Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study.

BACKGROUND: First-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated. PATIENTS AND METHODS: RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed. RESULTS: In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade ≥3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events. CONCLUSIONS: Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents.

Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder.

Neuromyelitis optica is an autoimmune inflammatory disorder of the central nervous system that preferentially targets the spinal cord and optic nerve. Following the discovery of circulating antibodies against the astrocytic aquaporin 4 (AQP4) water channel protein, recent studies have expanded our knowledge of the unique complexities of the pathogenesis of neuromyelitis optica and its relationship with the immune response. This review describes and summarizes the recent advances in our understanding of the molecular mechanisms underlying neuromyelitis optica disease pathology and examines their potential as therapeutic targets. Additionally, we update the most recent research by proposing major unanswered questions regarding how peripheral AQP4 antibodies are produced and their entry into the central nervous system, the causes of AQP4-IgG-seronegative disease, why peripheral AQP4-expressing organs are spared from damage, and the impact of this disease on pregnancy.

Adjuvant chemotherapy for gastric cancer: a randomised phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201).

BACKGROUND: This phase 3 study evaluated the efficacy of new adjuvant chemotherapy (MFP), which intensified the mitomycin-C (MMC) plus short-term doxifluridine (Mf) for gastric cancer. PATIENTS AND METHODS: A total of 855 patients (424 in Mf, 431 in MFP) with pathological stage II-IV (M0) gastric cancer after D2 gastrectomy were randomly assigned to receive either Mf (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 3 months) or MFP (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 12 months with 6 monthly infusions of 60 mg m(-2) of cisplatin) chemotherapy. RESULTS: With a median follow-up of 6.6 years, there was no difference between the two groups in recurrence-free survival (RFS) (5-year RFS 61.1% in Mf and 57.9% in MFP; hazard ratio 1.10 (95% CI 0.89-1.35); P=0.39) and overall survival (OS) (5-year OS 66.5% in Mf and 65.0% in MFP; hazard ratio 1.11 (95% CI 0.89-1.39); P=0.33). CONCLUSION: Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients.

Phase II study of everolimus with biomarker exploration in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum.

BACKGROUND: To evaluate the activity and safety of everolimus and identify potential biomarkers for efficacy of everolimus in patients with advanced gastric cancer (AGC), who failed both fluoropyrimidine and platinum. METHODS: Fifty-four patients received everolimus (10 mg day(-1)). The primary objective was to determine the 4-month progression-free survival (PFS) rate, assumed to be 30%. We additionally investigated the potential biomarkers for everolimus as an exploratory endpoint in those who underwent tumour biopsies. RESULTS: Two patients (3.7%) achieved partial response and the disease control rate (DCR) was 38.9%. At a median follow-up duration of 8.7 months, the 4-month PFS rate was 18.4%, not fulfilling the primary hypothesis, with a median PFS of 1.7 months and a median overall survival of 8.3 months. The high expression of pS6(Ser240/4) at baseline was significantly associated with higher DCR (P=0.043) and prolonged PFS (P=0.001). Grade 1/2 asthenia (96.3%) recorded as the leading toxicity and hyperglycaemia (20.4%) was the most common non-hematological grade 3/4 toxicity. Three patients experienced grade 3/4 pneumonitis. Notably, two experienced treatment-related deaths. CONCLUSION: Everolimus is active against a limited number of patients with AGC. pS6(Ser240/4) may be a potential predictive biomarker for everolimus, which requires validation. Careful monitoring is necessary despite generally favourable toxicity profile.

Phase II and UGT1A1 genotype study of irinotecan dose escalation as salvage therapy for advanced gastric cancer.

BACKGROUND: To assess the efficacy and safety of individualised dose optimisation of irinotecan monotherapy as salvage treatment for advanced gastric cancer (AGC). METHODS: A total of 43 patients were enrolled. Intravenous irinotecan (350 mg m(-2)) was administered every 3 weeks. The dose was increased (425 mg m(-2) and 500 mg m(-2)) or decreased (250 mg m(-2)) depending on patient tolerance. UGT1A1 genotypes were determined by direct sequencing of genomic DNA extracted from peripheral blood. RESULTS: A total of 183 cycles of irinotecan were administered, with a median of four cycles per patient. The overall response rate was 9.3%, and the disease control rate was 62.8%. Median time to disease progression was 2.8 months, and median overall survival was 8.0 months. Grade 3-4 neutropenia was the most common toxicity (53.5%), and febrile neutropenia was the least common toxicity (4.6%). Compared with defective allele groups, UGT1A1 *1/*1 was associated with a lower incidence of grade 3-4 neutropenia during the first cycle (P=0.018). CONCLUSION: Individualised irinotecan dose escalation based on patient tolerance was not associated with increased toxicity and shows modest activity as salvage chemotherapy for AGC. The role of UGT1A1 genotype in clinical toxicity requires further evaluation.

