Utility of digital subtraction angiography-based collateral evaluation in medically treated acute symptomatic basilar artery stenosis.

BACKGROUND AND PURPOSE: Although a stroke from atherosclerosis in the basilar artery (BA) often presents with mild initial stroke severity, it has heterogeneous clinical courses. We investigated the efficacy of digital subtraction angiography (DSA)-based collateral perfusion evaluation in association with long-term outcomes of medically treated symptomatic basilar artery stenosis. METHODS: From a registry database of all consecutive patients with stroke, we included 98 medically treated patients (due to mild initial stroke severity) [National Institute of Health Stroke Scale (NIHSS) scores ≤ 4; symptomatic basilar artery stenosis, 70-99%] with available initial diagnostic DSA. Basilar collateral scoring was performed via the DSA, using a modified version of the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology grading system in both the superior cerebellar artery and anterior/posterior-inferior cerebellar artery territories (score 0-8). The outcomes were designated as the 90-day modified Rankin Scale (mRS90) score (poor, 3-6). Student's t-test, chi-square test and logistic regression analyses were used to identify factors associated with a poor outcome. RESULTS: The median initial NIHSS score was 2 [interquartile range (IQR), 0-3], median posterior circulation Alberta Stroke Program Early CT Score was 8 (IQR, 7-10), median collateral score was 7 (IQR, 7-8) and 20 (20.4%) had poor mRS90 scores. In multivariate analysis, poorer collateral scores (P = 0.003), higher NIHSS scores (P = 0.005) and lower posterior circulation Alberta Stroke Program Early CT Score (P = 0.017) were independently associated with a poor mRS90 score. CONCLUSIONS: The DSA-based collateral scoring of the BA large branches might predict long-term outcome in medically treated symptomatic basilar artery stenosis with mild initial severity. Evaluation of BA collateral perfusion status might be useful to determine appropriate treatment strategies.

Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study.

BACKGROUND: The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC. PATIENTS AND METHODS: Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis. RESULTS: Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% [95% confidence interval (CI) 17.2-34.4] for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2-30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89-9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62-9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74-1.36). The response rates were 49.1% (95% CI 39.7-58.6) and 45.9% (95% CI 36.4-55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%). CONCLUSION: No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity. CLINICAL TRIAL NUMBER: NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.

Effects of celecoxib on hematoma and edema volumes in primary intracerebral hemorrhage: a multicenter randomized controlled trial.

BACKGROUND AND PURPOSE: We investigated the effect of celecoxib, a selective inhibitor of cyclo-oxygenase 2, in patients with intracerebral hemorrhage (ICH). METHODS: We conducted a multicenter, randomized, controlled, and open with blinded end-point trial of 44 Korean patients 18 years or older with ICH within 24 h of onset. The intervention group (n = 20) received celecoxib (400 mg twice a day) for 14 days. The control group (n = 24) received the standard medical treatment for ICH. The primary end-point was the number of patients with a change in the volume of perihematomal edema (PHE) from the 1st to the 7th ± 1 day (cut-off value, 20%). RESULTS: The time from onset to computed tomography scan slightly differed between groups (177 ± 160 min for control vs. 297 ± 305 min for the celecoxib group; P = 0.10). In the primary end-point analysis using cut-off values, there was a significant shift to reduced expansion of PHE in the celecoxib group (P = 0.005). With respect to the secondary end-points, there was also a significant shift to reduced expansion of ICH in the celecoxib group (P = 0.046). In addition, the expansion rate of PHE at follow-up tended to be higher in the control group than in the celecoxib group (90.6 ± 91.7% vs. 44.4 ± 64.9%; P = 0.058). CONCLUSIONS: In our small, pilot trial, administration of celecoxib in the acute stage of ICH was associated with a smaller expansion of PHE than that observed in controls.

Prolonged use of aspirin alters human and rat intestinal cells and thereby limits the absorption of clopidogrel.

