Indigo naturalis is effective even in treatment-refractory patients with ulcerative colitis: a post hoc analysis from the INDIGO study.

BACKGROUND: We recently reported the efficacy of indigo naturalis (IN) in patients with active ulcerative colitis (UC) in a randomized controlled trial (INDIGO study). However, few studies have been conducted to investigate whether IN is effective even in treatment-refractory cases, such as in those with steroid dependency and anti-TNF refractoriness. METHODS: In the INDIGO study, 86 patients with active UC were randomly assigned to an IN group (0.5-2.0 g daily) or placebo group. The rate of clinical response (CR), mucosal healing (MH), and change in fecal calprotectin (FCP) levels was compared between refractory [patients with steroid-dependent disease, previous use of anti-TNF-α, and concomitant use of immunomodulators (IM)] and non-refractory patients. We also analyzed factors predicting CR and MH at week 8. RESULTS: The rates of CR of IN group were significantly higher than placebo group, even in patients with steroid-dependent disease (p < 0.001), previous use of anti-TNF-α (p = 0.002), and concomitant use of IM (p = 0.013). The rates of MH in IN group were significantly higher than in placebo group in patients with steroid-dependent disease (p = 0.009). In the IN group, median FCP levels, at week 8, were significantly lower than baseline in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α (p < 0.001, respectively). Multivariate analysis indicated that the previous use of anti-TNF-α was not a predictive factor for CR and MH at week 8. CONCLUSIONS: In a sub-analysis of data from a randomized placebo-controlled trial, we found that IN may be useful even in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α.

Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Indigo naturalis (IN) is a traditional Chinese medicine that contains ligands for the aryl hydrocarbon receptor and promotes regeneration of the mucosa by inducing production of interleukin 22. IN might induce mucosal healing in patients with ulcerative colitis (UC). We performed a randomized controlled trial to investigate the safety and efficacy of IN in patients with UC. METHODS: We performed a multicenter, double-blind trial evaluating the safety of 86 patients in Japan with active UC (Mayo scores of 6 or more), enrolled from March 30 through December 27, 2016. Patients were randomly assigned to groups and given a daily dose of 0.5, 1.0, or 2.0 g IN or placebo (1:1:1:1 ratio) for 8 weeks. The primary endpoint was the rate of clinical response at week 8, defined as a 3-point decrease in the Mayo score and a decrease of at least 30% from baseline, with a decrease of at least 1 point for the rectal bleeding subscore or absolute rectal bleeding score of 0-1. The main secondary endpoint was the rate of clinical remission at week 8, defined as a Mayo score or ≤2 and no subscores with a value >1. Mucosal healing was also assessed at week 8. RESULTS: The trial was terminated because of an external reason: a report of pulmonary arterial hypertension in a patient who used self-purchased IN for 6 months. In the intent-to-treat analysis, we observed a significant, dose-dependent linear trend in proportions of patients with clinical responses (13.6% with a clinical response to placebo; 69.6% to 0.5 g IN; 75.0% to 1.0 g IN; and 81.0% to 2.0 g IN) (Cochran-Armitage trend test P < .0001 compared with placebo). Proportions of patients in clinical remission at week 8 were significantly higher in the 1.0 g IN group (55.0%, P = .0004) and the 2.0 g IN group (38.1%, (P = .0093) than in the placebo group (4.5%). Proportions of patients with mucosal healing were 13.6% in the placebo group, 56.5% in the 0.5 g IN group, 60.0% in the 1.0 g IN group, and 47.6% in the 2.0 g IN group (P = .0278 compared with placebo). Although mild liver dysfunction was observed in 10 patients who received IN, no serious adverse events were observed. CONCLUSIONS: In a randomized, placebo-controlled trial, we found 8 weeks of IN (0.5-2.0 g per day) to be effective in inducing a clinical response in patients with UC. However, IN should not yet be used because of the potential for adverse effects, including pulmonary arterial hypertension. Clinical Trials Registry no: UMIN000021439 (http://www.umin.ac.jp/ctr/).

