Prospective observational study of the efficacy of oral uracil and tegafur plus leucovorin for stage II colon cancer with risk factors for recurrence using propensity score matching (JFMC46-1201).

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783 , date of registration: 18/04/2012).

Changeability of the fully methylated status of the 15q11.2 region in induced pluripotent stem cells derived from a patient with Prader-Willi syndrome.

Prader-Will syndrome (PWS) is characterized by hyperphagia, growth hormone deficiency and central hypogonadism caused by the dysfunction of the hypothalamus. Patients with PWS present with methylation abnormalities of the PWS-imprinting control region in chromosome 15q11.2, subject to parent-of-origin-specific methylation and controlling the parent-of-origin-specific expression of other paternally expressed genes flanking the region. In theory, the reversal of hypermethylation in the hypothalamic cells could be a promising strategy for the treatment of PWS patients, since cardinal symptoms of PWS patients are correlated with dysfunction of the hypothalamus. The genome-wide methylation status dramatically changes during the reprograming of somatic cells into induced pluripotent stem cells (iPSCs) and during the in vitro culture of iPSCs. Here, we tested the methylation status of the chromosome 15q11.2 region in iPSCs from a PWS patient using pyrosequencing and a more detailed method of genome-wide DNA methylation profiling to reveal whether iPSCs with a partially unmethylated status for the chromosome 15q11.2 region exhibit global methylation aberrations. As a result, we were able to show that a fully methylated status for chromosome 15q11.2 in a PWS patient could be reversed to a partially unmethylated status in at least some of the PWS-iPSC lines. Genome-wide DNA methylation profiling revealed that the partial unmethylation occurred at differentially methylated regions located in chromosome 15q11.2, but not at other differentially methylated regions associated with genome imprinting. The present data potentially opens a door to cell-based therapy for PWS patients and, possibly, patients with other disorders associated with genomic imprinting.

Treatment Rationale and Study Design for Clinical Trial on the Efficacy of UFT/LV for Stage II Colorectal Cancer With Risk Factors for Recurrence (JFMC46-1201).

BACKGROUND: The usefulness of adjuvant chemotherapy for stage II colon cancer has not been established. Meanwhile, the presence of stage II colon cancer with high-risk factors for recurrence has been reported. To our knowledge, no prospective study of adjuvant chemotherapy for stage II colon cancer with high-risk factors has been implemented to date. PATIENTS AND METHODS: This study is a prospective nonrandomized controlled study based on patients' selection of treatment option, including randomized therapeutic decision-making, to evaluate the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) with leucovorin (LV) for stage II colon cancer with high-risk factors for recurrence, compared with surgery alone. Five courses of UFT/LV therapy will be given as follows: UFT (300 mg/m(2)/d) with LV (75 mg/d) will be orally administered in 3 doses per day. Treatment will be received daily for 28 days, followed by a 7-day rest or will be received daily for 5 days, followed by a 2-day rest. For both regimens, 1 course will last 5 weeks, and 5 courses will be given. The primary end point is disease-free survival. A propensity score matching will be conducted based on 7 variables that represent risk factors to minimize selection bias in a comparison between the nonrandomized arms. For this nonrandomized comparison, a target sample size is set at 1200 (400 and 800 patients for the surgery alone and UFT/LV groups, respectively) and 1720 patients will be enrolled. In this study we aim to evaluate the therapeutic usefulness of adjuvant chemotherapy with UFT/LV for stage II colorectal cancer with risk factors for recurrence.

Safety and efficacy of linezolid in 16 infants and children in Japan.