Clopidogrel therapy to prevent atherothrombosis faces the challenge of reduced responsiveness. The absorption of clopidogrel is regulated by multidrug-resistance protein 1 (MDR1) in the intestinal epithelium. Given that aspirin induces MDR1 in cancer cells and peripheral blood cells, it may induce MDR1 in intestinal epithelial cells as well, thereby affecting the absorption of clopidogrel. In this study, aspirin treatment induced the expression of MDR1 in human epithelial colorectal (Caco-2) cells in vitro and in rat intestine in vivo, as evidenced by dose-dependent increases in gene, protein, and efflux function. Along with the upregulation of MDR1 proteins by aspirin, clopidogrel absorption was significantly decreased in the aspirin-treated Caco-2 cells and in rat intestine. Our data provide evidence that prolonged use of aspirin may reduce the intestinal absorption of clopidogrel. Further human studies would be necessary to clarify whether these data have any relevance to prevention of stroke or myocardial infarction.

Reduced circulating angiogenic cells in Alzheimer disease.

OBJECTIVE: Neurovascular dysfunction and senescent endothelium contribute to the progression of Alzheimer disease (AD). Circulating angiogenic cells (CACs), such as endothelial progenitor cells (EPCs), provide a cellular reservoir for the endothelial replacement. To study the involvement of CACs in AD pathogenesis, we investigated the levels of CACs in patients with AD. METHODS: Consecutive patients with newly diagnosed AD (n = 55), patients with non-AD neurodegenerative diseases (n = 37), and nondemented risk factor control subjects (RF control, n = 55 and 37) were enrolled after matching for age, sex, and Framingham risk score. Peripheral blood samples were taken, and EPC colony-forming units (CFU-EPC) were cultured and counted. RESULTS: The patients with AD had significantly lower CFU-EPC than the RF controls. In the patients with AD, a lower CFU-EPC was independently associated with either a lower Mini-Mental State Examination score or a higher Clinical Dementia Rating scale score, indicating a greater reduction in CFU-EPC in advanced AD. Patients with non-AD neurodegenerative diseases did not show a significant decrease in CFU-EPC levels. CONCLUSION: Our results indicate that patients with Alzheimer disease (AD) have reduced circulating angiogenic cells, suggesting that an abnormal capacity to regenerate endothelium is associated with AD.

Clinical features and treatment outcomes of advanced stage primary hepatic angiosarcoma.

BACKGROUND: Primary hepatic angiosarcoma is a very rare malignancy with a poor prognosis. While surgical resection has been validated as curative choice, most cases are diagnosed too late for resection. Nonetheless, treatment protocols have not been established and also there are very few reports on the clinical features and treatment outcomes. PATIENTS AND METHODS: Among 11,939 patients diagnosed with primary hepatic tumors from January 1985 to December 2007 at two centers, five patients were diagnosed with primary hepatic angiosarcoma. We analyzed patients' demographics, tumor characteristics, treatment modality, and outcomes using imaging, serology, and pathology. RESULTS: All five patients were diagnosed at advanced stage with distant metastases. The most common symptom was abdominal pain. The levels of the tumor markers were within the normal range and serological tests were negative for hepatitis B and C viruses. Two of four patients who received chemotherapy died <3 months after diagnosis, but the other two patients survived >6 months. CONCLUSIONS: A combination of chemotherapy resulted in an improved outcome for two of four patients, suggesting the potential usefulness of palliative chemotherapy to improve survival. This case study may aid in planning chemotherapy for patients with advanced hepatic angiosarcoma.

Association of the ABCB1 gene polymorphisms 2677G>T/A and 3435C>T with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients.

BACKGROUND: ABCB1 is responsible for multidrug resistance, the principal mechanism by which many cancers develop resistance to chemotherapeutic drugs. There is a controversy whether ABCB1 gene polymorphisms correlate with survival and response in cancer patients treated with chemotherapy. We evaluated the association between clinical outcome (safety and efficacy) of paclitaxel monotherapy in metastatic breast cancer patients with ABCB1 gene polymorphisms 2677G>T/A or 3435C>T. PATIENTS AND METHODS: Patients with metastatic breast cancer were treated with 175 mg/m(2) paclitaxel per 3-week cycle. Peripheral blood mononuclear cells from patients were used to genotype ABCB1 2677G>T/A and 3435C>T polymorphisms. Genotypes were investigated for their association with tumor response, survival, toxicity, and chemoresistance. RESULTS: ABCB1 3435 CT showed a significantly lower disease control rate than the CC genotype (P = 0.025). ABCB1 3435 CT was correlated with shorter overall survival (OS) in Cox regression analysis (P = 0.026). The 2677 GG genotype showed a significant association with chemoresistance to paclitaxel and anthracycline (P = 0.04 and 0.04, respectively). None of the ABCB1 genotypes correlated with toxicity. CONCLUSIONS: ABCB1 genotypes may be a predictor of paclitaxel activity as well as a prognostic factor in metastatic breast cancer patients.