Phase II study of S-1 combined with oxaliplatin as therapy for patients with metastatic biliary tract cancer: influence of the CYP2A6 polymorphism on pharmacokinetics and clinical activity.

BACKGROUND: Advanced biliary cancer is often treated with fluoropyrimidine-based chemotherapy. In this study, we evaluated the efficacy and tolerability of a combination of S-1, an oral fluoropyrimidine prodrug, and oxaliplatin in patients with metastatic biliary cancer. METHODS: Patients with histologically confirmed metastatic biliary cancer and no history of radiotherapy or chemotherapy were enrolled. Oxaliplatin was administered intravenously (130 mg m(-2)), followed by 14-day administration of oral S-1 (40 mg m(-2) twice daily) with a subsequent 7-day rest period every 21 days. Pharmacokinetic analysis of S-1 was performed at cycle 1. Patients were genotyped for CYP2A6 polymorphisms ((*)1, (*)4, (*)7, (*)9 or (*)10), and pharmacokinetic and clinical parameters compared according to the CYP2A6 genotype. RESULTS: In total, 49 patients were evaluated, who received a median of four cycles. The overall response rate was 24.5%. Median progression-free and overall survival was 3.7 and 8.7 months, respectively. The most common haematological grade 3 out of 4 toxicity was neutropenia (14%), while non-hematological grade 3 out of 4 toxicities included anorexia (14%), nausea (12%), asthenia (10%), vomiting (10%), and diarrhoea (4%). Biotransformation of S-1 (AUC(0-24 h) of 5-fluorouracil/AUC(0-24 h) of tegafur) was 1.85-fold higher for the *1/*1 group than for the other groups (90% confidence interval 1.37-2.49). Diarrhoea (P=0.0740), neutropenia (P=0.396), and clinical efficacy (response rate, P=0.583; PFS, P=0.916) were not significantly associated with CYP2A6 genotype, despite differences in 5-FU exposure. CONCLUSION: The combination of S-1 and oxaliplatin appears to be active and well tolerated in patients with metastatic biliary cancer, and thus is feasible as a therapeutic modality. CYP2A6 genotypes are associated with differences in the biotransformation of S-1. However, the impact of the CYP2A6 polymorphism on variations in clinical efficacy or toxicity requires further evaluation.

A study on white organic light-emitting diodes co-doped with red fluorescent and blue phosphorescent dopants.

White organic light-emitting diodes (WOLEDs) have drawn increasing attention due to their potential use in various applications such as solid-state lighting and backlight of liquid crystal displays and full-color OLEDs of red, green, and blue pixel. N,N'-dicabazolyl-3,5-benzene (mCP), the host material, was co-doped with Iridium (III) bis[(4,6-difluorophenyl)-pyridinato-N,C2']-picolinate (FIrpic), which functions not only as phosphorescent sensitizer but also blue emitter, and (2Z,2'Z)-3,3'-[4,4"-bis (dimethylamino)-1,1':4',1"-terphenyl-2',5'-diyl]bis (2-phenylacrylonitrile) (ABCV-P), which is a red fluorescent material. The fabricated device structures were as follows: (device A) Indium tin oxide (ITO)/N,N'-bis-(1-naphyl)-N,N'-diphenyl-1,1'-biphenyl-4,4'-diamine (NPB)/(mCP)/mCP:ABCV-P (1%)/4,7-diphenyl-1,10-phenanthroline (Bphen)/lithium quinolate (Liq)/aluminum (Al), (device B) ITO/NPB/mCP/mCP:FIrpic (8%)/Bphen/Liq/Al and (device C) ITO/NPB/mCP/mCP:FIrpic:ABCV-P (8%, 1%)/Bphen/Liq/Al, respectively. Phosphorescent FIrpic harvesting both singlet and triplet excitions not only emitted blue light but also transferred energy to fluorescent ABCV-P. The maximum luminance efficiency, external quantum efficiency, and luminance of white light device were measured to be 5.95 cd/A, 2.45% and 2500 cd/m2, respectively. The white device gave practically white light with the Commision Internationale de l'Eclairage (CIE(xy)) coordinate of (0.44, 0.49) which was close to warm white color (CIE(xy) = 0.45, 0.45).

