Takaho Tanaka

Changes of membrane fluidity and Na+, K+-ATPase activity during cellular differentiation in the guinea pig epidermis

SummaryThe dynamic properties of plasma membrane in epidermal cells were determined by means of electron spin resonance using two kinds of doxyl stearic acid spin labeling agents: 5-DSA and 12-DSA. 5-DSA and 12-DSA are stearic acid analogues with a nitroxide radical ring at the 5th and 12th carbon positions, and these motions reflect molecular motion of lipid bilayer surrounding the hydrophilic region and the hydrophobic region, respectively. Guinea pig epidermal cells were separated into three regions of keratinocytes by Percoll density gradient centrifugation; the upper, middle, and lower epidermal cells. The order parameter S values for 5-DSA and 12-DSA incorporated into the isolated keratinocytes increased, suggesting a decrease in the plasma membrane fluidity, as cells approached the upper epidermal cell layer. The Na+, K+-ATPase activity as a plasma membrane-bound enzyme was determined in each epidermal cell region, and was found to decrease gradually as the cells approached the upper layer. Accordingly, the differentiation of epidermal cells in the keratinization process was found to be assiciated with a decrease in plasma membrane fluidity and with a decline of Na+, K+-ATPase activity.

Multicenter Phase II Study of a New Effective S-1 and Irinotecan Combination Schedule in Patients with Unresectable Metastatic or Recurrent Colorectal Cancer

Introduction This multicenter phase II study determined the efficacy and safety of new daily oral S-1 and weekly irinotecan (CPT-11) combination schedule in patients with previously untreated advanced or recurrent colorectal cancer. Patients and Methods Patients received first-line chemotherapy comprising S-1 80 mg/m2/day given on days 3 to 7, 10 to 14, and 17 to 21 and 60 mg/m2 CPT-11 administered intravenously on days 1, 8, and 15 of a 28-day cycle. Results A total of 45 eligible patients were enrolled in this study. The overall response rate was 48.9%. Median progression-free survival and median overall survival was 8.1 months and 20.9 months, respectively. The rates of grade 3 or 4 toxicity were as follows: neutropenia, 8.9%; anemia, 4.4%; anorexia, 6.7%; and diarrhea, 6.7%. Conclusions This new S-1 and irinotecan combination schedule appeared to be an effective, well-tolerated, and convenient regimen in patients with advanced colorectal cancer as compared with conventional regimens such as FOLFIRI and IRIS.

A prospective study of XELOX plus bevacizumab as first-line therapy in Japanese patients with metastatic colorectal cancer (KSCC 0902)

BackgroundThis study was designed to evaluate the efficacy and safety of XELOX plus bevacizumab in a Japanese metastatic colorectal cancer population that included elderly patients.MethodsThis was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated metastatic colorectal cancer, presence of measurable lesions, agexa0≥20xa0years; Eastern Cooperative Oncology Group performance status of 0–2, and adequate organ function. Patients received bevacizumab (7.5xa0mg/kg on day 1) and XELOX (130xa0mg/m2 oxaliplatin on day 1 plus 1,000xa0mg/m2 capecitabine b.i.d. on days 1–14) every 3xa0weeks. The primary endpoint was confirmed objective response rate.ResultsThe study included 47 patients (male/female 30/17; median age 69xa0years; age range 38–81xa0years with 10 patientsxa0≥75xa0years; PS 0/1/2, 40/5/2) enrolled between May 2010 and March 2011. Responses were assessed in 46 eligible patients. The objective response rate was 52.2xa0% (95xa0% confidence interval [CI] 37.0–67.1). The median progression-free survival and overall survival were 10.0xa0months (95xa0% CI 7.8–12.3) and 34.6xa0months (95xa0% CI 19.9–not estimable), respectively. Frequently encountered grade 3 and 4 adverse events in this study were aspartate aminotransferase elevation (23.4xa0%), alanine aminotransferase elevation (21.3xa0%), anorexia (12.8xa0%), neutropenia (10.6xa0%), fatigue (8.5xa0%) and anemia (6.4xa0%). Grade 3 or 4 peripheral neuropathy was not observed.ConclusionFirst-line treatment with XELOX plus bevacizumab showed a promising response rate and an acceptable tolerability profile in the clinical practice of Japanese metastatic colorectal cancer patients that included elderly patients.RegistryUMIN-CTR, ID number: UMIN000003915, URL:https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000004706&language=E

Clinicopathological evaluation of anoxic mucosal injury in strangulation ileus

BackgroundIn patients with strangulation ileus, the severity of bowel ischemia is unpredictable before surgery. To consider a grading scale of anoxic damage, we evaluated the pathological findings and investigated predictive factors for bowel gangrene.MethodsWe assessed 49 patients with strangulation ileus who underwent a laparotomy between January 2004 and November 2012. Laboratory tests and the contrast computed tomography (CT) were evaluated before surgery. According to the degree of mucosal degeneration, we classified anoxic damages into the following 3 grades. Ggrade 1 shows mild mucosal degeneration with extended subepithelial space. Grade 2 shows moderate degeneration and mucosal deciduation with residual mucosa on the muscularis mucosae. Grade 3 shows severe degeneration and mucosal digestion with disintegration of lamina propria.ResultsResected bowel specimens were obtained from the 36 patients with severe ischemia, while the remaining 13 patients avoided bowel resection. The mucosal injury showed grade 1 in 11 cases, grade 2 in 10 cases, and grade 3 in 15 cases. The patients were divided into two groups. One group included grade 1 and non-resected patients (nu2009=u200924) while the other included grades 2 and 3 (nu2009=u200925). When comparing the clinical findings for these groups, elevated creatine kinase (Pu2009=u20090.017), a low base excess (Pu2009=u20090.021), and decreased bowel enhancement on the contrast CT (Pu2009=u20090.001) were associated with severe mucosal injury.ConclusionIn strangulation ileus, anoxic mucosal injury progresses gradually after rapid spreading of bowel congestion. Before surgical intervention, creatine kinase, base excess, and bowel enhancement on the contrast CT could indicate the severity of anoxic damage. These biomarkers could be the predictor for bowel resection before surgery.

