Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients.

Background: To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and methods: We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples. Results: Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications. Conclusions: The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.

Identification of lactoferrin and glutamate receptor-interacting protein 1 in bovine cervical mucus: A putative marker for oestrous detection.

Accurate detection of oestrus is important for artificial insemination. The aim of this study was to identify oestrous-specific bovine cervical mucus proteins that could be used to determine the optimal time for artificial insemination. Non-oestrous and controlled internal drug release (CIDR)-induced oestrous-stage mucus proteins were purified and subjected to surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, sodium dodecyl sulphate polyacrylamide gel electrophoresis and MALDI-TOF/TOF. Among differentially expressed proteins, lactoferrin (LF) and glutamate receptor-interacting protein 1 (GRIP1) showed a twofold increase during the CIDR-induced oestrous stage compared to the levels in non-oestrous stage in bovine cervical mucus. The RT-PCR, Western blotting and immunohistochemistry results showed that LF and GRIP1 expression was significantly increased during the oestrous stage in the uterus. This study demonstrated that bovine LF and GRIP1 exist during the oestrous stage, but not during the non-oestrous stage, suggesting that cervical mucus LF and GRIP1 are useful oestrous detection markers in cattle.

Profiling of rectal cancers MRI in pathological complete remission states after neoadjuvant concurrent chemoradiation therapy.

AIM: To fully characterise the magnetic resonance imaging (MRI) traits of rectal cancers in a large sample of patients, each experiencing pathological complete remission (pCR) after neoadjuvant concurrent chemoradiation therapy (CCRT). MATERIALS AND METHODS: A total of 120 patients (77 male, 43 female; median age, 59.5 years; range, 32-81 years) with rectal cancers in CCRT-induced pCR states who underwent pre- and post-CCRT MRI and eventual surgery between July, 2005 and September, 2014 were retrospectively reviewed. In most (n=100), diffusion-weighted imaging was also performed. Tumour volume, tumour regression grade (TRG), T-stage, mesorectal fascia (MRF) status, and T2 signal intensity (T2-SI) were analysed. Paired t-test and McNemar's test were applied for statistical comparisons. RESULTS: Tumour volume declined sharply after CCRT (pre-CCRT, 21.5 ± 22.4 cm(3); post-CCRT, 6.6 ± 8.4 cm(3); p<0.001). TRG distribution was as follows: G1 (clinical CR), 3; G2, 38; G3, 78; G4, 1; and G5 (marked progression), 0. Downstaging of T-stage (34%,16/47) and MRF status (19.7%,13/66) did occur; but on post-CCRT MRI, 25.8% (31/120) remained at T3 ≥ 5 mm or T4 stage, and 44.2% (53/120) were MRF-positive. A majority (88.3%, 106/120) of patients displayed intermediate T2-SI prior to CCRT. Most converted to dark T2-SI after CCRT, with 12.5% (15/120) unchanged. On post-CCRT MRI, 11% (11/100) of patients showed diffusion restriction. CONCLUSION: MRI findings in CCRT-induced pCR-status rectal cancers were highly variable. Tumour volume and T2-SI mostly decreased; however, such lesions occasionally presented with unexpected atypical features, such as large residual volume and/or intermediate T2-SI.

Multicentre study of robotic intersphincteric resection for low rectal cancer.

BACKGROUND: There is a lack of information regarding the oncological safety of robotic intersphincteric resection (ISR) with coloanal anastomosis. The objective of this study was to compare the long-term feasibility of robotic compared with laparoscopic ISR. METHODS: Between January 2008 and May 2011, consecutive patients who underwent robotic or laparoscopic ISR with coloanal anastomosis from seven institutions were included. Propensity score analyses were performed to compare outcomes for groups in a 1 : 1 case-matched cohort. The primary endpoint was 3-year disease-free survival. RESULTS: A total of 334 patients underwent ISR with coloanal anastomosis, of whom 212 matched patients (106 in each group) formed the cohort for analysis. The overall rate of conversion to open surgery was 0.9 per cent in the robotic ISR group and 1.9 per cent in the laparoscopic ISR group. Nine patients (8.5 per cent) in the laparoscopic group and three (2.8 per cent) in the robotic ISR group still had a stoma at last follow-up (P = 0.075). Total mean hospital costs were significantly higher for robotic ISR (€ 12,757 versus € 9223 for laparoscopic ISR; P = 0.037). Overall 3-year local recurrence rates were similar in the two groups (6.7 per cent for robotic and 5.7 per cent for laparoscopic resection; P = 0.935). The combined 3-year disease-free survival rates were 89.6 (95 per cent c.i. 84.1 to 95.9) and 90.5 (85.4 to 96.6) per cent respectively (P = 0.298). CONCLUSION: Robotic ISR with coloanal anastomosis for rectal cancer has reasonable oncological outcomes, but is currently too expensive with no short-term advantages.