Investigation of papulopustular eruptions caused by cetuximab treatment shows altered differentiation markers and increases in inflammatory cytokines.

BACKGROUND: Epidermal growth factor receptor (EGFR) critically regulates tumour cell division, survival and metastasis. Agents that inhibit EGFR have been used in the treatment of advanced-stage malignancies, but cause variable cutaneous side-effects, most often papulopustular eruptions and xerosis. OBJECTIVES: We assayed expression of inflammatory cytokines [interleukin (IL)-1alpha, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, human leucocyte antigen (HLA)-DR and intercellular adhesion molecule (ICAM)-1], differentiation markers (filaggrin, involucrin and loricrin) and phosphorylated EGFRs (pEGFRs) in papulopustular eruptions to determine the association between these markers and the eruptions caused by cetuximab. PATIENTS/METHODS: Twelve papulopustular lesion biopsies were selected from patients with colon cancer who had received cetuximab treatment. Immunohistochemistry and immunofluorescence with a confocal laser scanning microscopy were performed. RESULTS: Filaggrin expression decreased and expression of involucrin, various inflammatory markers (IL-1alpha, TNF-alpha, ICAM-1 and HLA-DR) increased and the expression of pEGFR was markedly downregulated in papulopustular eruptions. In perilesions, decreased pEGFR expression was noted in hair follicles compared with interfollicular epidermis. The increase of IL-1alpha and TNF-alpha was observed in perilesions as in the lesions. CONCLUSIONS: The early inflammatory events (IL-1alpha and TNF-alpha expression) seen, and the lack of pEGFR in perilesional follicles, indicate that inflammatory events induced by EGFR inhibition may initiate papulopustular eruptions along with the altered differentiations. The decrease of filaggrin may contribute to the pathogenesis of the xerosis caused by cetuximab.

A randomized controlled trial of rivastigmine in patients with cognitive impairment no dementia because of cerebrovascular disease.

OBJECTIVES: The safety and efficacy of early acetylcholinesterase inhibitors therapy in patients with cognitive impairment no dementia (CIND) after a cerebrovascular accident have not been examined. In this study, we investigated the safety and efficacy of rivastigmine in cognition, particularly executive function in patients with CIND because of cerebrovascular disease. METHODS: This study was a 24-week, double-blind, randomized, placebo-controlled trial of ischemic stroke patients seen at a tertiary hospital who had cognitive impairment no dementia because of cerebrovascular disease. The intervention was either rivastigmine or placebo up to 9 mg/day. The primary outcome of interest was mean change from baseline in the Ten-Point Clock Drawing and Color Trails 1 and 2. RESULTS: Fifty patients were randomized into rivastigmine (n = 25) and placebo (n = 25) arms. Patients in the rivastigmine group showed statistically significant improvement (1.70 vs 0.13, P = 0.02) on the animal subtask of the verbal fluency measure compared with placebo. There was also a trend (non-significant) towards improvement in Color Trails II. CONCLUSIONS: In this pilot study, we demonstrated that rivastigmine was well tolerated in patients with CIND because of cerebrovascular disease and may potentially improve executive functioning.

Correction of a defect in mammalian GPI anchor biosynthesis by a transfected yeast gene.

Glycosylphosphatidylinositol (GPI) serves as a membrane anchor for a large number of eukaryotic proteins. A genetic approach was used to investigate the biosynthesis of GPI anchor precursors in mammalian cells. T cell hybridoma mutants that cannot synthesize dolichol-phosphate-mannose (Dol-P-Man) also do not express on their surface GPI-anchored proteins such as Thy-1 and Ly-6A. These mutants cannot form mannose-containing GPI precursors. Transfection with the yeast Dol-P-Man synthase gene rescues the synthesis of both Dol-P-Man and mannose-containing GPI precursors, as well as the surface expression of Thy-1 and Ly-6A, suggesting that Dol-P-Man is the donor of at least one mannose residue in the GPI core.