Changing ischaemic lesion patterns in adult moyamoya disease.

OBJECTIVES: Ischaemic stroke is a frequent manifestation in patients with adult moyamoya disease (MMD), but the relationship between the lesion pattern and disease severity has rarely been investigated. METHODS: Data were collected on a consecutive series of 65 adult patients with MMD who visited our hospital between 1999 and 2006. Among them, 32 patients with first ever ischaemic stroke were included. The ischaemic lesions were categorised by location and compared as follows: (1) cortical versus subcortical involvement and (2) anterior (fronto-temporal) versus posterior (parieto-occipital) involvement. The lesions were also compared by disease severity, as determined by the extent of intracranial artery involvement (Suzuki's grading method) and by perfusion status visualised on single photon emission computed tomography (SPECT). RESULT: Disease severity was significantly greater in patients with cortical involvement than in those with subcortical involvement (Suzuki's grade 4.17 (0.72) vs 2.70 (0.73); p<0.001). Disease severity was also significantly greater in patients with posterior involvement than in those with anterior involvement (4.50 (0.53) vs 2.83 (0.76); p<0.001). In most of the patients (83.3%) the perfusion defect area shown on SPECT was larger than the ischaemic lesion area shown on MRI. CONCLUSIONS: Patients with advanced stage adult MMD tended to have ischaemic lesions involving the cortex and posterior part of the brain and the stroke mechanism in these patients was largely associated with haemodynamic compromise. Our results suggest that the lesion pattern of ischaemic stroke may change along with the extent of arterial involvement.

Decreased number and function of endothelial progenitor cells in patients with migraine.

OBJECTIVE: Migraine carries an increased risk for cardiovascular and cerebrovascular diseases that cannot be explained by traditional cardiovascular risk factors. The circulating endothelial progenitor cell (EPC) number is a surrogate biologic marker of vascular function, and diminished EPC counts are associated with higher cardiovascular risk. We investigated whether abnormalities in EPC levels and functions are present in migraine patients. METHODS: Consecutive headache patients (n =166) were enrolled, including those with tension type headache (TTH; n = 74), migraine without aura (MO; n = 67), and migraine with aura (MA; n = 25). EPC colony-forming units in peripheral blood samples and migratory capacity to chemoattractants (stromal cell-derived factor 1 and vascular endothelial growth factor) and cellular senescence levels were assayed in risk factor-matched subjects (n = 6 per group). RESULTS: The TTH group had more cardiovascular risk factors, more headache days, and higher Framingham risk scores than the other two groups. Mean numbers of EPC colony-forming units were 47.8 +/- 24.3 in TTH, 20.4 +/-22.2 in MO, and 8.6 +/- 10.1 in MA patients (p < 0.001 in TTH vs MO; p = 0.001 in MO vs MA). EPC colony counts of normal subjects (n = 37) were not significantly different from those with TTH. Multiple linear regression models identified only MO, MA, and the presence of migraine (MO + MA) as significant predictors of EPC levels. In addition, EPCs from migraine patients (MO and MA) showed reduced migratory capacity and increased cellular senescence compared with EPCs from TTH or normal subjects. CONCLUSION: Circulating endothelial progenitor cell (EPC) numbers and functions are reduced in migraine patients, suggesting that EPCs can be an underlying link between migraine and cardiovascular risk.

Phase II study of combination chemotherapy of 5-fluorouracil, low-dose leucovorin, and oxaliplatin (FLOX regimen) in pretreated advanced gastric cancer.

