Prostaglandin E2/EP signaling in the tumor microenvironment of colorectal cancer

This article belongs to the Special Issue Molecular and Translational Research on Colorectal CancerThe number of colorectal cancer (CRC) patients is increasing worldwide. Accumulating evidence has shown that the tumor microenvironment (TME), including macrophages, neutrophils, and fibroblasts, plays an important role in the development and progression of CRC. Although targeting the TME could be a promising therapeutic approach, the mechanisms by which inflammatory cells promote CRC tumorigenesis are not well understood. When inflammation occurs in tissues, prostaglandin E2 (PGE2) is generated from arachidonic acid by the enzyme cyclooxygenase-2 (COX-2). PGE2 regulates multiple functions in various immune cells by binding to the downstream receptors EP1, EP2, EP3, and EP4, and plays an important role in the development of CRC. The current therapies targeting PGE2 using non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors have failed due to the global prostanoid suppression resulting in the severe adverse effects despite the fact they could prevent tumorigenesis. Therefore, therapies targeting the specific downstream molecules of PGE2 signaling could be a promising approach. This review highlights the role of each EP receptor in the TME of CRC tumorigenesis and their therapeutic potential

The Impact of Japan's 2004 Postgraduate Training Program on Intra-Prefectural Distribution of Pediatricians in Japan

Objective: Inequity in physician distribution poses a challenge to many health systems. In Japan, a new postgraduate training program for all new medical graduates was introduced in 2004, and researchers have argued that this program has increased inequalities in physician distribution. We examined the trends in the geographic distribution of pediatricians as well as all physicians from 1996 to 2010 to identify the impact of the launch of the new training program. Methods: The Gini coefficient was calculated using municipalities as the study unit within each prefecture to assess whether there were significant changes in the intra-prefectural distribution of all physicians and pediatricians before and after the launch of the new training program. The effect of the new program was quantified by estimating the difference in the slope in the time trend of the Gini coefficients before and after 2004 using a linear change-point regression design. We categorized 47 prefectures in Japan into two groups: 1) predominantly urban and 2) others by the definition from OECD to conduct stratified analyses by urban-rural status. Results: The trends in physician distribution worsened after 2004 for all physicians (p value<.0001) and pediatricians (p value = 0.0057). For all physicians, the trends worsened after 2004 both in predominantly urban prefectures (p value = 0.0012) and others (p value<0.0001), whereas, for pediatricians, the distribution worsened in others (p value = 0.0343), but not in predominantly urban prefectures (p value = 0.0584). Conclusion: The intra-prefectural distribution of physicians worsened after the launch of the new training program, which may reflect the impact of the new postgraduate program. In pediatrics, changes in the Gini trend differed significantly before and after the launch of the new training program in others, but not in predominantly urban prefectures. Further observation is needed to explore how this difference in trends affects the health status of the child population

Validation of a dietary balance score

This study assessed the validity of dietary balance scores (DBSs) by investigating the association between DBSs and nutrient adequacy (NA) in two Japanese populations. The participants were 65 community-dwelling Japanese from Tokushima Prefecture and 2,330 community-dwelling Japanese from Aichi Prefecture. Based on food frequency questionnaires or 3-day dietary records, we obtained 18 food groups. The NA score integrates nine beneficial nutrients and two nutrients that should be limited. We calculated four different DBSs: DBS1 consisted of five food groups (score range : 0–20), DBS2 consisted of nine food groups (score range : 0–36), DBS3 consisted of eight food groups (score range : 0–32), and DBS4 consisted of 10 food groups (score range : 0–40). Both the Spearman rank correlation coefficient with NA and the area under the receiver operating characteristic curve (AUC-ROC) for the nine beneficial nutrients were then estimated to test the performance of each DBS in predicting nutrient intake. The results showed that DBS1 and DBS4 were positively correlated with NA, while the AUC-ROC showed that DBS4 could moderately discriminate individuals with adequate intake levels of all nine nutrients. These findings suggest DBSs (especially DBS4) are useful in assessing dietary balance in middle-aged and older community-dwelling Japanese

Effect of herbal medicine daikenchuto on gastrointestinal symptoms following laparoscopic colectomy in patients with colon cancer: A prospective randomized study

We conducted a prospective randomized study to investigate the effect of daikenchuto (DKT) on abdominal symptoms following laparoscopic colectomy in patients with left-sided colon cancer. Patients who suffered from abdominal pain or distention on postoperative day 1 were randomized to either the DKT group or non-DKT group. The primary endpoints were the evaluation of abdominal pain, abdominal distention, and quality of life. The metabolome and gut microbiome analyses were conducted as secondary endpoints. A total of 17 patients were enrolled: 8 patients in the DKT group and 9 patients in the non-DKT group. There were no significant differences in the primary endpoints and postoperative adverse events between the two groups. The metabolome and gut microbiome analyses showed that the levels of plasma lipid mediators associated with the arachidonic acid cascade were lower in the DKT group than in the non-DKT group, and that the relative abundance of genera Serratia and Bilophila were lower in the DKT group than in the non-DKT group. DKT administration did not improve the abdominal symptoms following laparoscopic colectomy. The effects of DKT on metabolites and gut microbiome have to be further investigated

Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K‐RAS status for unresectable colorectal liver metastasis (BECK study): Long‐term results of survival

[Background/Purpose]To investigate the long‐term outcome and entire treatment course of patients with technically unresectable CRLM who underwent conversion hepatectomy and to examine factors associated with conversion to hepatectomy. [Methods]Recurrence and survival data with long‐term follow‐up were analyzed in the cohort of a multi‐institutional phase II trial for technically unresectable colorectal liver metastases (the BECK study). [Results]A total of 22/12 patients with K‐RAS wild‐type/mutant tumors were treated with mFOLFOX6 + cetuximab/bevacizumab. The conversion R0/1 hepatectomy rate was significantly higher in left‐sided primary tumors than in right‐sided tumors (75.0% vs 30.0%, P = .022). The median follow‐up was 72.6 months. The 5‐year overall survival (OS) rate in the entire cohort was 48.1%. In patients who underwent R0/1 hepatectomy (n = 21), the 5‐year RFS rate and OS rate were 19.1% and 66.3%, respectively. At the final follow‐up, seven patients had no evidence of disease, five were alive with disease, and 20 had died from their original cancer. All 16 patients who achieved 5‐year survival underwent conversion hepatectomy, and 11 of them underwent further resection for other recurrences (median: 2, range: 1‐4). [Conclusions]Conversion hepatectomy achieved a similar long‐term survival to the results of previous studies in initially resectable patients, although many of them experienced several post‐hepatectomy recurrences. Left‐sided primary was found to be the predictor for conversion hepatectomy

Low-Dose Intravenous Alteplase in Wake-Up Stroke

Background and Purpose—We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods—This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0–1). Results—Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68–1.41]; P=0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P>0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06–12.58]; P>0.999), respectively. Conclusions—No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions