Naldemedine for Opioid-Induced Constipation in Patients With Cancer: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial.

PURPOSE: Opioid-induced constipation is the most frequent and non-self-limiting adverse effect of opioid analgesia, reducing adherence and interfering with pain relief. This clinical trial aimed to clarify the preventive effect of naldemedine versus placebo for constipation in patients with cancer starting regularly dosed strong opioids therapy. METHODS: This multicenter, double-blinded, randomized, placebo-controlled, confirmatory trial was conducted between July 2021 and May 2023 at four academic hospitals in Japan (ClinicalTrials.gov identifier: jRCTs031200397). Patients with cancer starting a first-time regularly dosed strong opioid for cancer pain and age 20+ years were included. Eligible patients were randomly assigned to the naldemedine (Symproic 0.2 mg) or placebo group in a 1:1 ratio for 14 days with protocol treatment. The primary end point was the proportion of patients with a Bowel Function Index (BFI) of <28.8 on day 14. The secondary end points included frequency of spontaneous bowel movements (SBM), quality of life (QOL), and frequency of opioid-induced nausea and vomiting (OINV). RESULTS: Of the 103 patients assessed for eligibility, 99 received either naldemedine (n = 49) or placebo (n = 50). A BFI of <28.8 on day 14 was significantly more likely to occur in the naldemedine group (64.6%; 95% CI, 51.1 to 78.1) versus placebo (17.0%; 95% CI, 6.3 to 27.8), and the difference between groups was 47.6% (95% CI, 30.3 to 64.8; P < .0001). The frequency of SBM, QOL, and the severity of OINV were nominally significant in the naldemedine group than in the control group. CONCLUSION: Naldemedine prevented constipation and improved constipation-related QOL, with possible preventive effect on OINV in patients with cancer starting regularly dosed opioids therapy.

Deficiency of kynurenine 3-monooxygenase exacerbates impairment of prepulse inhibition induced by phencyclidine.

Phencyclidine (PCP) causes mental symptoms that closely resemble schizophrenia through the inhibition of the glutamatergic system. The kynurenine (KYN) pathway (KP) generates metabolites that modulate glutamatergic systems such as kynurenic acid (KA), quinolinic acid (QA), and xanthurenic acid (XA). Kynurenine 3-monooxygenase (KMO) metabolizes KYN to 3-hydroxykynurenine (3-HK), an upstream metabolite of QA and XA. Clinical studies have reported lower KMO mRNA and higher KA levels in the postmortem brains of patients with schizophrenia and exacerbation of symptoms in schizophrenia by PCP. However, the association between KMO deficiency and PCP remains elusive. Here, we demonstrated that a non-effective dose of PCP induced impairment of prepulse inhibition (PPI) in KMO KO mice. KA levels were increased in the prefrontal cortex (PFC) and hippocampus (HIP) of KMO KO mice, but 3-HK levels were decreased. In wild-type C57BL/6 N mice, the PPI impairment induced by PCP is exacerbated by KA, while attenuated by 3-HK, QA and XA. Taken together, KMO KO mice were vulnerable to the PPI impairment induced by PCP through an increase in KA and a decrease in 3-HK, suggesting that an increase in the ratio of KA to 3-HK (QA and XA) may play an important role in the pathophysiology of schizophrenia.

Rationale and design of a multicenter, double-blinded, randomized, placebo-controlled trial to investigate the effects of naldemedine on opioid-induced constipation for patients with cancer pain: A study protocol.

Background: It is unclear which laxatives are appropriate to prevent opioid-induced constipation (OIC). This study will evaluate whether prophylactic use of naldemedine prevents OIC in patients with cancer who start opioid administration. Methods: This study is a multicenter, double-blinded, randomized, placebo-controlled trial. Patients who meet the eligibility criteria and give consent will be randomly assigned to the naldemedine or placebo group. Both groups will take each drug once a day after breakfast for 14 days. Results: The primary endpoint is the proportion of patients with a Bowel Function Index of less than 28.8 on Day 14. The secondary endpoints include assessment scales of the impact of constipation on comprehensive quality of life. Conclusions: This is the first study proposed to assess the superiority of naldemedine over placebo in the prevention of OIC. If naldemedine is found to be effective in reducing OIC compared with the placebo, it will be regarded as a new standard for OIC prophylaxis at opioid initiation. Trial registration: jRCT identifier: jRCTs031200397. Registered March 5, 2021, https://rctportal.niph.go.jp/en/detail?trial_id=jRCTs031200397.