Linezolid, an oxazolidinone antibiotic, exhibits a broad spectrum of activity against Gram-positive bacteria. It has been licensed for adult use in Japan since 2006 for MRSA infections, and has also been used off-label for pediatric patients. At our university hospital, a total of 16 infants and children (including one non-Japanese Asian) were administered linezolid owing to infection with multidrug-resistant Gram-positive bacteria, after consent had been provided. All patients had severe underlying diseases or indications for surgery. Eighty-eight percent of the causal microorganisms were methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant coagulase-negative Staphylococcus and all were sensitive to linezolid. Linezolid was administered because the antecedent anti-MRSA medications were ineffective or contraindicated, or intravenous-to-oral switch therapy was requested owing to cardiac or orthopedic surgical-site infections. The median duration of administration was 13 days (range 3-31 days). The overall efficacy was 91 % (10/11) in those for whom efficacy could be evaluated. Only two patients (both teen-aged) encountered linezolid-related adverse effects (13 %, 2/16). One patient showed elevation of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), requiring that administration be withdrawn, but enzyme levels returned to normal after the patient had been switched to vancomycin. The other patient showed transiently decreased platelet counts. Linezolid is considered generally safe and effective for children in Japan, especially for those who cannot use other anti-MRSA medications or those who require oral antibiotics for infections with multidrug-resistant Gram-positive bacteria.

Strategy for synchronous and multiple liver metastasis.

BACKGROUND/AIMS: Surgical indications for resection of synchronous metastasis from colorectal cancer (CRC) and the optimal timing of hepatectomy are still controversial and widely debated. METHODOLOGY: Synchronous and multiple metastatic liver tumors were detected in 57 patients since May 2005. Our treatment policy was to perform hepatectomy if the resection could be done with no limit on size and number of tumors. However, if curative resection could not be done, chemotherapy was begun and timing for the possibility of a radical operation was planned immediately. RESULTS: In 37 patients whose tumors were located only in the liver, primary tumor resection was performed in 16 patients and after tumor-decreasing by chemotherapy, in 7 patients. In 20 patients in whom chemotherapy was performed first, after controlling the distant metastasis, hepatectomy was performed in 3 patients and staged hepatectomy was performed in 10. Recurrence was detected after hepatectomy in 75.0% of simultaneous resection cases and in 70.0% of staged cases. In the recurrence cases, early detection after tumor resection occurred in 58.3% of the simultaneous and 14.2% of the staged. CONCLUSIONS: The present data show that neoadjuvant chemotherapy does not increase the risk of postoperative complications or the surgical difficulties of hepatectomy for colorectal metastases.

[The 9th international conference of the asian clinical oncology society in Japan after a twenty year interval--what is the standpoint of Japan in Asia ?].

The 9th International Conference of the Asia Clinical Oncology Society(ACOS)was held at Gifu Grand Hotel, Gifu Japan on August 25, 26, and 27 2010. The Society was established in Osaka, Japan, in October 1991. Meeting have been held every two years, starting in Osaka, and then to Bangkok, Kunming, Bali, Taipei, Seoul, Beijing, Manila, and now to Gifu. There was a twenty year interval in Japan between meetings in Osaka and Gifu. The main theme of the 9th ACOS was titled "Talk to the Worldwide from Asia," and the sub-theme was titled "Multidisciplinary Treatment for Asian Cancer Patients "For this 9th ACOS, we gathered 42 councilors from Asian countries to serve on the ACOS committee and 365 doctors from Japan to serve on a local organizing committee. For congress program, we scheduled 161 special sessions for the president's lectures, key note lectures, special lectures, educational lectures, symposium, workshop, luncheon seminars, etc. We received about 500 abstracts for oral or poster presentations; among them, 140 abstracts came from Asian countries. As for speakers, 475 were from Japan, 85 from Korea, 34 from Taiwan, 27 from China, over 10 from India, Indonesia, Viet Nam, USA, and other countries. Finally a total of 704 speakers were gathered from 20 countries(from the outside Asia; UK, France, Germany, and Australia). The total number of registered investigators was 1, 136, and the total number of participants, including our congress staffs, volunteers, neighborhood doctors, Gifu citizens, patients, etc., was over 1, 500. In this 9th ACOS we discussed some new ideas, such as Asian cancer statistics, mission, vision and core values of ACOS, new anti-cancer drugs developed from Japan(TS-1 and Xeloda), Inter group clinical trials among Asian countries, less invasive surgery using endoscopic assisted operation, Asian traditional medicine, open workshops with citizens, etc. Moreover, we published a commemorative book entitled" Recent Advances of Cancer in Asian Countries.