BACKGROUND: This phase II study describes the efficacy and safety of combination chemotherapy of 5-fluorouracil (5-FU), low-dose leucovorin, and oxaliplatin (FLOX regimen) for pretreated advanced gastric cancer. PATIENTS AND METHODS: Patients who had been previously treated with greater than or equal to one regimen were enrolled. Patients received an oxaliplatin 75 mg/m(2) on day 1, 5-FU 1000 mg/m(2) on days 1-3, and leucovorin 20 mg/m(2) on days 1-3, every 3 weeks. The primary end point was overall survival (OS). RESULTS: Among the 52 patients enrolled, 26 patients were treated as second line, and the remaining 26 patients were enrolled as third- or fourth line. A total of 203 cycles of chemotherapy were administered with the median being three cycles (range 1-15) per patient. The median OS was 6.6 months [95% confidence interval (CI) 4.5-8.8] and the median progression-free survival was 2.5 months (95% CI 1.9-3.0). The response rate was 4% (95% CI 0-9%), and the disease control rate was 48% (95% CI 34-62%). The most common toxic effects of grade 3/4 were neutropenia (16%) and vomiting (6%). CONCLUSIONS: The FLOX regimen showed modest activity as a salvage treatment in pretreated advanced gastric cancer with a favorable compliance.

Survival benefit of combined curative resection of the stomach (D2 resection) and liver in gastric cancer patients with liver metastases.

BACKGROUND: The benefit of surgical resection of liver metastases from gastric cancer has not been well established. The aim of this study was to evaluate the rationale for hepatic resection in patients with hepatic metastases from gastric cancer. METHODS: Among 10 259 patients diagnosed with gastric adenocarcinoma in the Yonsei University Health System from 1995 to 2005, we reviewed the records of 58 patients with liver-only metastases from gastric cancer who underwent gastric resection regardless of hepatic surgery. RESULTS: The overall 1-year, 3-year, and 5-year survival rates of 41 patients who underwent hepatic resection with curative intent were 75.3%, 31.7%, and 20.8%, respectively, and three patients survived >7 years. Of the 41 patients, 22 had complete resection and 19 had palliative resection. Between the curative and palliative resections, survival rates after curative intent were not different. The number of liver metastasis (solitary or multiple) was a marginally significant prognostic factor for survival. CONCLUSIONS: Surgery for liver metastases arising from gastric adenocarcinoma is reasonable if complete resection seems feasible after careful preoperative staging, even if complete resection is not actually achieved. Hepatic resection should be considered as an option for gastric cancer patients with hepatic metastases.

Does microbleed predict haemorrhagic transformation after acute atherothrombotic or cardioembolic stroke?

OBJECTIVES: Cerebral microbleeds (MBs) are known to be indicative of bleeding-prone microangiopathy and may predict incident intracerebral haemorrhage. However, there is controversy concerning the causal relationship between the presence of MBs and haemorrhagic transformation (HTf) after ischaemic stroke. METHODS: Of the 1034 patients with acute ischaemic stroke who were consecutively admitted to our hospital, 377 patients with stroke due to large-artery atherothrombosis or cardioembolism were selected for participation in this study. We examined the MBs using T2*-weighted gradient-echo MRI performed within 24 hours after admission, and the incidence of HTf was assessed using follow-up brain MRI during the hospitalisation period. RESULTS: Of the 377 patients with stroke, 234 were male (62.1%) and the mean age was 66.2 +/-11.7 years. MBs were initially found in 109 patients (28.9%), and newly incident HTf was noted during the hospitalisation period in 74 patients (19.6%). The presence of MBs was not increased in the patients with HTf (24.3% vs. 30.0% in the patients without HTf; p = 0.331). In addition, the number of MBs was not higher in the patients with HTf (0.7+/-1.5 vs. 1.8+/-8.1; p = 0.234). This lack of significance between MBs and HTf persisted after stratification by stroke mechanism. CONCLUSIONS: This study suggests that underlying MBs do not predict incident HTf after acute ischaemic stroke. The clinical significance of MBs should be differentially evaluated according to the type of disease (intracerebral haemorrhage vs. HTf).

Lack of carcinogenicity of lyophilized Agaricus blazei Murill in a F344 rat two year bioassay.

