ATP-binding cassette protein G5 (ABCG5)/ABCG8 heterodimer exports cholesterol from cells, while Niemann-Pick C1-like 1 (NPC1L1) imports cholesterol and vitamin K. We examined whether ABCG5/ABCG8 ...transports vitamin K similar to NPC1L1. Since high concentrations of vitamin K
show cytotoxicity, the cytoprotective effects of ABCG5/ABCG8 were examined. BHK cells expressing ABCG5/ABCG8 were more resistant to vitamin K
cytotoxicity than control cells, suggesting that ABCG5/ABCG8 transports vitamin K
out of cells. The addition of vitamin K
reversed the effects of ABCG5/ABCG8, suggesting that vitamin K
competitively inhibits the transport of vitamin K
. To examine the transport of vitamin K
by ABCG5/ABCG8, vitamin K
levels in the medium and cells were measured. Vitamin K
levels in cells expressing ABCG5/ABCG8 were lower than those in control cells, while vitamin K
efflux increased in cells expressing ABCG5/ABCG8. Furthermore, the biliary vitamin K
concentration in Abcg5/Abcg8-deficient mice was lower than that in wild-type mice, although serum vitamin K
levels were not affected by the presence of Abcg5/Abcg8. These findings suggest that ABCG5 and ABCG8 are involved in the transport of sterols and vitamin K. ABCG5/ABCG8 and NPC1L1 might play important roles in the regulation of vitamin K absorption and excretion.
Background
Peripheral sensory neurotoxicity is a frequent adverse effect of oxaliplatin therapy. Calcium and magnesium (Ca/Mg) infusions are frequently used as preventatives, but a recent phase III ...trial failed to show that they prevent neurotoxicity. We therefore conducted a multicenter randomized phase III trial to compare fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) with and without
Goshajinkigan
(GJG), a traditional Japanese herbal medicine (Kampo), to determine GJG’s potential for reducing peripheral neuropathy in patients with colorectal cancer.
Methods
Patients with colon cancer who were undergoing adjuvant therapy with infusional mFOLFOX6 were randomly assigned to GJG (7.5 mg three times daily) or placebo in a double-blind manner. The primary endpoint was the time to grade 2 or greater neuropathy, which was determined at any point during or after oxaliplatin-based therapy using version 3 of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).
Findings
An interim analysis was performed when 142 of the planned 310 patients had been enrolled and the safety assessment committee recommended that the study be discontinued. One hundred eighty-two patients were evaluable for response. They included 89 patients in the GJG group and 93 patients in the placebo group. The incidence of grade 2 or greater neurotoxicity was 50.6 % in the GJG group and 31.2 % in the placebo group. A Cox proportional hazards analysis indicated that the use of GJG was significantly associated with the incidence of neuropathy (hazard ratio, 1.908;
p
= 0.007).
Conclusion
Goshajinkigan
did not prevent oxaliplatin-associated peripheral neuropathy in this clinical trial. The clinical study was therefore terminated.
The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus ...leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors.
We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm.
Overall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% 77.9%-83.4%) than in NR-Group S (74.0% 69.3%-78.0%) (hazard ratio, 0.64 0.50-0.83; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW.
Adjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes.
Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783 , date of registration: 18/04/2012).
Dietary oxysterols are believed to be associated with the progression of non-alcoholic fatty liver disease (NAFLD). However, the molecular basis of the association between dietary oxysterols and ...NAFLD is poorly understood. We hypothesized that hepatic Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol re-absorber from bile to the liver, would regulate hepatic oxysterol levels and affects NAFLD progression.
Considering the species differences in hepatic NPC1L1 expression, we used liver-specific NPC1L1 transgenic (NPC1L1Tg) mice as a human model and demonstrated that oxysterol-rich heated cholesterol exacerbated high-fat diet-induced steatosis, an early stage of NAFLD, in a hepatic NPC1L1-dependent manner. Analyses of hepatic and biliary oxysterol levels in NPC1L1Tg mice and in vitro oxysterol uptake assays with NPC1L1-overexpressing cells revealed that NPC1L1 can uptake some, but not all, oxysterols and suppress their biliary excretion. Furthermore, in vitro and in vivo analyses revealed that 22(R)-hydroxycholesterol (22R-OHC) and 25-hydroxycholesterol (25-OHC), which are NPC1L1 substrates, were primarily involved in steatosis progression, via the activation of liver X receptor α and retinoid-related orphan receptor γ, respectively. Consistent with these results, examination of clinical specimens revealed that among the 14 major oxysterols analyzed, plasma concentrations of 22R-OHC and 25-OHC were significantly positively correlated with hepatic fat accumulation in humans.
