Background
This study was designed to evaluate the efficacy and safety of XELOX plus bevacizumab in a Japanese metastatic colorectal cancer population that included elderly patients.
Methods
This was ...a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated metastatic colorectal cancer, presence of measurable lesions, age ≥20 years; Eastern Cooperative Oncology Group performance status of 0–2, and adequate organ function. Patients received bevacizumab (7.5 mg/kg on day 1) and XELOX (130 mg/m
2
oxaliplatin on day 1 plus 1,000 mg/m
2
capecitabine b.i.d. on days 1–14) every 3 weeks. The primary endpoint was confirmed objective response rate.
Results
The study included 47 patients (male/female 30/17; median age 69 years; age range 38–81 years with 10 patients ≥75 years; 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 52.2 % (95 % confidence interval CI 37.0–67.1). The median progression-free survival and overall survival were 10.0 months (95 % CI 7.8–12.3) and 34.6 months (95 % CI 19.9–not estimable), respectively. Frequently encountered grade 3 and 4 adverse events in this study were aspartate aminotransferase elevation (23.4 %), alanine aminotransferase elevation (21.3 %), anorexia (12.8 %), neutropenia (10.6 %), fatigue (8.5 %) and anemia (6.4 %). Grade 3 or 4 peripheral neuropathy was not observed.
Conclusion
First-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.
Registry
UMIN-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
Introduction
Single‐incision laparoscopic cholecystectomy (SILC) is increasingly applied for cholecystectomy and has been reported as safe and feasible, with short‐term operative outcomes equivalent ...to four‐port cholecystectomy. Although many investigators in randomized studies have noted the cosmetic advantages of SILC, the benefit of decreased pain in SILC remains controversial. Therefore, this study aimed to assess the efficacy of the rectus sheath block in SILC with respect to subjective pain.
Methods
From April 2010 to March 2012, 75 patients with symptomatic gallstone or gallbladder polyps were assigned to one of three groups: (i) four‐port laparoscopic cholecystectomy (n = 29); (ii) SILC (n = 15); and (iii) rectus sheath block in SILC (n = 30). We evaluated the operative details, length of hospital stay, and the need and usage of analgesia. Postoperative pain was recorded at 2, 6, 12, and 24 h after surgery based on a visual analog scale.
Results
There was no difference with regard to age, ASA score, BMI, duration of operation, or length of hospital stay among the three groups. A significantly lower pain score was observed in the rectus sheath block in SILC group than in the SILC group at 2 and 6 h after operation. The pain score and need for analgesia were similar between the SILC group and the four‐port cholecystectomy group.
Conclusion
SILC using an ultrasound‐guided rectus sheath block significantly reduces postoperative pain.
Background
A prospective feasibility study was planned to clarify the proportion of compliance and adverse events in the administration of capecitabine as adjuvant chemotherapy for colon cancer in ...Japanese patients.
Methods
We aimed initially to register 92 cases of R0 stage III colon cancer. Capecitabine (2,500 mg/m
2
/day) was given orally on days 1–14 every 3 weeks for 8 cycles. The proportion of treatments completed as planned was selected as the primary endpoint.
Results
Ninety-seven cases were registered and treated between September 2008 and August 2009. The proportion of treatments completed in the full analysis set was 64/97 66.0%; 95% confidence interval (CI), 55.7–75.3% and in the per protocol set was 64/91 (70.3%; 95% CI, 59.8–79.5%). Adverse events which led to treatment discontinuation included hand–foot syndrome (HFS) (7), haematotoxicity (5) and increased hepatic damage (4). The proportions of patients with major grade 3/4 adverse events were HFS 22.7%, neutropenia 7.2%, diarrhoea 2.1%, and increased bilirubin 0.0%.
Conclusions
This collaborative multi-facility study, the first of its kind in Japan, presented results of a safety confirmation experiment on capecitabine as adjuvant chemotherapy for stage III colon cancer. The results suggest that capecitabine may be administered safely to Japanese patients.
The aim of this study was to clarify the molecular mechanisms of the sequence-dependent antitumor activity of SN-38 and 5-fluorouracil (5-FU) against colon cancer cells.
KM12SM and HCT116 colon ...cancer cells were exposed to 5-FU and/or SN-38 in various conditions. The nature of interactions was determined by median-effect analysis. Cell cycle, apoptosis, and expression of thymidylate synthase (TS) were analyzed.
A strong synergism was observed after initial sequential exposure of SN-38, and the activity was enhanced by a 24 h-interval to the drug-exposure. Antagonism was observed after low-dosage initial sequential exposure of 5-FU. Low-dosage 5-FU caused G(2) arrest and high-dosage 5-FU caused G(1) arrest. TS protein level significantly decreased after exposure to SN-38.
The sequence dependency between SN-38 and 5-FU against colon cancer cells may be related to the dual action on cell cycle regulation by 5-FU and to the down-regulation of TS level by SN-38.
