Anti-inflammatory effect of covalent PPARγ ligands that have a hybrid structure of GW9662 and a food-derived cinnamic acid derivative.

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear receptor superfamily and is involved in the inflammatory process. Previously, we synthesized the ligands of PPARγ that possess the hybrid structure of a food-derived cinnamic acid derivative (CA) and GW9662, an irreversible PPARγ antagonist. These ligands activate the transcription of PPARγ through the covalent bond formation with the Cys285 residue of PPARγ, whereas their anti-inflammatory effect has not been examined yet. Here, we show the anti-inflammatory effect of the covalent PPARγ ligands in RAW264 cells, murine macrophage-like cells. GW9662 suppressed the production of nitric oxide (NO) stimulated by lipopolysaccharide and exerted a synergistic effect in combination with CA. The compounds bearing their hybrid structure dramatically inhibited NO production and transcription of proinflammatory cytokines. A comparison study suggested that the 2-chloro-5-nitrobenzoyl group of the ligands is important for anti-inflammation. Furthermore, we synthesized an alkyne-tagged analogue that becomes an activity-based probe for future mechanistic study.

Clinical Outcomes of Preserving Bronchial Arteries During Radical Esophagectomy: A Propensity-Score Matched Analysis.

BACKGROUND: Postoperative pneumonia is a common and major cause of mortality after radical esophagectomy. Intraoperative preservation of the bronchial arteries is often aimed at avoiding tracheobronchial ischemia; however, it is unknown whether this contributes to a reduction in postoperative pneumonia. PATIENTS AND METHODS: We enrolled 348 consecutive patients who underwent radical esophagectomy for esophageal cancer at Toranomon Hospital from January 2011 to July 2018. We classified patients into a bronchial artery-resected (BA-R) group (n = 93) and a bronchial artery-preserved (BA-P) group (n = 255) and compared the incidence of postoperative pneumonia between the two groups. A propensity score-matching analysis for bronchial artery preservation versus resection was performed. RESULTS: Overall, 182 patients were matched. Univariate analysis of the propensity score-matched groups showed that Brinkman index ≥ 400, vital capacity (%VC) < 80%, and bronchial artery resection were associated with the development of postoperative pneumonia. Multivariate analysis revealed three significant factors associated with postoperative pneumonia: Brinkman index ≥ 400 [p = 0.006, odds ratio (HR) 3.302, 95% confidence interval (95% CI) 1.399-7.790], %VC < 80% (p = 0.034, HR 6.365, 95% CI 1.151-35.205), and bronchial artery resection (p = 0.034, HR 2.131, 95% CI 1.060-4.282). The incidence of postoperative complications (CD grade III) was higher in the BA-R group (BA-R 42.8% versus BA-P 27.5%, p = 0.030). There was no significant difference in overall survival between the two groups at 5 years (BA-R 63.1% versus BA-P 72.1%, p = 0.130). CONCLUSION: Preserving the bronchial artery is associated with a decreased incidence of postoperative pneumonia.

Early corticosteroid dose tapering in patients with acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Although corticosteroid therapy with dose tapering is the most commonly used treatment for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), there is no consensus on the tapering regimen. This study aimed to investigate the association between early corticosteroid dose tapering and in-hospital mortality in patients with AE-IPF. METHODS: In this retrospective cohort study, we analyzed the data of a cohort from eight Japanese tertiary care hospitals and routinely collected administrative data from a cohort from 185 Japanese hospitals. Patients with AE-IPF were classified into the early and non-early tapering groups depending on whether the maintenance dose of corticosteroids was reduced within two weeks of admission. Propensity score analysis with inverse probability weighting (IPW) was performed to estimate the effect of early corticosteroid dose tapering. RESULTS: The multi-center cohort included 153 eligible patients, of whom 47 (31%) died, whereas the administrative cohort included 229 patients, of whom 51 (22%) died. Patients with early tapering tended to have a better prognosis than those without it (unadjusted hazard ratio [95% confidence interval] 0.41 [0.22-0.76] and 0.65 [0.36-1.18] in the multi-center and administrative cohorts, respectively). After IPW, the early tapering group had a better prognosis than the non-early tapering group (IPW-adjusted hazard ratio [95% confidence interval] 0.37 [0.14-0.99] and 0.27 [0.094-0.83] in the multi-center and administrative cohorts, respectively). CONCLUSION: Early corticosteroid dose tapering was associated with a favorable prognosis in patients with AE-IPF. Further studies are warranted to confirm the effects of early corticosteroid dose tapering in patients with AE-IPF.