Association between eNOS polymorphisms and risk of coronary artery disease in a Korean population: a meta-analysis.

Coronary artery disease (CAD), a multifactorial disease, is a common cause of mortality in humans. Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene (-786T>C, 4a4b, and 894G>T) have been previously associated with increased CAD risk. However, the sample size of this previous study was too small and limited to comprehensively define an association between eNOS polymorphisms and CAD; therefore, this analysis was duplicated with a larger population. The study was conducted on 559 patients with CAD and 574 healthy controls. Genetic DNA was extracted using the commercial G-DEX blood extraction kit and statistical analyses were performed on the GraphPad prism 4.0 and MedCalc 12.0 statistical software platforms. No single variant of the eNOS polymorphism was associated with CAD risk. The combination genotypes of eNOS -786TT/4a4b+4a4a [adjusted odds ratio (AOR) = 0.122; 95% confidence interval (CI): 0.042-0.358] and eNOS -786TC+CC/4b4b (AOR = 0.379; 95%CI: 0.147-0.979) were associated with decreased CAD incidence. Haplotype analysis revealed that the T-4a haplotype of eNOS -786T>C and 4a4b exerted a protective effect against CAD. The association between eNOS -786T>C and increased CAD risk was not replicated in this (larger) population. However, some combined genotypes showed a meaningful association with CAD risk.

Overview of anal fistula and systematic review of ligation of the intersphincteric fistula tract (LIFT).

Anal fistula management has long been a challenge for surgeons. Presently, no technique exists that is ideal for treating all types of anal fistula, whether simple or complex. A higher incidence of poor sphincter function and recurrence after surgery has encouraged the development of a new sphincter-sparing procedure, ligation of the intersphincteric fistula tract (LIFT), first described by Van der Hagen et al. in 2006. We assessed the safety, feasibility, success rate, and continence of LIFT as a sphincter-saving procedure. A literature search of articles in electronic databases published from January 2006 to August 2012 was performed. Analysis followed Preferred Reporting Items for Systematic Reviews recommendations. All LIFT-related articles published in the English language were included. We excluded case reports, abstracts, letters, non-English language articles, and comments. The procedure was described in detail as reported by Rojanasakul. Thirteen original studies, including 435 patients, were reviewed. The most common fistula procedure type was transsphincteric (92.64 %). The overall median operative time was 39 (±20.16) min. Eight authors performed LIFT as a same-day surgery, whereas the others admitted patients to the hospital, with an overall median stay of 1.25 days (range 1-5 days). Postoperative complications occurred in 1.88 % of patients. All patients remained continent postoperatively. The overall mean length of follow-up was 33.92 (±17.0) weeks. The overall mean healing rate was 81.37 (±16.35) % with an overall mean healing period of 8.15 (±5.96) weeks. Fistula recurrence occurred in 7.58 % of patients. LIFT represents a new, easy-to-learn, and inexpensive sphincter-sparing procedure that provides reasonable results. LIFT is safe and feasible, with favorable short- and long-term outcomes. However, additional prospective randomized studies are required to confirm these findings.

Association of transforming growth factor-beta 1 gene polymorphism with genetic susceptibility to ossification of the posterior longitudinal ligament in Korean patients.

Ossification of the posterior longitudinal ligaments (OPLL) has been considered to be associated with abnormalities of bone metabolism, and transforming growth factor-ß1 (TGF-ß1) has been demonstrated to affect the bone remodeling process. We investigated two SNPs of the TGF-ß1 promoter (-509C>T; rs1800469) and exon 1 (869T>C; rs1982073) in 298 Koreans (98 patients with OPLL and 200 control subjects). The promoter SNP -509C>T was determined by PCR and RFLP, and the TaqMan probe assay was used to determine 869T>C polymorphism genotypes. The subjects were divided into OPLL continuous group (continuous type plus mixed type) and OPLL segmental group (segmental and localized type). We also separately analyzed this association according to gender difference. There was no significant difference in genotype distributions of -509C>T and 869T>C polymorphisms of the TGF-ß1 gene between OPLL patients and controls. A combined analysis of TGF-ß1 -509C>T and 869T>C polymorphisms showed no significant association with OPLL, and a subgroup analysis did not show any significant correlation between the SNP -509C>T or SNP 869T>C and OPLL subgroups. Stratification by gender demonstrated no significant effect. We conclude that promoter region (-509C>T) and exon 1 (869T>C) polymorphisms are not associated with OPLL in the Korean population.

Association between VEGF and eNOS gene polymorphisms and lumbar disc degeneration in a young Korean population.

