Successful excision of an inflammatory endobronchial polyp using biopsy forceps with improvement in FEV1 in a patient with allergic bronchopulmonary aspergillosis: A case report.

Inflammatory endobronchial polyps (IEPs) are rare, benign bronchial tumors posing diagnostic and therapeutic challenges owing to limited data. A 55-year-old man, receiving treatment for allergic bronchopulmonary aspergillosis, presented with a one-week history of fever and purulent sputum. Diagnosed with pneumonia, he received antimicrobial treatment. However, because of persistent symptoms, an endobronchial tumor was suspected on computed tomography. IEP was confirmed through flexible bronchoscopy with forceps biopsy, and polyp removal improved symptoms, lung function, and imaging.

Safety of Readministration of EGFR-TKI After Onset of Interstitial Lung Disease in Advanced EGFR-Mutated NSCLC: A Systematic Review and Meta-Analysis.

BACKGROUND: In patients with epidermal growth factor receptor (EGFR) mutated non-small-cell lung cancer (NSCLC), EGFR-tyrosine kinase inhibitor (TKI) interruption due to EGFR-TKI-induced interstitial lung disease (ILD) is a factor for shorter overall survival (OS). Several retrospective cohort studies have reported an OS-prolonging effect of the readministration of EGFR-TKIs. This study aimed to determine the safety of readministration of EGFR-TKIs after the onset of EGFR-TKI-induced ILD. METHODS: The PubMed, CINAHL, and Web of Science databases were systematically searched until May 30, 2023. The primary outcome was successful readministration of EGFR-TKIs after the onset of EGFR-TKI-induced ILD. RESULTS: A total of 690 patients were included in this meta-analysis. The initial EGFR-TKI-induced ILD rate was 13.6% (95% confidence interval [CI]:6.4-20.9). Readministration rate of EGFR-TKI after onset of EGFR-TKI-induced ILD was 40.2% (95% CI: 26.7-53.7). The successful readministration rate of EGFR-TKIs after onset of EGFR-TKI-induced ILD was 81.9% (95% CI: 73.8-90.0). Successful rate of EGFR-TKI readministration in patients with Grade 2 or higher adverse events post initial EGFR-TKI therapy was 76.1% (95% CI: 55.6-96.6). CONCLUSIONS: Although initial EGFR-TKI-induced ILD has a relatively high incidence, EGFR-TKI readministration after the onset of EGFR-TKI-induced ILD may be a viable treatment option.

Hemodialysis requirement after the first dose of durvalumab following chemoradiation therapy: a case report.

Durvalumab is the first immune check point inhibitor that was approved for use following concurrent platinum-based chemoradiation, in patients with unresectable stage III non-small cell lung cancer. The new treatment regimen of durvalumab administered after chemoradiation resulted in higher response rates and required careful immune-related adverse effects management. We experienced a rare case of severe acute kidney injury (AKI) requiring hemodialysis after only the first dose of durvalumab, in a patient who was diagnosed with immune-related AKI by renal biopsy. Although severe (Grade 3 or more) immune-related AKI occurred in 0.9% of patients treated with durvalumab, some drugs and radiation may increase immune-related AKI. Further research is needed to identify the clinical characteristics of patients who tend to develop severe AKI so as to prevent it, by reviewing such rare cases as ours.

Differentiating primary central nervous system lymphoma from glioblastoma by time-dependent diffusion using oscillating gradient.

BACKGROUND: This study aimed to elucidate the impact of effective diffusion time setting on apparent diffusion coefficient (ADC)-based differentiation between primary central nervous system lymphomas (PCNSLs) and glioblastomas (GBMs) and to investigate the usage of time-dependent diffusion magnetic resonance imaging (MRI) parameters. METHODS: A retrospective study was conducted involving 21 patients with PCNSLs and 66 patients with GBMs using diffusion weighted imaging (DWI) sequences with oscillating gradient spin-echo (Δeff = 7.1 ms) and conventional pulsed gradient (Δeff = 44.5 ms). In addition to ADC maps at the two diffusion times (ADC7.1 ms and ADC44.5 ms), we generated maps of the ADC changes (cADC) and the relative ADC changes (rcADC) between the two diffusion times. Regions of interest were placed on enhancing regions and non-enhancing peritumoral regions. The mean and the fifth and 95th percentile values of each parameter were compared between PCNSLs and GBMs. The area under the receiver operating characteristic curve (AUC) values were used to compare the discriminating performances among the indices. RESULTS: In enhancing regions, the mean and fifth and 95th percentile values of ADC44.5 ms and ADC7.1 ms in PCNSLs were significantly lower than those in GBMs (p = 0.02 for 95th percentile of ADC44.5 ms, p = 0.04 for ADC7.1 ms, and p < 0.01 for others). Furthermore, the mean and fifth and 95th percentile values of cADC and rcADC were significantly higher in PCNSLs than in GBMs (each p < 0.01). The AUC of the best-performing index for ADC7.1 ms was significantly lower than that for ADC44.5 ms (p < 0.001). The mean rcADC showed the highest discriminating performance (AUC = 0.920) among all indices. In peritumoral regions, no significant difference in any of the three indices of ADC44.5 ms, ADC7.1 ms, cADC, and rcADC was observed between PCNSLs and GBMs. CONCLUSIONS: Effective diffusion time setting can have a crucial impact on the performance of ADC in differentiating between PCNSLs and GBMs. The time-dependent diffusion MRI parameters may be useful in the differentiation of these lesions.