Clinical significance of initial treatment for peritoneal lavage cytology-positive gastric cancer: outcomes according to treatment strategy.

BACKGROUND: Although patients with positive lavage cytology (CY1) are classified as having stage IV disease, long-term survival without other unresectable factors (P0CY1) has been reported. Conversion gastrectomy in patients with a change in cytology status after induction chemotherapy might improve survival, but appropriate treatment remains controversial. Here, we reviewed our experience in treating CY1 gastric cancer to evaluate the best treatment strategy. METHODS: Clinical and pathological findings of patients with a diagnosis of P0CY1 gastric cancer at Toranomon Hospital between February 2006 and April 2019 were retrospectively analyzed. Patients were classified into two groups according to initial treatment: a surgery-first group and a chemotherapy-first group. In addition, the patients were categorized into subgroups based on the subsequent treatment pattern. The surgery-first group was divided into two subgroups: adjuvant chemotherapy and palliative gastrectomy only. The chemotherapy-first group was divided into three subgroups with the subsequent treatment pattern depending on the response to chemotherapy: conversion gastrectomy, palliative gastrectomy after induction therapy, and palliative chemotherapy. RESULTS: In total, 38 patients were eligible for inclusion in this study. After initial assessment of cytology status, 21 patients underwent gastrectomy as initial treatment (surgery first) and 17 received induction chemotherapy (chemotherapy first). Ten patients underwent surgery first with adjuvant chemotherapy, 11 underwent palliative gastrectomy alone, 5 underwent conversion surgery, 5 with CY1 disease after induction chemotherapy underwent palliative gastrectomy, and 7 received palliative chemotherapy only. The 3-year survival rate was 23.4% (median survival, 17.7 months) in the surgery-first group and 27.3% (median survival, 19.7 months) in the chemotherapy-first group. The 3-year survival rate was 75% for conversion gastrectomy, 16.7% for palliative chemotherapy, and 0% for palliative gastrectomy after induction chemotherapy. CONCLUSIONS: There was no significant difference in outcome according to whether surgery or chemotherapy was performed first. The prognosis of conversion surgery with curative resection was better than that of the other types of treatment. However, the outlook after induction chemotherapy was poor. Patients with advanced gastric cancer should be treated cautiously until more effective treatment options become available.

Identification of Preoperative Fat-Free Mass Index for the Prognosis of Curatively Resected Esophageal Cancer.

BACKGROUND: The progressive, systemic depletion of muscle mass is a poor prognostic factor for various types of cancers. However, the assessment of body composition for patients with esophagectomy remains unclear. Therefore, we evaluated the significance of the fat-free mass index (FFMI) and estimated the appropriate cutoff value. METHODS: We compiled clinicopathological characteristics of patients who underwent curative operation for esophageal cancer between October 2013 and March 2018 at Toranomon Hospital and reviewed them until December 2020. We analyzed the short- and long-term outcomes, compared to conventional nutritional factors, and calculated the area under the receiver operating characteristic (ROC) curve. RESULTS: A total of 200 patients were eligible for inclusion. FFMI was ineffective in predicting postoperative complications, with no correlation with other nutritional biomarkers. Preoperative low FFMI led to poor overall survival (OS), and the lower cutoff values based on the time-dependent ROC analysis were 14.4 and 16.8 kg/m2 in women and men, respectively. Multivariate analysis for OS revealed that low FFMI (p = 0.010, HR 2.437, 95% CI 1.234-4.815) and clinical stage (p = 0.010, HR 4.781, 95% CI 1.447-15.796) were independent prognostic factors. The 3-year survival rates were 68.9% in low FFMI and 88.6% in normal FFMI. CONCLUSIONS: The low FFMI was not predictive of postoperative complications but an independent prognostic factor in esophageal cancer with curative resection, having no correlation with other biomarkers. Our cutoff FFMI values could be useful in selecting the target for muscle improvement programs.

Importance of long-term surveillance after curative esophagectomy for esophageal squamous cell carcinoma.