Phase II trial of alternating mFOLFOX6 and FOLFIRI regimens in the first-line treatment for unresectable or metastatic colorectal cancer (KSCC0701) Kyushu study group of clinical cancer

Objective: This phase II study examined the efficacy and safety of alternating regimens of mFOLFOX6 and FOLFIRI as a first-line treatment for unresectable or metastatic colorectal cancer. Patients and Methods: Forty-eight patients were enrolled in this study. Patients received an alternating regimen of 4 cycles of mFOLFOX6 followed by 4 cycles of FOLFIRI. Results: The characteristics of the study population were as follows: males/females 34/12, median age 66 years (range 43–75) and Eastern Cooperative Oncology Group performance status 0/1/2 in 37/9/0 patients. The overall response rate was 58.7% [95% confidence interval (CI) 43.9–73.5]. The median progression-free survival was 10.3 months (95% CI 7.5–11.9), and the median overall survival was 28.4 months (95% CI 22.5–35.7). Among the 47 patients evaluated for toxicity, the most common grade 3–4 adverse events were leukopenia (26%), neutropenia (55%), anemia (4%), neurotoxicity (0%), diarrhea (2%), febrile neutropenia (4%), nausea (4%), vomiting (2%), and hypersensitivity (0%). Conclusions: The results of this phase II study indicate that this alternating schedule is effective and well tolerated as a first-line treatment for unresectable or metastatic colorectal cancer. The low rate of grade 3 neurotoxicity is also promising.

Distribution Pattern of DNA Polymerases in Epidermis

DNA polymerases are known to play important roles in DNA replication and repair processes. The present study revealed that the DNA polymerase α and β participate in the cell differentiation of normal and n‐hexadecane‐induced hyperplastic epidermis of the guinea pigs. The epidermal cells were separated into three layers; high (HDCL), middle (MDCL), and low (LDCL) density cell layer, respectively, by Percoll gradient centrifugation. In epidermal homogenate, the activity of DNA polymerase β was higher than that of DNA polymerase α. DNA polymerase α activity was higher in the HDCL than in the other layers; however, DNA polymerase β was higher in the LDCL than in the other layers. In hyperplastic epidermis, distribution of DNA polymerase α activity was similar to the normal pattern, but DNA polymerase β was lower in the LDCL than in the other layers. The distribution of DNA polymerase α activity in epidermal nuclei was similar to that of the whole epidermal cell pattern; however, DNA polymerase β activity differed from the enzyme distribution of whole epidermal cell homogenate. Its activity was higher in the HDCL than in the other layers. In hyperplastic epidermis, both nuclear DNA polymerase α and β activities were similar to the distribution patterns of polymerase activities in hyperplastic epidermal cells. From these results, it is concluded that the distribution pattern of DNA polymerases in n‐hexadecane induced‐hyperplastic epidermis is not a simple augmentation of the distribution pattern in normal epidermis.

Multicenter phase II study of combination therapy with cetuximab and S-1 in patients with KRAS exon 2 wild-type unresectable colorectal cancer previously treated with irinotecan, oxaliplatin, and fluoropyrimidines (KSCC 0901 study)

PurposeAnti-epidermal growth factor receptor antibody therapy alone or in combination with irinotecan is recognized as a standard third-line treatment for KRAS wild-type unresectable metastatic colorectal cancer. However, in some cases, it is difficult to administer irinotecan after third-line treatment. Therefore, we examined the efficacy and safety of the combination of cetuximab and S-1 in patients with KRAS wild-type unresectable metastatic colorectal cancer who were previously treated with irinotecan, oxaliplatin, and fluoropyrimidines.MethodsThe study was designed as a phase II, non-randomized, open-label, multicenter trial. Cetuximab was initially administered at 400xa0mg/m2, followed by weekly infusion at 250xa0mg/m2. S-1 was administered at a fixed dose of 80xa0mg/m2 orally twice daily for 28xa0days followed by a 14-day break, resulting in a 6-week treatment course. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), disease control rate (DCR), time to treatment failure, dose intensity, safety, and BRAF mutation status.ResultsThirty-seven patients were eligible. The median PFS was 5.5xa0months, the median OS was 13.5xa0months, the ORR was 29.7xa0%, and the DCR was 73.0xa0%. The relative dose intensity was 86.8xa0% for cetuximab and 88.1xa0% for S-1. Grade 3–4 adverse events that occurred in >10xa0% of the patient population included rash, dry skin, diarrhea, paronychia, anorexia, fatigue, mucositis, and neutropenia.ConclusionsCombination therapy with cetuximab and S-1 was effective and well tolerated in patients with irinotecan-, oxaliplatin-, and fluoropyrimidine-refractory metastatic colorectal cancer.

Phase I/II study of metronomic chemotherapy using S-1 and irinotecan in patients with advanced colorectal cancer (KSCOG CR-01)

2535 Background: The antiangiogenic efficacy of chemotherapy would seem to be optimized by administering comparatively lower dosages of drugs on a more frequent (daily, several times a week, or wee...