Disturbances in blood flow to intervertebral discs (IVD) play an important role in IVD degeneration. Vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) are extremely important angiogenic factors for vasodilation and neovascularization. We investigated the relationship between single nucleotide polymorphisms (SNPs) of the VEGF and eNOS genes and genetic susceptibility to lumbar IVD degeneration in a young adult Korean population. Two hundred and forty-one participants (aged 18 to 30 years), with or without low back pain, were selected for the study. Magnetic resonance imaging was made of the lumbar spine in all participants. The patient group (N = 102) had low back pain clinically and lumbar IVD degeneration radiographically. The control group (N = 139) included subjects with and without low back pain; all were negative radiographically for lumbar IVD degeneration. Using PCR-RFLP analysis, we analyzed VEGF (-2578C>A, -1154G>A, -634G>C, and 936C>T) and eNOS (-786T>C, 4a4b and 894G>T) SNPs. We made combined analyses of the genes and performed haplotype analyses. There were no significant differences in the genotype distribution of polymorphisms of VEGF and eNOS genes among patients and controls. However, the frequency of VEGF -2578CA +AA/-634CC combined genotypes was significantly higher in patients when compared with controls [odds ratio (OR) = 21.00; 95% confidence interval (CI) = 2.590- 170.240]. The frequencies of the -2578A/-1154A/-634C/936C (OR = 3.831; 95%CI = 1.068-13.742), -2578A/-1154A/-634C (OR = 3.356; 95%CI = 1.198-9.400), and -2578A/-634C/936C (OR = 10.820; 95%CI = 2.811-41.656) haplotypes were also significantly higher in patients than in controls. We conclude that the combined genotype VEGF -2578CA+AA/-634CC is a possible risk factor for IVD degeneration and the VEGF -2578A/-1154A/-634C/936C haplotype may increase the risk for development of IVD degeneration. Furthermore, the VEGF -634C allele appears to be associated with susceptibility to IVD degeneration.

Genetic Polymorphisms of the Bovine NOV Gene Are Significantly Associated with Carcass Traits in Korean Cattle.

The objective of this study was to investigate single nucleotide polymorphisms (SNPs) in the bovine nephroblastoma overexpressed (NOV) gene and to evaluate whether these polymorphisms affect carcass traits in the Korean cattle population. We resequenced to detect SNPs from 24 unrelated individuals and identified 19 SNPs within the full 8.4-kb gene, including the 1.5-kb promoter region. Of these 19 SNPs, four were selected for genotyping based on linkage disequilibrium (LD). We genotyped 429 steers to assess the associations of these four SNPs with carcass traits. Statistical analysis revealed that g.7801T>C and g.8379A>C polymorphisms in the NOV gene were associated with carcass weight (p = 0.012 and 0.008, respectively), and the g.2005A>G polymorphism was associated with the back fat thickness (BF) trait (p = 0.0001). One haplotype of the four SNPs (GGTA) was significantly associated with BF (p = 0.0005). Our findings suggest that polymorphisms in the NOV gene may be among the important genetic factors affecting carcass yield in beef cattle.

Adenosine triphosphate-based chemotherapy response assay-guided chemotherapy in unresectable colorectal liver metastasis.

BACKGROUND: This study aims to evaluate the effectiveness of adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided neoadjuvant chemotherapy for increasing resectability in patients with unresectable colorectal liver metastasis. PATIENTS AND METHODS: Patients were randomised into two groups: Group A was treated by conventional chemotherapy regimen and Group B was treated by chemotherapy regimen according to the ATP-CRA. Three chemotherapeutic agents (5-fluorouracil, oxaliplatin and irinotecan) were tested by ATP-CRA and more sensitive agents were selected. Either FOLFOX or FOLFIRI was administered. Between Group A and B, treatment response and resectability were compared. RESULTS: Between November 2008 and October 2010, a total 63 patients were randomised to Group A (N=32) or Group B (N=31). FOLFOX was more preferred in Group A than in Group B (26 out of 32 (81.3%) vs 20 out of 31 (64.5%)). Group B showed better treatment response than Group A (48.4% vs 21.9%, P=0.027). The resectability of hepatic lesion was higher in Group B (35.5% vs 12.5%, P=0.032). Mean duration from chemotherapy onset to the time of liver resection was 11 cycles (range 4-12) in Group A and 8 cycles (range 8-16) in Group B. CONCLUSION: This study showed that tailored-chemotherapy based on ATP-CRA could improve the treatment response and resectability in initially unresectable colorectal liver metastasis.

Transanal specimen extraction in robotic rectal cancer surgery.