Intracranial large artery disease in Alzheimer's disease and vascular dementia among ethnic Asians.

BACKGROUND AND PURPOSE: An underlying vascular etiology underpins vascular dementia (VaD) and possibly Alzheimer's disease (AD). Intracranial large artery disease (ICLAD) is a common site of disease among ethnic Asians, and carries a poor prognosis. We studied the prevalence of ICLAD among ethnic Asian patients with AD and VaD. METHODS: We recruited patients with AD and VaD from a retrospective review of consecutive ethnic Asian patients presenting to our dementia clinic. ICLAD was evaluated by visual inspection of brain magnetic resonance angiography by two observers in consensus, and defined as >50% luminal narrowing. RESULTS: There were 56 patients with probable AD and 47 with probable VaD. ICLAD was prevalent among 53% of VaD patients and 18% of AD patients. CONCLUSIONS: There is a relatively high burden of ICLAD among AD and VaD patients of Asian ethnicity. We suggest that ethnic Asian dementia patients are a potential group to investigate if ICLAD is associated with clinical symptoms or prognosis and if treatment strategies targeted at ICLAD retard the progression of cognitive impairment.

Metabolic syndrome and quality of life (QOL) using generalised and obesity-specific QOL scales.

OBJECTIVES: We investigated the association between metabolic syndrome (MS) and health-related quality of life (HRQOL) assessed using generalised and obesity-specific QOL instruments. METHODS: We recruited 456 outpatients [age: 19-81 years, body mass index (BMI): 16.3-36.7 kg/m2] in the primary care division from 12 general hospitals in Korea. HRQOL was measured using EuroQol comprising the health states descriptive system (EQ-5D) and visual analogue scale (EQ-VAS) as a general instrument. The Korean Obesity-related QOL scale (KOQOL) composed of six domains was used as a disease-specific QOL instrument. MS was defined on the basis of International Diabetes Federation (IDF) criteria with Korean-specific waist circumference cutoffs (men: 90 cm, women: 85 cm). RESULTS: Subjects with MS displayed significantly higher impairment of EQ-5D and KOQOL. Binary logistic regression analysis of MS patients with controls for age, gender, smoking, alcohol, exercise, education, income, marital status and medication history disclosed odds ratio (OR) values of 2.13 (1.33-3.41) for impaired total KOQOL, 2.07 (1.31-3.27) for impaired physical health, 1.63 (1.03-2.60) for impaired work-related health, 2.42 (1.45-4.04) for impaired routine life, 2.08 (1.27-3.40) for impaired sexual life and 2.56 (1.59-4.11) for diet distress. Among the EQ-5D dimensions, only pain/discomfort displayed a significantly increased OR of 1.60 (1.01-2.56) in MS group. CONCLUSIONS: Subjects with MS displayed a significantly impaired HRQOL compared with those without MS. MS and HRQOL were more strongly associated in obesity-specific QOL than in generalised QOL.

A randomised multicentre phase II trial of capecitabine vs S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer.

This randomised multicentre phase II study was conducted to investigate the activity and safety of two oral fluoropyrimidines, capecitabine or S-1, in elderly patients with advanced gastric cancer (AGC). Elderly (>or=65 years) chemo-naive patients with AGC were randomly assigned to receive capecitabine 1250 mg m(-2) two times daily on days 1-14 every 3 weeks or S-1 40-60 mg two times daily according to body surface area on days 1-28 every 6 weeks. Ninety-six patients were enrolled and 91 patients were randomised to capecitabine (N=46) or S-1 (N=45). Overall response rate, the primary end point, was 27.2% (95% CI, 14.1-40.4, 12 of 44 assessable patients) with capecitabine and 28.9% (95% CI, 15.6-42.1, 13 of 45) with S-1. Median times to progression and overall survival in the capecitabine arm (4.7 and 9.5 months, respectively) were similar to those in the S-1 arm (4.2 and 8.2 months, respectively). The incidence of grade 3-4 granulocytopenia was 6.8% with capecitabine and 4.8% with S-1. Grade 3-4 nonhaematologic toxicities were: asthenia (9.1% with capecitabine vs 7.1% with S-1), anorexia (6.8 vs 9.5%), diarrhoea (2.3 vs 0%), and hand-foot syndrome (6.8 vs 0%). Both capecitabine and S-1 monotherapies were active and tolerable as first-line treatment for elderly patients with AGC.

Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer.

BACKGROUND: Identifying molecular markers for tumor recurrence is critical in successfully selecting patients with stage III colon cancer who are more likely to benefit from adjuvant chemotherapy. The present study analyzed a subset of 10 polymorphisms within eight genes involved in the tumor angiogenesis pathway and their impact on prognosis in stage III colon cancer patients treated with adjuvant chemotherapy. PATIENTS AND METHODS: Blood samples were obtained from 125 patients with locally advanced colon cancer at University of Southern California medical facilities. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR-restriction fragment length polymorphism and 5'-end [gamma-(33)P] ATP-labeled PCR protocols. RESULTS: Polymorphisms in vascular endothelial growth factor (VEGF) (C+936T; P = 0.003, log-rank test) and interleukin-8 (IL-8) (T-251A; P = 0.04, log-rank test) were independently associated with risk of recurrence in stage III colon cancer patients. In combined analysis, grouping alleles into favorable versus nonfavorable alleles, high expression variants of VEGF C+936T and IL-8 T-251A were associated with a higher likelihood of developing tumor recurrence (P < 0.001). CONCLUSION: High expression variants of VEGF C+936T and IL-8 T-251A were associated with shorter time to tumor recurrence, indicating that the analysis of angiogenesis-related gene polymorphisms may help to identify patient subgroups at high risk for tumor recurrence.

Profile and associations of central pulse wave velocity and central pulse pressure among ischemic stroke patients.

Arterial stiffness, a known risk factor for atherosclerosis, can be measured directly with carotid-femoral pulse wave velocity (CPWV) and indirectly with central pulse pressure (CPP). We aimed to compare central and brachial pulse pressures, and to profile CPWV and CPP among ischemic stroke patients. We studied 198 consecutive prospective ethnic Chinese and South Asian ischemic stroke patients, measuring brachial pressures, central pressures and CPWV under standardized conditions using established methods. The mean CPWV was 11.6 +/- 3.2 m/s and CPP was 64 +/- 28 mmHg. CPP was significantly lower than brachial pulse pressure. CPWV and CPP were both independently associated with older age and hypertension. Among ischemic stroke patients, brachial pulse pressure cannot be used as a surrogate for CPP. Older age and hypertension are associated with arterial stiffening.

Arterial stiffness, metabolic syndrome and inflammation amongst Asian ischaemic stroke patients.

BACKGROUND AND PURPOSE: Arterial stiffness and metabolic syndrome (MetS) are risk factors for ischaemic stroke. We studied the association of arterial stiffness, measured by carotid-femoral pulse wave velocity (PWV) and MetS amongst ischaemic stroke patients. We also investigated the role of inflammation measured by serum erythrocyte sedimentation rate (ESR) in the metabolic syndrome-arterial stiffness relationship. METHODS: Amongst the 229 prospectively recruited acute ischaemic stroke patients, we measured carotid-femoral PWV using applanation tonometry and the inflammatory marker serum ESR. RESULTS: Carotid-femoral PWV was significantly higher amongst patients with MetS (P = 0.002), increased waist circumference (P = 0.010), raised blood pressure (P < 0.001) and abnormal glycemia (P = 0.002); and increased with the number of MetS components (P = 0.002). In a sub-group of 199 patients, carotid-femoral PWV was significantly correlated with serum ESR (P < 0.001). In multivariate regression analysis including serum ESR and MetS as variables, carotid-femoral PWV was independently associated with higher ESR (P = 0.002) but not with MetS (P = 0.139). CONCLUSIONS: Arterial stiffness is significantly associated with MetS amongst ischaemic stroke patients, and inflammation appears to be involved in this relationship.

Arterial stiffness is associated with raised levels of the inflammatory marker erythrocyte sedimentation rate among ischaemic stroke patients.

We studied the relationship of arterial stiffness, measured by carotid-femoral pulse wave velocity and inflammation, measured by serum erythrocyte sedimentation rate among 334 ischaemic stroke patients. There was a significant correlation between carotid-femoral pulse wave velocity and erythrocyte sedimentation rate (P = 0.001), a relationship independent of age, hypertension, diabetes and smoking. Arterial stiffness and inflammation are associated among ischaemic stroke patients and are independent of established vascular risk factors.

Prediction of relapse or survival after resection in human hepatomas by DNA flow cytometry.