Differentiating brain metastasis from glioblastoma by time-dependent diffusion MRI.

BACKGROUND: This study was designed to investigate the use of time-dependent diffusion magnetic resonance imaging (MRI) parameters in distinguishing between glioblastomas and brain metastases. METHODS: A retrospective study was conducted involving 65 patients with glioblastomas and 27 patients with metastases using a diffusion-weighted imaging sequence with oscillating gradient spin-echo (OGSE, 50 Hz) and a conventional pulsed gradient spin-echo (PGSE, 0 Hz) sequence. In addition to apparent diffusion coefficient (ADC) maps from two sequences (ADC50Hz and ADC0Hz), we generated maps of the ADC change (cADC): ADC50Hz - ADC0Hz and the relative ADC change (rcADC): (ADC50Hz - ADC0Hz)/ ADC0Hz × 100 (%). RESULTS: The mean and the fifth and 95th percentile values of each parameter in enhancing and peritumoral regions were compared between glioblastomas and metastases. The area under the receiver operating characteristic curve (AUC) values of the best discriminating indices were compared. In enhancing regions, none of the indices of ADC0Hz and ADC50Hz showed significant differences between metastases and glioblastomas. The mean cADC and rcADC values of metastases were significantly higher than those of glioblastomas (0.24 ± 0.12 × 10-3mm2/s vs. 0.14 ± 0.03 × 10-3mm2/s and 23.3 ± 9.4% vs. 14.0 ± 4.7%; all p < 0.01). In peritumoral regions, no significant difference in all ADC indices was observed between metastases and glioblastomas. The AUC values for the mean cADC (0.877) and rcADC (0.819) values in enhancing regions were significantly higher than those for ADC0Hz5th (0.595; all p < 0.001). CONCLUSIONS: The time-dependent diffusion MRI parameters may be useful for differentiating brain metastases from glioblastomas.

TORC1 inactivation promotes APC/C-dependent mitotic slippage in yeast and human cells.

Unsatisfied kinetochore-microtubule attachment activates the spindle assembly checkpoint to inhibit the metaphase-anaphase transition. However, some cells eventually override mitotic arrest by mitotic slippage. Here, we show that inactivation of TORC1 kinase elicits mitotic slippage in budding yeast and human cells. Yeast mitotic slippage was accompanied with aberrant aspects, such as degradation of the nucleolar protein Net1, release of phosphatase Cdc14, and anaphase-promoting complex/cyclosome (APC/C)-Cdh1-dependent degradation of securin and cyclin B in metaphase. This mitotic slippage caused chromosome instability. In human cells, mammalian TORC1 (mTORC1) inactivation also invoked mitotic slippage, indicating that TORC1 inactivation-induced mitotic slippage is conserved from yeast to mammalian cells. However, the invoked mitotic slippage in human cells was not dependent on APC/C-Cdh1. This study revealed an unexpected involvement of TORC1 in mitosis and provides information on undesirable side effects of the use of TORC1 inhibitors as immunosuppressants and anti-tumor drugs.

Ghrelin Enhancer, the Latest Evidence of Rikkunshito.