Loureirin C and Xanthoceraside Prevent Abnormal Behaviors Associated with Downregulation of Brain Derived Neurotrophic Factor and AKT/mTOR/CREB Signaling in the Prefrontal Cortex Induced by Chronic Corticosterone Exposure in Mice.

Brain derived neurotrophic factor (BDNF) is one of the most abundant neurotrophic factors, and its deficits are involved in the pathogenesis of major depressive disorders (MDD). Loureirin C (Lou C) is a compound derived from red resin extracted from the stems of Chinese dragon's blood. Xanthoceraside (Xan) is a triterpenoid saponin extracted from the husks of Xanthoceras sorbifolia Bunge. These compounds have neuroprotective effects through upregulation of BDNF. The present study aimed to evaluate whether Lou C and Xan attenuate abnormal behaviors induced by chronic corticosterone (CORT) administration. CORT was administered subcutaneously to mice for 3 weeks, and Lou C and Xan, dispensed orally once a day during the last 2 weeks of CORT administration. Chronic CORT administration induced abnormal behaviors such as prolonged starting latency in the open field test, decreased social interaction time in the social interaction test and prolonged latency to eat in the novelty suppressed feeding test. Chronic CORT administration decreased the expression levels of BDNF and the phosphorylation of protein kinase B (Akt), mammalian target of rapamycin (mTOR), and the cAMP response element binding protein (CREB) in the prefrontal cortex. Lou C and Xan dose-dependently prevented the abnormal behaviors and decreased the expression levels of BDNF and in phosphorylation of AKT, mTOR, and CREB in the prefrontal cortex of CORT mice. These results suggest that Lou C and Xan could be attractive candidates for pharmacotherapy of MDD at least in part, given their propensity to increase BDNF expression and phosphorylation of AKT, mTOR, and CREB.

Impact of Body Weight Loss on Survival in Patients with Advanced Gastric Cancer Receiving Second-Line Treatment.

Limited information is available regarding the impact of body weight loss (BWL) in patients with advanced gastric cancer (AGC) who receive second-line chemotherapy. We retrospectively reviewed data for consecutive AGC patients who received second-line treatment with taxane-based chemotherapy at our institution between January 2014 and September 2018. We calculated variables, including percent BWL per month during chemotherapy (%BWL/m), and analyzed the correlations between BWL and other clinicopathological parameters with survival. Forty-four AGC patients were registered (median age, 67.5 years; females, n = 16 [36.3%]; severe ascites, n = 12 [27.3%]). The median overall survival was significantly shorter among patients with a %BWL/m of 1% or more, compared with patients with less weight loss (6.3 mo, vs. 12.3 mo, P = 0.038). The %BWL/m (≥1% vs. <1%) was significantly correlated with survival in a univariate analysis (HR = 2.11, P = 0.04), and the survival period was shorter for patients with severe ascites (HR = 1.92; 95% CI, 0.90-3.90) and if their %BWL/m was 1% or more (HR = 2.01; 95% CI, 0.98-4.10) in a multivariate analysis. In conclusion, BWL during second-line chemotherapy was associated with a poor prognosis among patients with AGC.

Kynurenine 3-monooxygenase deficiency induces depression-like behavior via enhanced antagonism of α7 nicotinic acetylcholine receptors by kynurenic acid.

Tryptophan (TRP) is metabolized via the kynurenine (KYN) pathway, which is related to the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the metabolism of KYN to 3-hydroxykynurenine. In rodents, KMO deficiency induces a depression-like behavior and increases the levels of kynurenic acid (KA), a KYN metabolite formed by kynurenine aminotransferases (KATs). KA antagonizes α7 nicotinic acetylcholine receptor (α7nAChR). Here, we investigated the involvement of KA in depression-like behavior in KMO knockout (KO) mice. KYN, KA, and anthranilic acid but not TRP or 3-hydroxyanthranilic acid were elevated in the prefrontal cortex of KMO KO mice. The mRNA levels of KAT1 and α7nAChR but not KAT2-4, α4nAChR, or ß2nAChR were elevated in the prefrontal cortex of KMO KO mice. Nicotine blocked increase in locomotor activity, decrease in social interaction time, and prolonged immobility in a forced swimming test, but it did not decrease sucrose preference in the KMO KO mice. Methyllycaconitine (an α7nAChR antagonist) antagonized the effect of nicotine on decreased social interaction time and prolonged immobility in the forced swimming test, but not increased locomotor activity. Galantamine (an α7nAChR allosteric agonist) blocked the increased locomotor activity and prolonged immobility in the forced swimming test, but not the decreased social interaction time in the KMO KO mice. In conclusion, elevation of KA levels contributes to depression-like behaviors in KMO KO mice by α7nAChR antagonism. The ameliorating effects of nicotine and galantamine on depression-like behaviors in KMO KO mice are associated with the activation of α7nAChR.

