Dexamethasone-sparing on days 2-4 with combined palonosetron, neurokinin-1 receptor antagonist, and olanzapine in cisplatin: a randomized phase III trial (SPARED Trial).

BACKGROUND: This study evaluated the non-inferiority of dexamethasone (DEX) on day 1, with sparing on days 2-4 in cisplatin-based chemotherapy. METHODS: Patients with malignant solid tumors who were treated with cisplatin (≥50 mg/m²) were randomly assigned (1:1) to receive either DEX on days 1-4 (Arm D4) or DEX on day 1 (Arm D1) plus palonosetron, NK-1 RA, and olanzapine (5 mg). The primary endpoint was complete response (CR) during the delayed (24-120 h) phase. The non-inferiority margin was set at -15%. RESULTS: A total of 281 patients were enrolled, 278 of whom were randomly assigned to Arm D4 (n = 139) or Arm D1 (n = 139). In 274 patients were included in the efficacy analysis, the rates of delayed CR in Arms D4 and D1 were 79.7% and 75.0%, respectively (risk difference -4.1%; 95% CI -14.1%-6.0%, P = 0.023). However, patients in Arm D1 had significantly lower total control rates during the delayed and overall phases, and more frequent nausea and appetite loss. There were no significant between-arm differences in the quality of life. CONCLUSION: DEX-sparing is an alternative option for patients receiving cisplatin; however, this revised administration schedule should be applied on an individual basis after a comprehensive evaluation. CLINICAL TRIALS REGISTRY NUMBER: UMIN000032269.

Impact of prior bevacizumab therapy on the incidence of ramucirumab-induced proteinuria in colorectal cancer: a multi-institutional cohort study.

BACKGROUND: The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups. RESULTS: We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). CONCLUSION: Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

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.

Nerve growth factor facilitates redistribution of adrenergic and non-adrenergic non-cholinergic perivascular nerves injured by phenol in rat mesenteric resistance arteries.

We previously reported that nerve growth factor (NGF) facilitated perivascular sympathetic neuropeptide Y (NPY)- and calcitonin gene-related peptide (CGRP)-containing nerves injured by the topical application of phenol in the rat mesenteric artery. We also demonstrated that mesenteric arterial nerves were distributed into tyrosine hydroxylase (TH)-, substance P (SP)-, and neuronal nitric oxide synthase (nNOS)-containing nerves, which had axo-axonal interactions. In the present study, we examined the effects of NGF on phenol-injured perivascular nerves, including TH-, NPY-, nNOS-, CGRP-, and SP-containing nerves, in rat mesenteric arteries in more detail. Wistar rats underwent the in vivo topical application of 10% phenol to the superior mesenteric artery, proximal to the abdominal aorta, under pentobarbital-Na anesthesia. The distribution of perivascular nerves in the mesenteric arteries of the 2nd to 3rd-order branches isolated from 8-week-old Wistar rats was investigated immunohistochemically using antibodies against TH-, NPY-, nNOS-, CGRP-, and SP-containing nerves. The topical phenol treatment markedly reduced the density of all nerves in these arteries. The administration of NGF at a dose of 20µg/kg/day with an osmotic pump for 7 days significantly increased the density of all perivascular nerves over that of sham control levels. These results suggest that NGF facilitates the reinnervation of all perivascular nerves injured by phenol in small resistance arteries.

Characterization of Perivascular Nerve Distribution in Rat Mesenteric Small Arteries.