Rikkunshito is a Japanese herbal medicine (Kampo) that has been attracting attention and researched by many researchers not only in Japan but also worldwide. There are 214 rikkunshito articles that can be searched on PubMed by August 2021. The reason why rikkunshito has attracted so much attention is due to an epoch-making report (Gastroenterology, 2008) discovered that rikkunshito promotes the secretion of the orexigenic peptide ghrelin. Since then, many researchers have discovered that rikkunshito has a direct effect on the ghrelin receptor, GHS-R1a, and an effect of enhancing the ghrelin signal to the brain. Additionally, a lot of evidence that rikkunshito is expected to be effective for various gastrointestinal diseases have also been demonstrated. Numerous basic and clinical studies have suggested that rikkunshito affects (i) various discomforts caused by anticancer drugs, gastroesophageal reflux disease, functional dyspepsia, (ii) various stress-induced anorexia, (iii) hypophagia in the elderly, and (iv) healthy lifespan. In this review, as one who discovered the ghrelin enhancer effect of rikkunshito, we will review the research of rikkunshito so far and report on the latest research results.

Relationship between Orexigenic Peptide Ghrelin Signal, Gender Difference and Disease.

Growth hormone secretagogue receptor 1a (GHS-R1a), which is one of the G protein-coupled receptors (GPCRs), is involved in various physiological actions such as energy consumption, growth hormone secretion promoting action, and cardiovascular protective action. The ligand was searched for as an orphan receptor for a while, but the ligand was found to be acylated ghrelin (ghrelin) discovered by Kangawa and Kojima et al. in 1999. Recently, it has also been reported that dysregulation of GHS-R1a mediates reduced feeding in various diseases. On the other hand, since the physiological effects of ghrelin have been studied exclusively in male mice, few studies have been conducted on gender differences in ghrelin reactivity. In this review, we describe (1) the characteristics of GHS-R1a, (2) the role of ghrelin in hypophagia due to stress or anticancer drugs, and (3) the gender differences in the physiological effects of GHS-R1a and the influence of stress on it.

Vulnerability to psychological stress-induced anorexia in female mice depends on blockade of ghrelin signal in nucleus tractus solitarius.

BACKGROUND AND PURPOSE: Women have a higher incidence of eating disorders than men. We investigated whether the effects of ghrelin on feeding are affected by sex and stress, and to elucidate the mechanisms that may cause sex differences in stress-mediated anorexia, focusing on ghrelin. EXPERIMENTAL APPROACH: Acylated ghrelin was administered to naïve and psychologically stressed male and female C57BL/6J mice, followed by measurements of food intake and plasma hormone levels. Ovariectomy was performed to determine the effects of ovary-derived oestrogen on stress-induced eating disorders in female mice. The numbers of Agrp or c-Fos mRNA-positive cells and estrogen receptor α/c-Fos protein-double-positive cells were assessed. KEY RESULTS: Ghrelin administration to naïve female mice caused a higher increase in food intake, growth hormone secretion, Agrp mRNA expression in the arcuate nucleus and c-Fos expression in the nucleus tractus solitarius (NTS) than in male mice. In contrast, psychological stress caused a more sustained reduction in food intake in females than males. The high sensitivity of naïve females to exogenous ghrelin was attenuated by stress exposure. The stress-induced decline in food intake was not abolished by ovariectomy. Estrogen receptor-α but not -ß antagonism prevented the decrease in food intake under stress. Estrogen receptor-α/c-Fos-double-positive cells in the NTS were significantly increased by stress only in females. CONCLUSION AND IMPLICATIONS: Stress-mediated eating disorders in females may be due to blockade of ghrelin signalling via estrogen receptor-α activation in the NTS. Targeting the ghrelin signal in the brain could be a new treatment strategy to prevent these disorders.

Peptide YY Causes Apathy-Like Behavior via the Dopamine D2 Receptor in Repeated Water-Immersed Mice.

Apathy is observed across several neurological and psychiatric conditions; however, its pathogenesis remains unclear. We clarified the involvement of brain-gut signaling in the disruption of goal-directed behavior. Male C57BL/6J mice were exposed to water immersion (WI) stress for 3 days. Food intake and nesting behavior were measured as indexes of motivation. Repeated WI caused decrease in food intake and nesting behavior. Plasma levels of peptide YY (PYY), IL-6, and ratio of dopamine metabolites in the striatum were significantly elevated after WI. PYY and IL-6 administration significantly decreased nesting behavior. The reductions in feeding and nesting behavior were blocked by PYY receptor (Y2R) antagonist or dopamine agonist. The ameliorative effect of the Y2R antagonist was diminished by the dopamine D2 receptor (D2R) antagonist. The reduction in goal-directed behavior is associated with dysfunction of D2R signaling via increased peripheral PYY, suggesting that PYY antagonism is a novel candidate for decline of motivation in several depressive diseases.