BACKGROUND: The long-term outcomes after esophagectomy for esophageal cancer remain uncertain and the optimal surveillance strategy after curative surgery remains controversial. METHODS: In this study, the clinicopathological characteristics of patients who underwent curative thoracic esophagectomy between 1991 and 2015 at Toranomon Hospital were retrospectively analyzed and reviewed until December 2020. We evaluated the accumulated data regarding the pattern and rates of recurrence and second malignancy. RESULTS: A total of 1054 patients were eligible for inclusion in the study. Of these, 97% were followed up for 5 years, and the outcomes after 25 years could be determined in 65.5%. Recurrence was diagnosed in 318 patients (30.2%), and the most common pattern was lymph node metastasis (n = 168, 52.8%). Recurrence was diagnosed within 1 year in 174 patients (54.7%) and within 3 years in 289 (90.9%). Second malignancy possibly occurred through the entire study period after esophagectomy even in early-stage cancer, keeping 2%-5% of the incidental risk. There was no significant difference in the prognosis between 3-year survivors with and without a second malignancy. CONCLUSIONS: Most recurrences after resection of esophageal cancer occurred within 3 years regardless of disease stage. However, these patients have an ongoing risk of developing a second malignancy after esophagectomy. Further consideration is required regarding the efficacy of long-term surveillance.

Impact of Primary Tumor Resection on Mortality in Patients with Stage IV Colorectal Cancer with Unresectable Metastases: A Multicenter Retrospective Cohort Study.

BACKGROUND: Primary tumor resection (PTR) before commencing systemic chemotherapy in patients with stage IV colorectal cancer and unresectable metastases (mCRC) remains controversial. This study aimed to assess whether PTR before systemic chemotherapy is associated with mortality in mCRC patients, after adjusting for confounding factors, such as the severity of the primary tumor and metastatic lesions. METHODS: We analyzed hospital-based cancer registries from nine designated cancer hospitals in Fukushima Prefecture, Japan. Patients were divided into two groups (PTR and non-PTR), based on whether PTR was performed as initial therapy for mCRC or not. The primary outcome was all-cause mortality. Kaplan-Meier survival analysis was performed, and survival estimates were compared using the log-rank test. Adjusted hazard ratios were calculated using Cox regression to adjust for confounding factors. All tests were two-sided; P-values < 0.05 were considered statistically significant. RESULTS: Between 2008 and 2015, 616 mCRC patients were included (PTR: 414 [67.2%]; non-PTR: 202 [32.8%]). The median follow-up time was 18.0 (interquartile range [IQR]: 8.4-29.7) months, and 492 patients (79.9%) died during the study period. Median overall survival in the PTR and non-PTR groups was 23.9 (IQR: 12.2-39.9) and 12.3 (IQR: 6.2-23.8) months, respectively (P < 0.001, log-rank test). PTR was significantly associated with improved overall survival (adjusted hazard ratio: 0.51; 95% confidence interval: 0.42-0.64, P < 0.001). CONCLUSIONS: PTR before systemic chemotherapy in patients with mCRC was associated with improved survival.

Adequate period of surveillance in each stage for curatively resected gastric cancer: analyzing the time and rates of recurrence.

BACKGROUND: Surveillance after curative surgery for gastric cancer is conventionally performed for 5 years. However, the appropriate follow-up period remains controversial. METHODS: This study retrospectively compiled a clinicopathological database of patients who underwent curative gastrectomy between 1975 and 2010 at Toranomon Hospital and were reviewed until March 2020. Analyzing the follow-up rate and recurrence rate for each stage in each postoperative year, we set each follow-up endpoint when the subsequent recurrence rate fell below 1%. RESULTS: A total of 5235 patients were eligible for inclusion in the study. The rate of patients followed up for 5 years was 90.3%. The rates of follow-up were 52.7% at 10 years, 38.3% at 15 years, and 10.3% at 20 years. Recurrence was confirmed in 850 patients in total (16.2%) and in 50 patients beyond 5 years. The adequate follow-up endpoints according to stage (with < 1% recurrence risk) were 2 years for stage IA, 4 years for IB, 6 years for IIA, 9 years for IIB, 7 years for IIIA, and 8 years for IV (curative). For stage IIIB and IIIC, the recurrence risk remained. CONCLUSIONS: The adequate surveillance duration of resected gastric cancer might be different in each stage. Although the follow-up duration for stage I disease could be reduced to less than 5 years, advanced gastric cancer such as stage III or IV disease has risk of recurrence beyond 5 years and therefore additional follow-up is required. These results could help decide the strategy for surveillance.