To investigate the change of DNA content and the effect of synthetic phase (S-phase) fraction on hepatocytes and hepatomas, DNA content and S-phase fraction were measured by flow cytometry in human livers and hepatoma tissues. The ploidy status of nontumor parts of resected hepatoma, fetal liver, and focal nodular hyperplasia were diploid, similar to that of the normal liver. Three patterns of DNA ploidy in human hepatoma cells were newly classified, namely, pattern I, diploid tumors; pattern II, aneuploid tumors with single G0/G1 peak; and pattern III, aneuploid tumors with more than one G0/G1 peaks. Among the 130 resectable hepatomas measured for DNA ploidy status, 84 (64.6%) were pattern I, 20 (15.4%) pattern II, and 26 (20%) pattern III. Multivariate analyses for those 130 patients who underwent hepatic resection showed that, in addition to tumor size, DNA ploidy was another prognostic factor in predicting overall survival and disease-free survival. Patients with small tumors (less than 5 cm) had a significantly higher overall survival rate than those with large tumor (greater than 5 cm). Patients with pattern III hepatomas had a significantly lower overall survival rate and a higher recurrent rate than did those with pattern I or pattern II tumors. The S-phase fraction was a significant predictor of overall survival rate in patients with pattern II, but not with pattern I, tumors. We conclude that DNA flow-cytometric measurements of ploidy and S-phase fraction are potential important prognostic predictors in patients with resectable hepatomas.

Differential expression of glycosylphosphatidylinositol-anchored proteins in a murine T cell hybridoma mutant producing limiting amounts of the glycolipid core. Implications for paroxysmal nocturnal hemoglobinuria.

A T cell hybridoma mutant, which expressed a markedly reduced level of glycosylphosphatidylinositol (GPI)-anchored proteins on the cell surface, was characterized. The surface expression level of Thy-1 was approximately 17% of the wild-type level, whereas the surface expression of Ly-6A was approximately 2.4% of the wild-type level. We show here that these cells synthesized limiting amounts of the GPI core and that the underlying defect in these cells was an inability to synthesize dolichyl phosphate mannose (Dol-P-Man) at the normal level. The defect in Ly-6A expression could be partially corrected by tunicamycin, which blocked the biosynthesis of N-linked oligosaccharide precursors and shunted Dol-P-Man to the GPI pathway. Full restoration of Thy-1 and Ly-6A expression, however, required the stable transfection of a yeast Dol-P-Man synthase gene into the mutants. These results revealed that when the GPI core is limiting, there is a differential transfer of the available GPI core to proteins that contain GPI-anchor attachment sequences. Our findings also have implications for the elucidation of the defects in paroxysmal nocturnal hemoglobinuria.

Adjuvant chemotherapy with 5-fluorouracil, doxorubicin and mitomycin-C (FAM) for 6 months after curative resection of gastric carcinoma.

AIM: This study aimed to evaluate the efficacy and safety of 5-fluorouracil (5-FU), doxorubicin and mitomycin-C (FAM) adjuvant chemotherapy in patients who had undergone curative resection of gastric carcinoma. METHODS: From Nov 1999 to Jan 2002, 291 consecutive patients with stage IB-IIIB gastric adenocarcinoma were given FAM adjuvant chemotherapy. Chemotherapy comprised intravenous 5-FU 600 mg/m(2) (days 1, 8, 29 and 36), doxorubicin 30 mg/m(2) (days 1 and 29) and mitomycin-C 10 mg/m(2) (day 1), every 8 weeks for 6 months. RESULTS: The median follow-up time was 60.6 months, 92 patients died, and 93 patients had recurrent disease. The 5-year overall survival (OS) rates were 85.9% for stage IB, 72.1% for stage II, 58.0% for stage IIIA, and 48.2% for stage IIIB (p=0.002). The 5-year relapse-free survival (RFS) rates were 85.2% for stage IB, 71.2% for stage II, 53.3% for stage IIIA, and 39.2% for stage IIIB (p<0.001). A total of 769 cycles of chemotherapy were delivered, and 15 patients experienced grade 3 or higher leukopenia. The most common grade 3 or higher non-hematologic toxicity was nausea/vomiting (11 patients), followed by stomatitis (3 patients). CONCLUSIONS: Adjuvant chemotherapy with FAM for 6 months for gastric carcinoma indicated comparable RFS and OS with an acceptable toxicity profile.