Psychological stress in aged female mice causes acute hypophagia independent of central serotonin 2C receptor activation.

Sex differences exist in the activation of the hypothalamic-pituitary-adrenal axis following exposure to stress, and the stress response is further affected by aging. This study was conducted to elucidate the mechanism of hypophagia in aged female mice exposed to stress. Immediately after a stress load, aged female mice exhibited acute hypophagia and a rise in plasma corticosterone levels. The administration of a serotonin 2C receptor (5-HT2CR) antagonist suppressed plasma corticosterone but did not affect the reduction in food intake. In contrast, an endogenous ghrelin enhancer, rikkunshito (RKT), significantly inhibited the reduction in food intake. An increase in peripheral acylated ghrelin levels during fasting, which occurs in young mice, was not observed in aged female mice. Moreover, in these mice, significantly increased levels of ghrelin and gastric preproghrelin mRNA expression were observed in the fed status. Moreover, plasma ghrelin levels were elevated by RKT and not by the 5-HT2CR antagonist. In female mice, the hypothalamic non-edited (INI) and partially edited mRNA 5-HT2CR isoforms (VNV, VNI, VSV or VSI) decreased with age, while in male mice, the editing isoform was unchanged by aging or stress. Estrogen receptor α (ERα)-positive cell counts in the arcuate nucleus of young male mice exposed to stress and control aged male mice were increased compared with those in young control mice. In aged male mice exposed to stress, the number of ERα-expressing cells in the paraventricular nucleus were significantly increased compared with those in aged control mice; in female mice, there was no increase in the number of ERα-positive cells. Hypophagia in aged female mice exposed to stress may be independent of 5-HT2CR activation. It seems likely that the mechanisms may be caused by sex dependent, differential regulation in 5-HT2CR mRNA expression, peripheral acylated ghrelin secretion and/or hypothalamic ERα expression.

Patterns of Brain Activation and Meal Reduction Induced by Abdominal Surgery in Mice and Modulation by Rikkunshito.

Abdominal surgery inhibits food intake and induces c-Fos expression in the hypothalamic and medullary nuclei in rats. Rikkunshito (RKT), a Kampo medicine improves anorexia. We assessed the alterations in meal microstructure and c-Fos expression in brain nuclei induced by abdominal surgery and the modulation by RKT in mice. RKT or vehicle was gavaged daily for 1 week. On day 8 mice had no access to food for 6-7 h and were treated twice with RKT or vehicle. Abdominal surgery (laparotomy-cecum palpation) was performed 1-2 h before the dark phase. The food intake and meal structures were monitored using an automated monitoring system for mice. Brain sections were processed for c-Fos immunoreactivity (ir) 2-h after abdominal surgery. Abdominal surgery significantly reduced bouts, meal frequency, size and duration, and time spent on meals, and increased inter-meal interval and satiety ratio resulting in 92-86% suppression of food intake at 2-24 h post-surgery compared with control group (no surgery). RKT significantly increased bouts, meal duration and the cumulative 12-h food intake by 11%. Abdominal surgery increased c-Fos in the prelimbic, cingulate and insular cortexes, and autonomic nuclei, such as the bed nucleus of the stria terminalis, central amygdala, hypothalamic supraoptic (SON), paraventricular and arcuate nuclei, Edinger-Westphal nucleus (E-W), lateral periaqueduct gray (PAG), lateral parabrachial nucleus, locus coeruleus, ventrolateral medulla and nucleus tractus solitarius (NTS). RKT induced a small increase in c-Fos-ir neurons in the SON and E-W of control mice, and in mice with surgery there was an increase in the lateral PAG and a decrease in the NTS. These findings indicate that abdominal surgery inhibits food intake by increasing both satiation (meal duration) and satiety (meal interval) and activates brain circuits involved in pain, feeding behavior and stress that may underlie the alterations of meal pattern and food intake inhibition. RKT improves food consumption post-surgically that may involve modulation of pain pathway.

Serotonin 2C receptor contributes to gender differences in stress-induced hypophagia in aged mice.