Analysis of fistula formation of T4 esophageal cancer patients treated by chemoradiotherapy.

BACKGROUND AND AIM: Fistula is one of the known complications of T4 esophageal cancer (T4-EC). The standard treatment for T4-EC is chemoradiotherapy, but detailed data about fistula resulting from chemoradiotherapy in this condition are limited. In particular, radiographic findings of T4-EC with fistula have not been reported. This study assessed the risk factors of fistula based on clinical information on patients with chemoradiotherapy for T4-EC. METHODS: We retrospectively reviewed the clinical data of 59 T4-EC patients who had squamous cell carcinoma without any fistula before receiving definitive or palliative chemoradiotherapy. RESULTS: A fistula was observed in 18 patients (31%) throughout their clinical course. The overall survival in the fistula group was significantly shorter than that in the non-fistula group (259 vs. 346 days; p = 0.0341). The axial tumor size on computed tomography (CT) was confirmed as an independent risk factor for esophageal fistula in multivariate analysis of stepwise methods [OR 1.226; 95% CI 1.109-1.411; p < 0.0001]. Twelve out of 14 patients with an axial tumor size of 50 mm or greater had developed a fistula. CONCLUSIONS: A large tumor size on the axial plane on CT is a risk factor for fistula formation.

Phase I study of the anti-heparin-binding epidermal growth factor-like growth factor antibody U3-1565 with cetuximab in patients with cetuximab- or panitumumab-resistant metastatic colorectal cancer.

KRAS wild-type colorectal cancers initially responsive to anti-endothelial growth factor receptor (EGFR) antibodies [cetuximab (Cetu)/panitumumab (Pani)] develop acquired resistance. Overexpression of EGFR ligands such as heparin-binding EGF-like growth factor (HB-EGF) may be one resistance mechanism. This phase I study of U3-1565, anti-HB-EGF antibody, and Cetu combination therapy enrolled patients with KRAS wild-type metastatic colorectal cancer who had received two ≤ regimens with fluoropyrimidine, oxaliplatin, irinotecan, and Cetu/Pani and had disease progression on Cetu/Pani. Recommended dose (RD) was determined in the 1st stage, followed by evaluation of efficacy at the RD level in the 2nd-stage. Cetu was given at a loading dose of 400 mg/m2 followed by weekly infusions of 250 mg/m2 in levels 1 and 0. U3-1565 was administered at a loading dose of 24 mg/m2 followed by biweekly infusions of 16 mg/m2 in level 1 and 16-12 mg/m2 in level 0. Twenty-two patients were enrolled. No dose-limiting toxicities were observed among three patients in level 1 in the first stage, which was determined as RD. Grade 3 or higher adverse events occurred in 59.1%; those in ≥5% of patients were anemia, γ-GTP elevation, and acneiform rash. Overall response rate was 0.0% [95% confidence interval (CI): 0.0%-15.4%] and disease control was achieved in 17 patients (77.3%, 95% CI: 54.6%-92.2%). Median progression-free survival time was 85.0 days (95% CI: 54.0-91.0) and median survival time was 196 days (95% CI: 113.0-306.0). RD was determined as level 1. The efficacy of this combination therapy after progression on Cetu/Pani was negligible. Trial Registration: UMIN000013006.

Chronic unpredictable mild stress-induced behavioral changes are coupled with dopaminergic hyperfunction and serotonergic hypofunction in mouse models of depression.

