention. In clinical practice, it is of great importance to prove the efficacy of combinations of traditional medicine and Western medicine and the utility of traditional medicine in the attenuation of adverse effects of Western medicine.