The combination of depression and anorexia may influence morbidity and progressive physical disability in the elderly. Gender differences exist in hypothalamic-pituitary-adrenal axis activation following stress exposure. The objective of this study was to investigate gender differences in feeding behavior under novelty stress in aged mice. Food intake measurement, immunohistochemical assessment, and mRNA expression analysis were conducted to investigate the role of serotonin 2C receptor (5-HT(2C)R) and its relationship with ghrelin in stress-induced suppression of feeding behavior in aged mice. After exposure to novelty stress, a 21-fold increase in plasma corticosterone and remarkable suppression of food intake were observed in aged male mice. Furthermore, a 5-HT(2C)R agonist suppressed food intake in aged male mice. Novelty stress induced a 7-fold increase in 5-HT(2C)R and c-Fos co-expressing cells in the paraventricular nucleus of the hypothalamus in aged male mice but caused no change in aged female mice. Plasma acylated ghrelin levels decreased in stressed aged male mice and administration of the 5-HT(2C)R antagonist inhibited this decrease. The 5-HT(2C)R antagonist also reversed the suppression of food intake in estrogen receptor α agonist-treated aged male mice. Therefore, conspicuously suppressed feeding behavior in novelty stress-exposed aged male mice may be mediated by 5-HT(2C)R hypersensitivity, leading to hypoghrelinemia. The hypersensitivity may partly be due to estrogen receptor activation in aged male mice.

Rikkunshito ameliorates cachexia associated with bleomycin-induced lung fibrosis in mice by stimulating ghrelin secretion.

Cachexia is a frequent complication in patients with respiratory failure, such as lung fibrosis, and it is a determining factor for functional capacity, health status, and mortality. Reductions in body weight and skeletal muscle mass are key features of cachexia that are resistant to current therapies. Rikkunshito (RKT), a traditional Japanese herbal medicine, is widely used for the treatment for patients with gastrointestinal symptoms and known to stimulate ghrelin secretion. By using bleomycin (BLM)-induced lung fibrosis mice in this study, we tested our hypothesis that RKT administration could ameliorate pulmonary cachexia. After BLM administration, mice were provided with either RKT or distilled water on a daily basis. Compared with the BLM-injected mice, the RKT-treated mice had smaller reductions of food intake and body weight. Skeletal muscle weights were retained in the RKT-treated mice, in conjunction with reduced expressions of MuRF-1 and atrogin-1 in the lysates of skeletal muscle found in lung fibrosis. Rikkunshito administration restored the plasma concentrations of ghrelin in BLM-injected mice. The anticachectic efficacies of RKT administration in BLM-injected mice were canceled by the concurrent treatment of a ghrelin receptor antagonist. Rikkunshito administration did not decrease the degree of loss of body weight or food intake reduction in either ghrelin-deficient mice or growth hormone secretagogue receptor-deficient mice. Our results indicate that RKT administration exerts protective effects on pulmonary cachexia by ameliorating skeletal muscle wasting and food intake reduction as mediated by the ghrelin system and, thus, highlight RKT as a potential therapeutic agent for the management of lung fibrosis.

Rikkunshito ameliorates bleomycin-induced acute lung injury in a ghrelin-independent manner.

Acute lung injury (ALI) is a critical syndrome consisting of acute respiratory failure associated with extensive pulmonary infiltrates. The pathological characterization of ALI includes injuries of alveolar epithelial cells (AECs), alveolar neutrophilic infiltration, and increases in proinflammatory cytokines, which cause destruction of the alveolar capillary barrier and subsequent devastating lung fibrosis. Rikkunshito (RKT), a traditional Japanese herbal medicine, is widely used for the treatment of patients with gastrointestinal symptoms and is known to stimulate ghrelin secretion. The therapeutic effects of RKT on organ inflammation and fibrosis remain unknown. We investigated the pharmacological potential of RKT in the treatment of ALI by using a bleomycin-induced ALI model in mice. RKT or distilled water (DW) was given to mice daily starting 12 h after bleomycin administration. The RKT-treated mice showed a definitively higher survival rate than the DW-treated mice after injury. They also had smaller reductions in body weight and food intake. The amelioration of neutrophil alveolar infiltration, pulmonary vascular permeability, induction of proinflammatory cytokines, activation of the NF-κB pathway, apoptosis of AECs, and subsequent lung fibrosis were notable in the RKT-treated mice. RKT administration increased the plasma ghrelin levels in wild-type mice, and it also mitigated the ALI response in both ghrelin-deficient mice and growth hormone secretagogue receptor-deficient mice after lung injury. Our results indicate that RKT administration exerts protective effects against ALI by protecting the AECs and regulating lung inflammation independently of the ghrelin system, and they highlight RKT as a promising therapeutic agent for the management of this intractable disease.