Accumulating evidence shows that stressful events evoke molecular alterations in the brain, considered a pathology in major depressive disorder (MDD). However, the abnormalities of neurotransmissions as well as intracellular signaling pathways affected by chronic stress in brain have not been fully explored. We investigated the effect of chronic unpredictable mild stress (CUMS) on the emotional behaviors, dopaminergic and serotoninergic function, and intracellular signaling in the nucleus accumbens, hippocampus and prefrontal cortex. Male C57BL/6J mice were exposed to CUMS for 4 weeks. CUMS was shown to induce hyperactivity in a novel environment, decrease interaction time in the social interaction test, prolong feeding latency in the novelty suppressed feeding test and enhance immobility in the forced swimming test. The levels of dopamine, its metabolites and turnover, and protein level of tyrosine hydroxylase (TH) were increased by CUMS in the nucleus accumbens (NAc). The level of serotonin and protein levels of tryptophan hydroxylase (TPH) and TH were decreased by CUMS in the hippocampus (HPC) and prefrontal cortex (PFC). Accompanying the increase in dopaminergic function, phosphorylation levels of extracellular signal-regulated kinases (ERK), protein kinase B (Akt) and cAMP response element-binding protein (CREB) were increased by CUMS in the NAc. Administration of fluoxetine (selective serotonin re-uptake inhibitor: 20 mg/kg i.p.) and aripiprazole (dopamine D2 receptor partial agonist: 0.1 mg/kg i.p.) during CUMS, prevented behavioral changes and increase of dopamine level in the NAc. These data suggest that CUMS-induced depression-like behaviors are coupled with dopaminergic hyperfunction in the NAc and serotonergic hypofunction in the HPC and PFC.

Clinical Implications of Decreased Computed Tomography Value after Ramucirumab in Advanced Gastric Cancer.

OBJECTIVES: This study aimed to evaluate whether a decrease of computed tomography (CT) value for tumors serves as a predictive marker in patients with advanced gastric cancer (aGC) who have undergone chemotherapy with vascular epithelial growth factor receptor 2 inhibitor (ramucirumab). METHOD: We retrospectively analyzed 44 patients with aGC who received taxane alone (TAX arm; n = 33), ramucirumab alone, or ramucirumab in combination with taxane (RAM arm; n = 11) as second-line or later chemotherapy between July 2010 and October 2016. In all patients, tumor size and tumor CT value were evaluated at two timepoints: pretreatment and first evaluation. We calculated the change of the tumors' CT value. The associations of these factors with tumor response, progression-free survival (PFS), and overall survival were investigated. RESULTS: Ten (90.9%) of 11 patients in the RAM arm and 18 (54.5%) of 33 patients in the TAX arm showed decreased CT values. The rate of CT value change in the RAM arm (median -32.80%, range -53.63 to 6.84%) was higher than that in the TAX arm (median -0.44%, range -37.47 to 40.64%; p = 0.0005). When using the median value of CT value change as a cut-off, PFS was significantly longer in patients with a high rate of CT value change (decrease ≥32.80%) than in those with a low rate (decrease <32.80%) in the RAM arm (median 292 and 112 days; p = 0.045), while no significant difference of this kind was found in the TAX arm (median 91 and 125 days; p = 0.45). CONCLUSIONS: Patients with aGC treated with ramucirumab experienced a significant decrease of CT value of tumors and had an association between the rate of CT value change and PFS. Our study suggests that CT value changes of tumors may be a predictor for the efficacy of ramucirumab in aGC.

Profile of trifluridine/tipiracil hydrochloride in the treatment of metastatic colorectal cancer: efficacy, safety, and place in therapy.

TAS-102, with its robust survival efficacy and feasible toxicity, is one of the standard salvage-line treatments for patients with metastatic colorectal cancer (mCRC). No definitive data are available to determine which drug should be administered first during salvage-line treatment. Therefore, it is imperative that we establish the sequence of administration by considering drug toxicity profiles based on patient characteristics, such as age, performance status, comorbidities, tolerability to previous treatments, and patient preferences. The identification of predictive biomarkers in response to TAS-102 or its toxicity is urgently needed for better patient selection. Moreover, to strengthen efficacy or relieve toxicity, combinations with other agents, which could potentially emerge as standard treatment regimens, have been investigated and compared to existing active regimens for mCRC.

Early morphological change for predicting outcome in metastatic colorectal cancer after regorafenib.