The Brazilian mushroom Agaricus blazei Murill has antimutagenic, antioxidant, immunostimulatory and antitumorigenic activities, and is increasingly consumed as a health food worldwide. We undertook the present study to evaluate the chronic toxicity and oncogenicity of A. blazei Murill in F344 rats. To establish a no-observed-adverse-effect level (NOAEL), four treatment groups of 100 rats each (50 males and 50 females) were fed a powder diet containing lyophilized A. blazei aqueous extract at 0, 6250, 12,500, and 25,000 ppm for up to 2 years. During this period, there was no remarkable change in mean body weight, body weight gain, hematologic or serum chemistry parameters, or absolute or relative organ weights in control or treatment groups. Mortality in male treatment groups (26%, 16%, and 30%), however, was significantly lower than in controls (48%). Histopathological studies showed no increased incidence of tumors in any treatment group, and total tumor incidence across all groups was comparable to historical data. In conclusion, an A. blazei Murill lyophilized powder diet even at 25,000 ppm (1176 mg/kgb x w x /day for male rats and 1518 mg/kgb.w./day for female rats) resulted in no remarkable carcinogenic effects in F344 rats over a 2-year period. Therefore, the dietary NOAEL is 25,000 ppm.

Phase III trial of adjuvant 5-fluorouracil and adriamycin versus 5-fluorouracil, adriamycin, and polyadenylic-polyuridylic acid (poly A:U) for locally advanced gastric cancer after curative surgery: final results of 15-year follow-up.

BACKGROUND: This phase III trial was to compare 5-fluorouracil (5-FU), adriamycin, and polyadenylic-polyuridylic acid (poly A:U) against 5-fluorouracil plus adriamycin (FA) for operable gastric cancer. PATIENTS AND METHODS: From 1984 to 1989, patients who had D(2-3) curative resection were randomly assigned to receive chemotherapy or chemoimmunotherapy. Chemotherapy consisted of 12 mg/kg 5-FU every week for 18 months and 40 mg/m2 adriamycin every 3 weeks for 12 cycles. Chemoimmunotherapy consisted of FA plus 100 mg of poly A:U weekly for six cycles and was followed 6 months later by six weekly 50-mg booster injections. RESULTS: A total of 292 patients were enrolled. After excluding 12 ineligible patients, 142 and 138 patients were allocated to each treatment. Patients were balanced with prognostic variables: age, sex, tumor location, differentiation, degree of tumor invasion (T2-T4a), and lymph node status (N0-N2). During the 15-year follow-up, chemoimmunotherapy significantly prolonged overall (P = 0.013) and recurrence-free (P = 0.005) survivals compared with chemotherapy alone. The survival benefits were prominent in the subset of patients with T3/T4a, N2, or stage III. Treatments were generally well tolerated in both arms. CONCLUSIONS: These results indicate a survival advantage of chemoimmunotherapy with a regimen of FA and poly A:U in curatively resected gastric adenocarcinoma.

A phase II study of S-1 monotherapy administered for 2 weeks of a 3-week cycle in advanced gastric cancer patients with poor performance status.

Systemic chemotherapy for gastric cancer is often associated with treatment-related toxicity, which is particularly severe in patients with a poor performance status. In this paper, we describe the first study to evaluate S-1 monotherapy as an option for advanced gastric cancer patients who are not candidates for combination chemotherapy due to poor clinical condition. Fifty-two patients with Eastern Cooperative Oncology Group (ECOG) performance scale 2-3, whose general condition had made use of combination chemotherapy impossible, were enrolled. S-1 was administered to 30 patients as second- or third-line therapy. The initial dose of S-1 was 35 mg m(-2), administered b.i.d for 14 days every 3 weeks. With a median follow-up period of 33 weeks, the median progression-free survival, and overall survival were 11 weeks (95% CI, 8-14) and 33 weeks (95% CI, 19-47), respectively. The overall 1-year survival rate was 29% by intent-to-treat analysis. The overall response rate was 12% (95% CI, 3-21), and the percentage of stable disease was 35%, resulting in the disease control rate of 47% (95% CI, 32-60). Significant drug-related toxicity included grade 3 diarrhoea (14%), anorexia (14%), fatigue (10%), neutropenia (10%), and leucopenia (6%). In conclusion, this study indicated the modest activity of S-1 in gastric cancer patients with poor performance status.

