Phase 1/2 study of concurrent chemoradiotherapy with weekly irinotecan hydrochloride for advanced/recurrence uterine cancer: A multi-institutional study of Kansai Clinical Oncology Group.

OBJECTIVE: Concurrent chemoradiotherapy using cisplatin was thought to be standard treatment for squamous cell carcinoma of cervix, but it had not been effective for adenocarcinoma. Concurrent chemoradiotherapy using irinotecan hydrochloride (CPT-11) had been effective for colorectal cancer, thus, we chose CPT-11 as a candidate for gynecologic adenocarcinoma. To evaluate the maximum tolerated dose (MTD) of weekly CPT-11 with external pelvic radiotherapy, a phase 1/2 study was conducted according to modified Fibonacci method. METHODS: Eligible patients were advanced uterine cancer with measurable diseases [performance score (PS): 0-2]. Study period was from August 1st, 2002 to December 31st, 2008. The starting dose level (DL) of CPT-11 was 30 mg/m2 (DL1) given weekly for 4 weeks. Subsequently, dose escalation was scheduled in 10 mg/m2 increments to 60 mg/m2 (DL4). The fixed radiotherapy consisted of whole pelvic 1.8 Gy/d, once a day in weekday for five weeks and it amounted to 45 Gy (25 fractions) in total. RESULTS: Seventeen patients were enrolled. As for toxicities, one (1/17: 5.9%) grade (G) 4 neutropenia lasting 7 days had been seen in DL4. G2 diarrhea was identified in 35.3% (6/17) of the patients, and 11.8% (2/17) G3 diarrhea was observed in DL3 and DL4. Thus, the MTD of CPT-11 was defined as dose of 60 mg/m2. The recommended dose was decided as 50 mg/m2. The response rate was 88.2% [9 complete response (CR), 3 partial response (PR), 3 stable disease (SD), 2 not evaluable (NE)]. Disease control rate at 1 month after treatment completion was 100% but distant metastases were found in 24% (4/17) in longer outcome. CONCLUSIONS: MTD was 60 mg/m2 and recommended dose was set as 50 mg/m2. This concurrent chemoradiation using weekly CPT-11 was feasible at 50 mg/m2, and it might be effective even in adenocarcinoma of the uterus.

Diverse genome-wide DNA methylation alterations in canine hepatocellular tumours.

BACKGROUND: Canine hepatocellular tumours (HCTs) are common primary liver tumours. However, the exact mechanisms of tumourigenesis remain unclear. Although some genetic mutations have been reported, DNA methylation alterations in canine HCT have not been well studied. OBJECTIVES: In this study, we aimed to analyse the DNA methylation status of canine HCT. METHODS: Tissues from 33 hepatocellular carcinomas, 3 hepatocellular adenomas, 1 nodular hyperplasia, 21 non-tumour livers from the patients and normal livers from 5 healthy dogs were used. We analysed the DNA methylation levels of 72,367 cytosine-guanine dinucleotides (CpG sites) in all 63 samples. RESULTS AND CONCLUSIONS: Although a large fraction of CpG sites that were highly methylated in the normal liver became hypomethylated in tumours from most patients, we also found some patients with less remarkable change or no change in DNA methylation. Hierarchical clustering analysis revealed that 32 of 37 tumour samples differed from normal livers, although the remaining 5 tumour livers fell into the same cluster as normal livers. In addition, the number of hypermethylated genes in tumour livers varied among tumour cases, suggesting various DNA methylation patterns in different tumour groups. However, patient and clinical parameters, such as age, were not associated with DNA methylation status. In conclusion, we found that HCTs undergo aberrant and diverse patterns of genome-wide DNA methylation compared with normal liver tissue, suggesting a complex epigenetic mechanism in canine HCT.

Unusual bilateral ureter strangulation by fibrous tissue after perineal hernia repair in a dog.

A 10-year-old castrated male cross-breed dog was referred for the repair of perineal hernia with bladder retroflexion and a mass lesion in the hernial sac. Surgical treatment was performed and the mass was identified as degenerated adipose tissue that was suspected to be derived from the omentum. The hernial contents were reduced without difficulty, and the dog exhibited a normal recovery. Two days after surgery, the dog suddenly exhibited anorexia and azotemia. Exploratory laparotomy was performed, which showed the dilation of both ureters with discoloration of the bladder serosa and strangulation of the urinary bladder neck. Careful inspection confirmed that a fibrous band, which was connected to the mass-like degenerated adipose tissue, had caused the strangulation. Two days after removal of these tissues, the dog recovered, with normal findings on blood biochemical analysis. The condition described in this report is an uncommon complication of perineal hernia repair. The findings suggest that degenerative fat tissue should be resected during perineal hernia repair in dogs, in order to prevent possible bladder strangulation after surgery.

Implication of maternal nitrogen balance in the regulation of circulating levels of insulin-like growth factor-I in human pregnancy.

Nutrition plays an important role in regulating the circulating levels of insulin-like growth factor-I (IGF-I). We have demonstrated that reduced nitrogen balance is related to changes in serum IGF-I levels but not serum growth hormone levels in pregnant rats. In the present study, we investigated the effects of changes in nitrogen balance on serum IGF-I levels in normal and malnourished pregnant women (defined as having negative nitrogen balance). Forty-eight pregnant women (threatened miscarriage and premature labor, 39; pre-eclampsia, 3; hyperemesis, 3; ileus, 2; bleeding from the colon, 1) and 19 non-pregnant women admitted in Kobe University Hospital were enrolled in this study. Blood samples of normal pregnant controls were also obtained from 172 healthy pregnant women attending the outpatient clinic. Serum IGF-I levels and nitrogen balance were measured serially in 9 pregnant women with threatened miscarriage and premature labor and 9 malnourished pregnant women out of 48 pregnant women. Serum IGF-I and urinary nitrogen levels were measured by radioimmunoassay with acid-ethanol extraction and the Dumas method, respectively. Nitrogen balance was expressed as the difference between daily nitrogen intake and nitrogen excretion assessed by urinary nitrogen levels. Serum IGF-I levels in normal pregnant controls significantly increased in the third trimester of pregnancy compared with non-pregnant controls. No difference in serum IGF-I levels in any trimester of pregnancy was observed between normal pregnant controls and pregnant women with threatened miscarriage and premature labor. There was no significant difference in nitrogen balance between the pregnant women with threatened miscarriage and premature labor and non-pregnant controls. In the longitudinal study, no correlation was found between the changes in serum IGF-I levels and those in nitrogen balance in the 9 pregnant women with threatened premature labor (daily nitrogen balance > 0 g/day) on the basis of linear regression analysis. On the other hand, the changes in serum IGF-I levels in the 9 malnourished pregnant women were significantly correlated with those in nitrogen balance (y = 1.72x + 17.5; r = 0.60; P < 0.05: linear regression analysis). These results indicate that maternal nutritional states have a major effect on serum IGF-I levels in malnourished pregnant women, but not in pregnant women with daily nitrogen balance > 0 g/day. Serum IGF-I levels can be a potent index of nutritional states under malnutrition during human pregnancy.