The distribution pattern of perivascular nerves in some branches of rat mesenteric arteries was studied. Mesenteric arteries isolated from 8-week-old Wistar rats were divided into the 1st-, 2nd-, and 3rd-order branches. The distribution of perivascular nerves in each branch was immunohistochemically evaluated using antibodies against neuropeptide Y (NPY), tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), substance P (SP), and neuronal nitric oxide synthase (nNOS). The density of NPY-, TH-, CGRP-, and SP-like immunoreactive (LI) nerves in the 2nd and 3rd branches was significantly greater than that in the 1st branch, and a negative relationship was found between nerve density and arterial diameter, except for TH-LI nerves. The density of NPY- and TH-LI nerves in all branches, which was similar, was greater than that of CGRP- (except for NPY-LI nerves in the 1st branch), SP-, or nNOS-LI nerves. Double immunostaining revealed that TH-LI nerves made contact with nNOS-LI, CGRP-LI, and SP-LI nerves and that CGRP-LI nerves made contact with TH-, NPY-, or nNOS-LI nerves, while TH-LI and CGRP-LI nerves nearly merged with NPY-LI and SP-LI nerves, respectively. These results suggest that the each branch of mesenteric arteries is densely innervated by vasoconstrictor nerves containing NPY, TH, and vasodilator CGRP nerves. They also suggest that the intense density of perivascular nerves in the 2nd and 3rd branches may contribute to maintaining vascular tone.

Nicotine facilitates reinnervation of phenol-injured perivascular adrenergic nerves in the rat mesenteric resistance artery.

Nicotine has been shown to have neuroprotective and neurotrophic actions in the central nervous system. To elucidate the peripheral neurotrophic effects of nicotine, we determined whether nicotine affected the reinnervation of mesenteric perivascular nerves following a topical phenol treatment. A topical phenol treatment was applied to the superior mesenteric artery proximal to the abdominal aorta in Wistar rats. We examined the immunohistochemistry of the distal small arteries 7 days after the treatment. The topical phenol treatment markedly reduced the density of tyrosine hydroxylase (TH)-LI and calcitonin gene-related peptide (CGRP)-LI fibers in these arteries. The administration of nicotine at a dose of 3 mg/kg/day (1.5 mg/kg/injection, twice a day), but not once a day or its continuous infusion using a mini-pump significantly increased the density of TH-LI nerves without affecting CGRP-LI nerves. A pretreatment with nicotinic acetylcholine receptor antagonists hexamethonium, mecamylamine, and methyllycaconitine, but not dextrometorphan, canceled the TH-LI nerve reinnervation induced by nicotine. Nicotine significantly increased NGF levels in the superior cervical ganglia (SCG) and mesenteric arteries, but not in the dorsal root ganglia, and also up-regulated the expression of NGF receptors (TrkA) in the SCG, which were canceled by hexamethonium. These results suggested that nicotine exhibited neurotrophic effects that facilitated the reinnervation of adrenergic TH-LI nerves by activating α7 nicotinic acetylcholine receptor and NGF in the SCG.

Altered function of nitrergic nerves inhibiting sympathetic neurotransmission in mesenteric vascular beds of renovascular hypertensive rats.

Neuronal nitric oxide (NO) has been shown to modulate perivascular adrenergic neurotransmission by inhibiting noradrenaline release from terminals in rat mesenteric arteries. This study was conducted to investigate changes in the inhibitory function of NO-containing nerves (nitrergic nerves) in mesenteric vascular beds of 2-kidney, 1-clip renovascular hypertensive rats (2K1C-RHR). Rat mesenteric vascular beds without endothelium were perfused with Krebs solution and the perfusion pressure was measured. In preparations from sham-operated rats (control) and 2K1C-RHRs, vasoconstriction induced by periarterial nerve stimulation (PNS; 2-8 Hz), but not vasoconstriction induced by exogenously injected noradrenaline (0.5, 1.0 nmol), was markedly facilitated in the presence of a nonselective NO synthase (NOS) inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME) (100 microM). The facilitatory effect of L-NAME in preparations from 2K1C-RHR was smaller than that in control preparations. L-NAME augmented PNS-evoked noradrenaline release, which was smaller in 2K1C-RHRs than in controls. The expression of neuronal NO synthase (nNOS) measured by western blotting in mesenteric arteries from 2K1C-RHRs was significantly decreased compared with control arteries. Immunohistochemical staining of mesenteric arteries showed dense innervation of nNOS-immunopositive nerves that was significantly smaller in arteries from 2K1C-RHR than that in control arteries. Mesenteric arteries were densely innervated by tyrosine hydroxylase-immunopositive nerves, which coalesced with nNOS-immunopositive nerves. These results suggest that the inhibitory function of nitrergic nerves in adrenergic neurotransmission is significantly decreased in 2K1C-RHRs. This functional alteration based on the decrease in nNOS expression and nitrergic innervation leads to enhanced adrenergic neurotransmission and contributes to the initiation and development of renovascular hypertension.