Imatinib and nutritional support can make successful treatment for a case of huge liver metastasis of duodenal gastrointestinal stromal tumor that initially showed jaundice and cachexia.

It is very difficult to treat patients with liver metastasis presenting with jaundice or cachexia. We herein report a successfully treated case of huge liver metastasis of gastrointestinal stromal tumor (GIST) that initially showed jaundice and cachexia. The patient was a woman in her early 40 s. She had a history of duodenal GIST 4 years before this admission. She was admitted to our hospital for abdominal fullness and anorexia. Abdominal computed tomography revealed huge liver metastasis of GIST. She showed jaundice and cancer cachexia with a modified Glasgow Prognostic Score of 2. After applying nutritional support, 400 mg of imatinib was administered. Although leg edema transiently worsened, the withdrawal of imatinib and administration of diuretics improved it. Imatinib was re-administered, and nutritional support was continued. The total bilirubin level decreased, and the serum albumin level increased. The tumor gradually decreased in size. Finally, she received surgical resection after 16 months of treatment with imatinib. Although adjuvant imatinib administration was continued after surgery, and no recurrence was observed as of 18 months after surgery.

Comparative analysis of the prognostic utility of preoperative nutritional parameters in patients with resectable esophageal carcinoma.

OBJECTIVE: Although surgical resection is a mainstay in the management of esophageal carcinoma (EC), its postoperative outcomes remain unsatisfactory. To optimize surgical strategies for EC, a simple method of stratifying patients according to risk factors is desired. Controlling nutritional status (CONUT), the prognostic nutritional index (PNI), transthyretin and transferrin are nutritional parameters used to predict the long-term outcomes of EC patients. We aimed to comparatively evaluate the prognostic significance of these four markers, measured preoperatively, in patients with operable EC. METHODS: In total, 224 patients undergoing surgical resection for EC were retrospectively reviewed. Overall/cancer-specific survivals (OS/CSS) were estimated applying the Cox proportional hazard model to univariate and multivariate analyses. PNI, transthyretin and transferrin levels were treated as continuous variables in these analyses. RESULTS: Preoperative CONUT had significant associations with tumor location, depth and preoperative irradiation. The other three markers all showed significant relationships with age and tumor depth. On univariate Cox regression analysis, preoperative CONUT, PNI, transthyretin and transferrin all correlated significantly with OS and CSS. On multivariate Cox regression analysis, the preoperative transthyretin level was identified as an independent predictor of OS (HR 0.51 per 10 mg/dL increase, 95% CI 0.29-0.88, p = 0.017) and CSS (HR 0.50, 95% CI 0.27-0.91, p = 0.027) as well as tumor depth, nodal metastasis and preoperative irradiation, while the other three parameters were not. CONCLUSIONS: Preoperative transthyretin, as a continuous variable, independently predicted both OS and CSS in resectable EC patients, appearing to be the best prognosticator among conventional nutrition-related parameters.

Usefulness of Percutaneous Transesophageal Gastro-Tubing in Patients Receiving Chemoradiotherapy for Advanced Esophageal Cancer: A Case Report.

Percutaneous endoscopic gastrostomy (PEG) is often performed for nutritional management in advanced esophageal cancer. We here report a patient who initially received enteral nutrition via a nasogastric tube and in whom the subsequent use of percutaneous transesophageal gastro-tubing (PTEG) circumvented the need for a gastrostomy. It is believed that PEG is less painful than a nasogastric tube. However, we selected PTEG because a PEG would have been within the planned irradiation field and there was concern about radiation dermatitis. We were able to administer chemoradiotherapy with sufficient nutrition via an enteral feeding tube via esophagostomy. PTEG is a very useful tool in patients at risk of radiation dermatitis of the abdomen.

ß-Hydroxy-ß-methyl Butyrate/L-Arginine/L-Glutamine Supplementation for Preventing Hand-Foot Skin Reaction in Sorafenib for Advanced Hepatocellular Carcinoma.