Metabolic syndrome is more associated with intracranial atherosclerosis than extracranial atherosclerosis.

To elucidate the relationship between metabolic syndrome (MetS) and cerebrovascular stenosis, we performed comparative studies of MetS and its components between ischemic stroke patients with intra- and extracranial atherostenosis. We evaluated 378 acute ischemic stroke patients who underwent brain magnetic resonance (MR) imaging and MR angiography. Stenosis was diagnosed in cases showing a degree of luminal narrowing of > or = 50%. The stroke subtypes were categorized as large artery atherosclerosis (LAA), small artery occlusion (SAO), cardioembolism (CE), and stroke of undetermined etiology (SUE). MetS was defined using the criteria of the Adult Treatment Panel III. The mean carotid intimal medial thickness values showed increased tendency as the number of MetS components increased (P < 0.001). Regardless of stroke subtype, the MetS (+) group showed an increasing tendency toward stenosis (LAA, SAO, all P < 0.001; CE, P = 0.001; SUE, P = 0.077). MetS was independently associated with intracranial atherosclerosis (odds ratio, 3.58; 95% CI, 2.28-5.63), which was prominent with more severe MetS components after adjustment for other risk factors (P < 0.001). Amongst the component conditions, elevated blood pressure, increased blood glucose/hyperglycemia, and abdominal obesity were dominantly associated with stenosis (all P < 0.001). Modifications of the individual MetS components need to be considered for stroke prevention because of intracranial atherogenic progression.

Irofulven as first line therapy in recurrent or metastatic gastric cancer: a phase II multicenter study by the Cancer Therapeutics Research Group (CTRG).

BACKGROUND: The purpose of this study was to evaluate the tolerability and efficacy of irofulven, a DNA interacting acylfulvene analog, as first line therapy for patients with recurrent or metastatic gastric cancer. PATIENTS AND METHODS: Twenty-three patients with recurrent or metastatic gastric cancer received irofulven at a dose of 0.45 mg/kg administered intravenously over 30-min infusion (up to a maximum of 50 mg), on days 1 and 8, every 3 weeks. RESULTS: The median number of cycles delivered per patient was 2 (range 1-6). Two patients (9%) had >or= 1-week delay in administration of subsequent cycle of chemotherapy. For the day 8 chemotherapy, dose reductions were required in seven patients (30%); dose omitting occurred in five patients (22%). Grade 3/4 anemia and neutropenia occurred in 22 and 17% of patients, respectively. There was no grade 4 thrombocytopenia and no neutropenic fever was observed. Of the 20 evaluable patients, there were no responses observed, 3 patients had stable disease after 2 cycles of treatment which was not confirmed by a further assessment. Median overall survival was 6.05 months (95% CI 4.55-9.39). CONCLUSIONS: Irofulven was tolerated at the dose of 0.45 mg/kg on days 1 and 8, every 3 weeks but showed no evidence of antitumor activity in patients with advanced gastric cancer.

A phase II trial of S-1 monotherapy in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens.

This is the first phase II study of S-1 monotherapy for patients with metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-containing regimens. The initial dose of S-1 was 35 mg m-2, administered twice daily for 14 days every 3 weeks. Treatment was repeated until the occurrence of disease progression. Twenty-eight patients were enrolled. S-1 was administered to 21 patients as third-line therapy and to the remaining seven patients as fourth-line therapy. Of 26 evaluable patients, the overall response rate was 14.3% (95% CI, 0.4-28.1), and the disease control rate was 42.9% (95% CI, 23.3-62.4). With a median follow-up period of 227 days, median time to progression and overall survival duration were 91 and 414 days, respectively. The 1-year survival rate of all patients was 60.7%. There was no grade 4 toxicity. Grade 3 haematological toxicities were documented only in two patients. In conclusion, S-1 shows potential as a salvage regimen in heavily pretreated colorectal cancer patients. The twice-daily dose of 35 mg m-2 was well tolerated and can be used in designing further combination chemotherapy.