Among the major dietary oxysterols, 22R-OHC and 25-OHC are particularly potent in promoting the progression of hepatic steatosis in a hepatic NPC1L1-dependent manner.
Display omitted
•Hepatic NPC1L1 exacerbates oxysterol-rich heated cholesterol-induced steatosis.•NPC1L1 uptakes some, but not all, oxysterols and inhibits their biliary excretion.•22R- and 25-hydroxycholesterol (OHC) are involved in the steatosis progression.•Plasma 22R- and 25-OHC levels positively correlate with liver fat mass in humans.
Purpose
Adjuvant FOLFOX therapy is an established standard-of-care for resected colon cancer. Peripheral sensory neuropathy (PSN) is regarded as the major toxicity issue related to FOLFOX therapy. ...There have been a few reports on the recovery status from PSN thereafter. JOIN trial investigated the tolerability and efficacy of adjuvant modified FOLFOX6 (mFOLFOX6) in Japanese patients with stage II/III colon cancer.
Methods
Twelve cycles of mFOLFOX6 were given to patients with stage II/III curatively resected colon cancer. Treatment outcomes, including disease-free survival (DFS), relapse-free survival (RFS), overall survival (OS), and recovery status of PSN during 3-year follow-up, were investigated.
Results
Of the 882 patients enrolled from 2010 to 2012, 864 were eligible for the efficacy analyses. Three-year DFS, RFS, and OS were favorable in 92.1, 92.8, and 97.4% of stage II patients; 76.4, 77.9, and 93.8% of stage IIIA/B; and 61.6, 62.7, and 85.9% of stage IIIC, respectively. The cumulative incidence of PSN during treatment was 47.8% in grade 1 (G1), 30.3% in G2, and 5.8% in G3. For those with G3 PSN during treatment, there was gradual recovery in 1.1% of patients at 12 months after enrollment, 0.5% at 24 months, and 0.2% at 36 months. However, G1 or G2 residual PSN after 3 years was observed in 21.0% (18.7%, G1; 2.3%, G2).
Conclusions
Adjuvant mFOLFOX6 therapy was effective and well tolerated in patients with stage II/III colon cancer. Most patients recovered from G3 PSN related to oxaliplatin, but approximately 20% of patients had G1 or G2 PSN at 3-year follow-up.
Objectives: In recent years, CapeOX therapy for patients with colorectal cancer is widely used. We previously reported that a multidisciplinary approach decreases the worsening of adverse events and ...increases patient satisfaction. In this study, we conducted a multicenter, prospective, observational study to evaluate the incidence of adverse events, health-related quality of life (HRQOL) of the patient, and efficacy of a management (intervention) according to the support system (SMILE study).Methods: As the interventional method, the following more than one method was carried out in each institute, 1: support with telephone, 2: dosing instruction by a pharmacist, 3: skin care instruction by a nurse, and 4: patient instruction by a doctor. The primary endpoint was the incidence of hand-foot syndrome (HFS) of more than grade 2. The secondary endpoint was the HRQOL evaluation and efficacy. The questionnaire (HADS) was administered before the start of the chemotherapy and in 1, 2, 4, 5, and 8 courses to evaluate quality of life (QOL).Results: From April 2011 to September 2012, 80 patients were enrolled from 14 sites, and all patients were the subjects of analysis. The demographic background was as follows: man/woman: 46/34, age median: 63 (36-75), and management interventional method 1/2/3/4: 36/68/73/78. The overall percentage of HFS that exceeded grade 2 within 6 months was 16.3%. It was 11.1% with the telephone support group and 20.5% without the telephone support group (p = 0.26).Conclusions: A multi-professional telephone support may reduce the deterioration of HFS. Further study which includes larger cohort is needed in the future.