BACKGROUND/AIM: Sorafenib is standard treatment for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a notorious side-effect of this therapy. This study evaluated prophylactic benefits of an oral nutritional supplement (ONS) on sorafenib-associated HFSR in advanced HCC. PATIENTS AND METHODS: This was a prospective, single-center, open-label trial arm using combined ONS and sorafenib in patients with unresectable HCC from August 2014 to February 2018. Control patients received sorafenib without ONS from 2011 to 2014. From September 2014, prophylactic ONS containing ß-hydroxy-ß-methylbutyrate (HMB), L-arginine, and L-glutamine was given. Sorafenib dosage was 400 mg/day for both groups. RESULTS: Each group comprised 22 men and three women. Age, sex, Child-Pugh score, and clinical stage excluding IV-B did not significantly differ between the groups. HFSR occurred after 2 weeks: 15/25 patients in the control group (60%; HFSR grade 1: 6, grade 2: 7, grade 3: 2) vs. 8/25 in the ONS group (32%; HFSR grade 1: 4, grade 2: 4, grade 3: 0; p=0.047, Pearson's Chi-square test). CONCLUSION: Prophylactic HMB, L-arginine and L-glutamine supplementation effectively prevented sorafenib-associated HFSR in patients with advanced HCC.

Pretreatment monocyte counts and neutrophil counts predict the risk for febrile neutropenia in patients undergoing TPF chemotherapy for head and neck squamous cell carcinoma.

BACKGROUND: Febrile neutropenia (FN) is the most serious hematologic toxicity of systemic chemotherapy. However, accurate prediction of FN development has been difficult because the risk varies largely depending on the chemotherapy regimen and various individual factors. METHODS: We retrospectively analyzed diverse clinical factors including pretreatment hematological parameters to clarify the reliable predictors of FN development during chemotherapy with a docetaxel, cisplatin, and fluorouracil (TPF) regimen in patients with head and neck squamous cell carcinoma. RESULTS: Among the 50 patients, grade ≥3 neutropenia, grade 4 neutropenia, and FN developed in 36 (72%), 21 (42%), and 12 (24%) patients, respectively. Multivariate logistic regression revealed that a pretreatment absolute monocyte count (AMC) <370/mm3 is an independent predictor of TPF chemotherapy-induced FN (odds ratio=6.000, p=0.017). The predictive performance of the model combining AMC and absolute neutrophil count (ANC), in which the high-risk group was defined as having an AMC <370/mm3 and/or ANC <3500/mm3, was superior (area under the curve [AUC]=0.745) to that of the model with a cutoff for AMC alone (AUC=0.679). CONCLUSIONS: On the basis of our results, we recommend primary prophylactic use of granulocyte colony-stimulating factor and/or antibiotics selectively for patients predicted to be at high risk for TPF chemotherapy-induced FN.

Trends in antipsychotic prescriptions for Japanese outpatients during 2006-2012: a descriptive epidemiological study.

PURPOSE: This study aimed to assess the trends in antipsychotic prescriptions for outpatients in Japan, where a community-based approach to mental healthcare is emphasized. METHODS: This descriptive epidemiological study used claims data from 1038 community pharmacies across Japan. Outpatients who were ≥18 years old and receiving their initial antipsychotic prescription during 2006-2012 were evaluated. The annual trends were reported for monotherapies, polypharmacy, antipsychotic doses, and the concurrent prescription of psychotropic medications. RESULTS: The 152 592 outpatients included 101 133 (66%) adults (18-64 years old) and 51 459 (34%) older adults (≥65 years old). Among the adults, second-generation antipsychotic monotherapy prescriptions increased from 49% in 2006 to 71% in 2012, first-generation antipsychotic monotherapy prescriptions decreased from 29 to 14%, and antipsychotic polypharmacy decreased from 23 to 15%, respectively. Among the older adults, second-generation antipsychotic monotherapy prescriptions increased from 64 to 82%, first-generation antipsychotic monotherapy prescriptions decreased from 29 to 12%, and antipsychotic polypharmacy decreased from 7 to 6%, respectively. During the study period, >80% of the adults and >90% of the older adults received antipsychotics at risperidone-equivalent doses of <6 mg/day. Anxiolytics/hypnotics, antidepressants, antiparkinson agents, mood stabilizers, and anti-dementia agents were concurrently prescribed with antipsychotics for 70, 33, 20, 20, and 0.3% of the adults and for 43, 16, 19, 8, and 16% of the older adults, respectively. CONCLUSIONS: The present study evaluated large-scale claims-based datasets and found that high-dose prescriptions and antipsychotic polypharmacy among Japanese outpatients were not as prevalent as has been previously thought. Copyright © 2017 John Wiley & Sons, Ltd.