Objective Invasive micropapillary carcinoma of the breast is a distinct variant of breast cancer. In the present study, we analyzed potential immunophenotypic changes in invasive micropapillary ...carcinoma. Methods Specimens from 15 patients with invasive micropapillary carcinoma were analyzed using clinicopathological and immunohistochemical methods. We also examined the relationship between clinicopathological factors using the Ki-67 labeling index. Results Immunohistochemical staining for cytoplasmic p63 expression was seen in four (27%) tumors, and p63 nuclear expression was also observed in four (27%) tumors. Involucrin and 34betaE12 were expressed in the invasive micropapillary carcinoma component of nine (60%) and four (27%) tumors, respectively. Cytokeratin 5/6 was expressed in three (20%) tumors and cytokeratin 14 staining was negative in all tumors. In one tumor (case 3), vimentin, epithelial membrane antigen and cytokeratin 8/18 were co-expressed. Four tumors (27%) were negative for the estrogen receptor/progesterone receptor/HER2. However, 11 out of 15 (73%) tumors were positive for the estrogen receptor. The Ki-67 labeling index was significantly higher in cases with p63 tumor expression than in those without (P < 0.0001), and also higher in cases with lymph node metastasis than in cases without (P = 0.0029). Conclusions Nuclear expression of p63, involucrin and 34betaE12 were detected indicating squamous differentiation. Cytoplasmic p63 expression was also identified. The fact that the Ki-67 labeling index was significantly higher in such cases may have been associated with the aggressive behavior of these tumors. Our findings suggest that the characteristic morphology of invasive micropapillary carcinomas may be due to immunophenotypical and oncogenic changes.
Objectives
The purpose of this phase II study was to explore the efficacy and safety of an alternating regimen consisting of folinic acid, 5-fluorouracil (5-FU) and oxaliplatin (mFOLFOX6) plus ...bevacizumab, and folinic acid, 5-FU and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer.
Methods
Fifty-two patients with metastatic colorectal cancer received an alternating regimen consisting of four cycles of mFOLFOX6 plus bevacizumab followed by four cycles of FOLFIRI plus bevacizumab until disease progression. The primary endpoint was progression-free survival.
Results
The median age was 60 years (range 37–75 years). Median progression-free survival was 14.2 months (95 % confidence interval CI 10.6–16.3) and median overall survival was 28.4 months (95 % CI 22.6–39.1). The overall response rate was 60.0 % (95 % CI 45.2–73.6). Regarding toxicity, the commonest grade 3–4 hematological adverse events were neutropenia (34.6 %) and leukopenia (7.7 %), and the commonest grade 3–4 non-hematological adverse events were anorexia (13.5 %), fatigue (9.6 %), nausea (9.6 %), and vomiting (9.6 %). Bevacizumab-related grade 3–4 adverse events included hypertension (1.9 %) and thrombosis (1.9 %).
Conclusions
An alternating regimen consisting of mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab is an effective and well-tolerated first-line chemotherapy combination for patients with metastatic colorectal cancer.
Although post-operative adjuvant chemotherapy (ACT) is only recommended for patients with stage II colon cancer who are at a high risk of recurrence, the definition of high risk remains unclear. The ...present study aimed to identify the risk factors for recurrence, which may also be indicators for adjuvant therapy, using a retrospective analysis of clinicopathological data obtained from stage II colon cancer patients who had undergone a curative resection. The present study also investigated the effects of ACT in patients who displayed the risk factors for recurrence. Univariate and multivariate analyses of the data collected from 377 stage II colon cancer patients, treated at Kurume University Hospital (Fukuoka, Japan) between 1982 and 2005, was conducted in order to determine and compare the risk factors for recurrence between the 163 patients who had undergone adjuvant therapy and the 214 patients who had not undergone adjuvant therapy. The risk factors for recurrence in patients who had not undergone adjuvant therapy were a serum carcinoembryonic antigen (CEA) level that was twice the cut-off value and pre-operative bowel obstruction. Adjuvant therapy provided no benefit to patients who presented with neither risk factor, but significantly decreased the recurrence rate in patients presenting with one or both risk factors. Based on these findings, serum CEA levels of twice the cut-off value and pre-operative bowel obstruction were proposed as indicators in the assessment for adjuvant chemotherapy following a curative resection for stage II colon cancer. These results warrant further clinical study of ACT in patients with one or both risk factors.
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.
Forty-eight patients ...were enrolled in this study. Patients received an alternating regimen of 4 cycles of mFOLFOX6 followed by 4 cycles of FOLFIRI.
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%).
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.
The precursor of matrix metalloproteinase 9 (proMMP-9, progelatinase B) noncovalently binds to tissue inhibitor of metalloproteinases (TIMP)-1 through the C-terminal domain of each molecule. We have ...isolated the proMMP-9•TIMP-1 complex from the medium of human fibrosarcoma HT-1080 cells and investigated the activation processes of the complex by 4-aminophenylmercuric acetate, trypsin, and matrix metalloproteinase 3 (MMP-3, stromelysin 1). The treatment of the proMMP-9•TIMP-1 complex with 4-aminophenylmercuric acetate or trypsin converts proMMP-9 to lower molecular weight species corresponding to active forms, but no gelatinolytic activity is detected. The lack of enzymic activity results from binding of TIMP-1 to the activated MMP-9. The treatment of the proMMP-9•TIMP-1 complex with a possible physiological proMMP-9 activator, MMP-3, does not reveal any gelatinolytic activity unless the molar ratio of MMP-3 to the complex exceeds 1. This is due to the inhibition of MMP-3 by TIMP-1 forming a ternary proMMP-9•TIMP-1•MMP-3 complex. The formation of the ternary complex weakens the interaction between proMMP-9 and TIMP-1, resulting in partial dissociation of the complex into proMMP-9 and the TIMP-1•MMP-3 complex. When MMP-3 is in excess, the propeptide is completely processed, and the full activity of MMP-9 is detected. Similarly, the proMMP-9•TIMP-1 complex inhibits MMP-1 (interstitial collagenase) and in turn renders the proMMP-9 activable by a catalytic amount of MMP-3. These results suggest that formation of the proMMP-9•TIMP-1 complex regulates extracellular matrix breakdown in tissue by switching the predominant MMP activity from one type to another.
PDF