Proton acts as a neurotransmitter for nicotine-induced adrenergic and calcitonin gene-related peptide-containing nerve-mediated vasodilation in the rat mesenteric artery.

Nicotine stimulates presynaptic nicotinic acetylcholine receptors in perivascular adrenergic nerves and releases unknown transmitter(s) that activate transient receptor potential vanilloid-1 (TRPV1) located on calcitonin gene-related peptide (CGRP)-containing (CGRPergic) nerves, resulting in vasodilation. The present study investigated a potential transmitter transmitting between perivascular adrenergic nerves and CGRPergic nerves. Rat mesenteric vascular beds without endothelium were contracted by perfusion with Krebs' solution containing methoxamine, and the perfusion pressure and pH levels of the perfusate were measured. Nicotine perfusion for 1 min induced concentration-dependent vasodilation and lowered pH levels, which were abolished by cold-storage denervation of preparations, guanethidine (adrenergic neuron blocker), and mecamylamine (nicotinic alpha(3)beta(4)-acetylcholine receptor antagonist). Capsazepine (TRPV1 antagonist) blunted nicotine-induced vasodilation, but had no effect on the reduction of pH. Injection of hydrochloric acid (HCl) and perfusion of Krebs' solution at low pH (6.0-7.2) induced vasodilation. HCl-induced vasodilation was inhibited by cold-storage denervation, capsazepine, capsaicin (CGRP depletor), and CGRP(8-37) (CGRP receptor antagonist). Perfusion of adrenergic transmitter metabolites (normetanephrine and 3-methoxydopamine), but not of other metabolites, induced vasodilation, which was not inhibited by capsaicin treatment. Immunohistochemical staining of mesenteric arteries showed dense innervation of CGRP- and TRPV1-immunopositive nerves, with both immunostainings appearing in the same neuron. Mesenteric arteries were densely innervated by neuropeptide Y-immunopositive nerves, which coalesced with CGRP-immunopositive nerves. Scanning and immunoscanning electron microscopic images showed coalescence sites of different perivascular fibers before they intruded into smooth muscles. These results indicate that nicotine initially stimulates adrenergic nerves via nicotinic alpha(3)beta(4)-receptors to release protons and thereby induces CGRPergic nerve-mediated vasodilation via TRPV1.

Neurotrophic effect of hepatic growth factor (HGF) on reinnervation of perivascular calcitonin gene-related peptide (CGRP)-containing nerves following phenol-induced nerve injury in the rat mesenteric artery.

Hepatic growth factor (HGF) has neurotrophic effects in the motor neurons and central nervous system. However, there has been no report about the neurotrophic action on perivascular nerves innervating the resistance artery. We investigated whether HGF can restore innervation or function of perivascular nerves, including neuropeptide Y (NPY)-containing sympathetic adrenergic nerves and calcitonin gene-related peptide (CGRP)-containing nerves, in rat mesenteric artery. To investigate HGF-mediated neurotrophic effects, Wistar rats under pentobarbital-Na anesthesia underwent in vivo perivascular denervation by topical application of phenol on the superior mesenteric artery, and then HGF or nerve growth factor (NGF) was administered for 7 days using an osmotic mini-pump after phenol-treatment. HGF significantly increased the density and number of CGRP-like immunoreactivity (LI)-containing nerve fibers compared with saline administration, while HGF did not affect the density of NPY-containing adrenergic nerve fibers. After 7-day treatment with HGF and phenol, the vascular response of vasodilation was recovered from nerve injury by phenol treatment, but vasoconstriction was not. HGF and NGF induced neurite outgrowth in rat cultured dorsal root ganglia (DRG). These results suggest that HGF has a specific neurotrophic action on reinnervation of vascular CGRP-LI-containing nerve fibers in the rat mesenteric artery and DRG.