Abstract Background When a rectal cancer is located at less than 4 cm from the anal verge, abdominoperineal resection (APR) is generally performed. If an ideal surgery that could replace APR were to ...be developed, it could contribute to anal preservation in patients with very low rectal cancer. The aim of this study was to investigate oncologically whether intersphincteric resection (ISR) could replace APR for a very low rectal cancer. Methods Between 2001 and 2011, ISR was curatively performed in 124 patients with a very low rectal cancer who might otherwise have been treated with APR. No patient received preoperative chemoradiotherapy. The median duration of follow-up was 65 months (range 14–122 months). Local recurrence was defined as only intra-pelvic recurrences including lateral lymph node metastasis. The survival rate was calculated using the Kaplan–Meier method. Results Postoperative morbidity including anastomotic leakage (5.6%) was 12%. There was no in-hospital mortality. In those patients with Stages I, II, and III disease, the local recurrence rate was 4.7%, 4.9%, and 5.0%, respectively. The recurrence-free 5-year survival rates were 92.2% (95% CI: 84–100%), 81.9% (95% CI: 70–94%) and 69.6% (95% CI: 53–87%) at each stage, respectively. The cancer-specific 5-year survival rates were 90.5% (95% CI: 81–100%), 91.0% (95% CI: 82–100%), and 83.6% (95% CI: 70–97%) at each stage, respectively. The overall recurrence-free survival and local recurrence rates after ISR were similar to those after APR. Conclusions The ISR procedure appears to be oncologically acceptable, replacing APR in selected patients. Accumulated experience supports this practice worldwide in future.
Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly ...inhibit normal cell growth. Antineoplastons contain 3-phenylacetylamino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, non- blinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver.
Sixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity.
Overall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the stomach and phlebitis. No serious toxicity, including bone marrow suppression, liver or renal dysfunction, were found in the AN arm.
Antineoplastons (A10 Injection and AS2-1) might be useful as adjunctive therapy in addition to HAI after hepatectomy in colorectal metastases to the liver.
ClinicalTrials.gov UMIN000012099.
No cases of late recurrence of colorectal cancer liver metastasis (CRLM) over 10 years have been reported in the literature. A 72-year-old woman had a surgical history of sigmoid colectomy and ...partial hepatic resections for sigmoid colon cancer and multiple liver metastases 15 years previously. The patient had been postoperatively treated with chemotherapy for 6 months and was observed regularly with no recurrence. Computed tomography (CT) performed due to high carcinoembryonic antigen (CEA) revealed a tumor of 70 mm in diameter at the anterior segment of the liver and a 6-mm nodule at the left lateral segment. There was no other malignant finding. We performed central bisegmentectomy and partial resection of the liver. Pathological findings showed the tumors to be well to moderately differentiated adenocarcinoma, and positive cytokeratin 20 (CK20) and caudal-type homeobox transcription factor 2 (CDX2) expression with negative expression of cytokeratin 7 (CK7). In addition, the tumors showed cluster of differentiation 44 (CD44) and 133 (CD133) positive signified cancer stem cell immunohistochemically. The postoperative diagnosis was recurrence of hepatic metastasis of sigmoid colon cancer. We report a rare case of late recurrence of CRLM more than 15 years after the primary diagnosis.
Background
Combination chemotherapy with S-1 and irinotecan is one of the standard treatments for metastatic colorectal cancer (mCRC) in Japan. However, there are few alternative practical ...second-line therapies. We conducted a phase II trial to evaluate the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab as a second-line treatment for oxaliplatin-refractory mCRC.
Methods
Patients with mCRC who were previously treated with oxaliplatin-containing regimens were enrolled. Oral S-1 at a dose of 80 mg/m
2
was administered twice daily for 2 weeks, followed by a 1-week drug-free interval. Irinotecan at a dose of 150 mg/m
2
and bevacizumab at a dose of 7.5 mg/kg were administered on day 1. The primary endpoint was progression-free survival (PFS).
Results
Thirty-seven patients were enrolled, and 34 and 36 patients were assessed for response and safety, respectively. The overall response rate was 20.6 % (95 % confidence interval CI 8.7–37.9), and the disease control rate was 76.5 % (95 % CI 58.8–89.3). The median PFS was 5.6 months (95 % CI 3.8–7.0). The median overall survival was 16.4 months (95 % CI 8.1–20.0). The most common grade 3/4 adverse events included neutropenia (25.0 %), anorexia (22.2 %), anemia (16.7 %), and fatigue/malaise (16.7 %). The most common grade 3/4 adverse event of special interest for bevacizumab was hypertension (30.6 %). One treatment-related death caused by gastrointestinal bleeding occurred.
Conclusions
The findings suggest that the combination of S-1 and irinotecan plus bevacizumab is effective and tolerable as second-line chemotherapy for patients with oxaliplatin-refractory mCRC.
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