BACKGROUND AND OBJECTIVE: It is unclear whether early morphological change (EMC) is a predictive marker for regorafenib in metastatic colorectal cancer (mCRC). Therefore, the present study investigated whether EMC can predict the outcome of mCRC patients receiving regorafenib. RESULTS: This study evaluated 68 patients. Among 52 patients with lung metastasis, 16 (31%) had cavity formation (CF). The median progression-free survival (PFS) and overall survival (OS) in patients with/without CF were 4.2/2.4 months (p<0.01) and 9.2/6.5 months (p=0.09), respectively. Among 45 patients with liver metastasis, 14 (31%) had active morphological response (MR). The median PFS and OS in patients with/without active MR were 5.3/2.4 months (p<0.01) and 13.6/6.9 months (p=0.02), respectively. Overall, 25 patients (37%) had EMC. The median PFS and OS in patients with/without EMC were 5.3/2.1 months (p<0.01) and 13.3/6.1 months (p<0.01), respectively. MATERIALS AND METHODS: This retrospective study included mCRC patients with lung and/or liver metastases receiving regorafenib. CF in lung metastasis and MR in liver metastasis were evaluated at the first post-treatment computed tomography scan. EMC was determined as CF and/or active MR. We compared PFS and OS between patients with and those without EMC. CONCLUSIONS: EMC could be a useful predictive marker for regorafenib in mCRC.

Infusion site adverse events in breast cancer patients receiving highly emetic chemotherapy with prophylactic anti-emetic treatment with aprepitant and fosaprepitant: A retrospective comparison.

The incidences of infusion site adverse events in chemotherapy regimens, including anthracyclines with either fosaprepitant or aprepitant as the anti-emetic, were not highlighted in the randomized trial comparing aprepitant and fosaprepitant. The present retrospective analysis was performed in breast cancer patients receiving anthracycline-containing chemotherapy, a combination of epirubicin and cyclophosphamide with or without 5-fluorouracil as the adjuvant or neoadjuvant, at the outpatient infusion center of St. Marianna University Hospital (Kawasaki, Japan). Infusion site adverse events were retrospectively compared between the 3 months prior to and three months following switching from 3 day oral administration of aprepitant to intravenous infusion of fosaprepitant. A total of 62 patients were included in the aprepitant group and 38 in the fosaprepitant group. Of these patients, 26 (42%) in the aprepitant group and 36 patients (96%) in the fosaprepitant group experienced any grade of infusion site adverse events at least once (P<0.001). As an anti-emetic treatment for chemotherapy using anthracyclines, fosaprepitant may be associated with a higher risk of infusion site adverse events compared with aprepitant.

Predictability of antitumor efficacy of cetuximab plus irinotecan based on skin rash severity according to observation period in patients with metastatic colorectal cancer following failure of fluorouracil, irinotecan and oxaliplatin.

The efficacy of cetuximab correlates with the severity of skin toxicity, although its onset may vary. The AIM of this retrospective study was to investigate the optimal observation period for skin rash as a predictor of the efficacy of cetuximab plus irinotecan. The subjects comprised 33 patients with KRAS wild-type metastatic colorectal cancer (mCRC) who had received prior chemotherapy with fluorouracil, irinotecan and oxaliplatin. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were compared according to the presence or absence of ≥grade 2 skin rash within 2, 4, 6, or 8 weeks following cetuximab initiation. The overall RR was 45% (15/33) and the median PFS and OS were 188 and 383 days, respectively. A total of 26 patients experienced ≥grade 2 skin rash within 8 weeks. The proportion of responders among patients who developed ≥grade 2 skin rash (severe group) decreased depending on the duration of the observation period (50% within 8 weeks), whereas the proportion of non-responders among patients with

Gastrointestinal stromal tumor presenting with prominent calcification.

We present a rare case of a gastrointestinal stromal tumor (GIST) in the stomach with prominent calcification at presentation. A 61-year-old woman visited our hospital because of epigastric discomfort. A spherical calcified lesion with a diameter of about 30 mm was incidentally shown in the left upper quadrant on an abdominal X-ray. Computed tomography demonstrated that the tumor was growing from the upper gastric body, with calcification in the peripheral ring area. A laparoscopic partial gastrectomy was performed, and the resected specimen revealed a well-circumscribed tumor with exophytic growth from the gastric muscularis propria. Microscopic examination revealed spindle-shaped tumor cells with calcification and hemorrhage. Additionally, positive immunoreactivity of the tumor to KIT and CD34 and a low mitotic index resulted in the diagnosis of very low risk GIST. There are a few case reports of heavily calcified GIST, although solitary or punctate calcification of primary GIST has been reported in several case series. Dystrophic calcification of necrotic or degenerative tissue is the supposed cause of primary calcified GISTs. In contrast, appearance of calcification after administration of imatinib mesylate, which may be one indicator of disease response, is possibly caused by a different mechanism.