Feasibility and Safety of Repeated Transarterial Chemoembolization Using Miriplatin-Lipiodol Suspension for Hepatocellular Carcinoma.

AIM: To retrospectively evaluate the feasibility and safety of repeated transarterial chemoembolization (TACE) three or more times using miriplatin-lipiodol (M-LPD) suspension (repeated M-LPD TACE) for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Sixteen patients who underwent repeated M-LPD TACE were examined. Total dose of miriplatin, lipiodol and porous gelatin sponge particles and adverse events of the first and last M-LPD TACE were evaluated. RESULTS: The mean±standard deviation (SD) of the total number of M-LPD TACE per patient was 3.7±1.1. The mean±SD dose of total miriplatin, lipiodol and porous gelatin sponge particles per patient was 303±103 mg, 21±7.3 ml and 84±57 mg, respectively. There were no significant differences in any adverse events between the first and last M-LPD TACE. CONCLUSION: Repeated M-LPD TACE for HCC is feasible and safe in selected patients.

Balloon-occluded transarterial chemoembolization using a 1.8-French tip coaxial microballoon catheter for hepatocellular carcinoma: technical and safety considerations.

OBJECTIVE: To evaluate the technical feasibility and safety considerations of balloon-occluded transarterial chemoembolization (B-TACE) using a newly developed 1.8-French (Fr) tip microballoon catheter for hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Between February 2013 and May 2013, 31 patients (20 males, 11 females; age range 56-85 years) underwent B-TACE using a 1.8-Fr tip microballoon catheter for unresectable HCC. The technical success rate, procedural complications, and adverse events of B-TACE were retrospectively investigated. RESULTS: A total of 31 patients were subjected to 70 sessions of B-TACE using a 1.8-Fr tip microballoon catheter. The level of B-TACE was sub-subsegmental in 11, subsegmental in 35, segmental in 14, lobar in five, and right inferior phrenic artery in five sessions. The overall technical success rate was 99% (69 out of 70 sessions). As procedural complications, rupturing of the microballoon (n = 3) and aneurysmal dilatation at the site of balloon occlusion (n = 2) were encountered. There were no significant differences in any parameters between blood biochemical examination before and between two to four weeks after the procedure. CONCLUSION: A 1.8-Fr tip microballoon catheter enables selective catheterization in patients with HCC and B-TACE using the 1.8-Fr tip microballoon catheter is a safe procedure.

Molecular background of alpha-fetoprotein in liver cancer cells as revealed by global RNA expression analysis.

alpha-Fetoprotein (AFP) is considered to be a diagnostic and prognostic biomarker in hepatocellular carcinoma (HCC). However, the role of AFP in the development of HCC is presently obscure. We hypothesized that a certain set of genes is expressed in a manner coordinate with AFP, and that these genes essentially contribute to the malignant characteristics of AFP-producing HCC. To address this hypothesis, we carried out global mRNA expression analysis of 21 liver cancer cell lines that produce varying levels of AFP. We identified 213 genes whose mRNA expression levels were significantly correlated with that of AFP (P < 0.0001). These included liver-specific transcription factors for AFP and other albumin family genes. Eighteen HCC-associated genes and 11 genes associated with malignancies other than HCC showed significant correlations with AFP production levels. Genes involved in lipid catabolism, blood coagulation, iron metabolism, angiogenesis, and the Wnt and mitogen-activated protein kinase pathways were also identified. Text data mining revealed that participation in the transcription factor network could explain the connection between 78 of the identified genes. Glypican 3, which is a component of the Wnt pathway and contributes to HCC development, had the fifth highest correlation coefficient with AFP. Reactivity to specific antibodies confirmed the significant correlation between AFP and glypican 3 expression in HCC tissues. These observations suggest that AFP-producing liver cancer cells may have a unique molecular background consisting of cancer-associated genes. From this genome-wide association study, novel aspects of the molecular background of AFP were revealed, and thus may lead to the identification of novel biomarker candidates.