BACKGROUND: The aim of this study was to identify the benefits of robotic transanal specimen extraction (RTSE) compared with minilaparotomy specimen extraction (MSE). METHODS: Patients who underwent totally robotic surgery with curative intent for treatment of adenocarcinoma of the rectum below 12 cm from the anal verge were selected from the authors' database. Patients were divided into RTSE and MSE groups according to the method of specimen delivery. Clinicopathological features and perioperative surgical outcomes were compared between the two groups. RESULTS: There were 53 patients in the RTSE group and 66 in the MSE group. No differences were observed in overall complications. Postoperative recovery was faster in the RTSE group in terms of resumption of a soft diet (mean(s.d.) 3·5(1·5) versus 4·6(1·7) days; P < 0·001) and length of hospital stay (9·0(4·8) versus 11·3(5·3) days; P = 0·016). Pain scores on a visual analogue scale were significantly lower in the RTSE group than in the MSE group from day 2 to day 5 after surgery (P = 0·021 to P < 0·001). CONCLUSION: RTSE in robotic rectal cancer surgery was associated with less pain and a faster recovery than MSE.

Effects of Dietary Fat Types on Growth Performance, Pork Quality, and Gene Expression in Growing-finishing Pigs.

This study was performed to determine the effects of dietary fat sources, i.e., beef tallow, soybean oil, olive oil and coconut oil (each 3% in feed), on the growth performance, meat quality and gene expression in growing-finishing pigs. A total of 72 crossbred pigs (Landrace×Large White×Duroc) were used at 71±1 kg body weight (about 130 d of age) in 24 pens (320×150 cm) in a confined pig house (three pigs per pen) with six replicate pens per treatment. The growing diet was given for periods of 14±3 d and the finishing diet was given for periods of 28±3 d. The fat type had no significant effect either on growth performance or on chemical composition or on meat quality in growing-finishing pigs. Dietary fat type affected fatty acid composition, with higher levels of unsaturated fatty acids (UFAs) and monounsaturated fatty acids (MUFAs) in the olive oil group. Microarray analysis in the Longissimus dorsi identified 6 genes, related to insulin signaling pathway, that were differentially expressed among the different feed groups. Real time-PCR was conducted on the six genes in the longissimus dorsi muscle (LM). In particular, the genes encoding the protein kinase, cAMP-dependent, regulatory, type II, alpha (PRKAR2A) and the catalytic subunit of protein phosphatase 1, beta isoform (PPP1CB) showed the highest expression level in the olive oil group (respectively, p<0.05, p<0.001). The results of this study indicate that the type of dietary fat affects fatty acid composition and insulin signaling-related gene expression in the LM of pigs.

CYP2A6 and ERCC1 polymorphisms correlate with efficacy of S-1 plus cisplatin in metastatic gastric cancer patients.

BACKGROUND: We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6)/excision repair cross-complementation group 1 (ERCC1)/X-ray repair cross-complementing group 1(XRCC1) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin. METHODS: Among MGC patients (n=108), who received S-1 (40 mg m(-2) b.i.d., days 1-14) and cisplatin (60 mg m(-2), day 1) every 3 weeks, we analysed the wild-type allele (W) and variants (V) of CYP2A6 (*4, *7, *9, *10), and the polymorphisms of ERCC1 (rs11615, rs3212986) and XRCC1 (rs25487). RESULTS: Patients having fewer CYP2A6 variants had better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4=66.7 vs 58.3 vs 32.3%; P=0.008), time to progression (TTP) (7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C>A (rs3212986) was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (4.4 vs 7.6 vs 7.9 months) (P=0.012). Patients carrying both risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C) vs those carrying none showed an adjusted odds ratio of 0.113 (P=0.004) for response, and adjusted hazard ratios of 3.748 (P=0.0001) for TTP and 2.961 (P=0.006) for death. CONCLUSION: Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin.

Phase II study of a triplet regimen of S-1 combined with irinotecan and oxaliplatin in patients with metastatic gastric cancer: clinical and pharmacogenetic results.

BACKGROUND: The aim of this study was to investigate the efficacy and safety of S-1/irinotecan/oxaliplatin (TIROX) in metastatic gastric cancer (MGC) and the association between treatment outcome and uridine diphosphate-glucuronosyltransferase (UGT) 1A polymorphisms. PATIENTS AND METHODS: Patients with previously untreated MGC received S-1 40 mg/m(2) b.i.d. on days 1-14 and irinotecan 150 mg/m(2) plus oxaliplatin 85 mg/m(2) on day 1 every 3 weeks. RESULTS: Forty-four patients were enrolled. In intent-to-treat analysis, the objective response rate was 75%, including the complete response (CR) rate of 14%. The median time to progression and overall survival was 10.2 and 17.6 months, respectively. Ten (26%) of the 39 patients with primary gastric tumor showed biopsy-confirmed gastric CR. Grade 3/4 neutropenia developed in 66% of patients and grade 3 febrile neutropenia in 16%. The most common grade 3 nonhematologic toxic effects were abdominal pain (18%), anorexia (16%), and diarrhea (14%). UGT1A polymorphisms were associated with significantly higher incidence of grade 4 leukopenia (UGT1A1*6), neutropenia (UGT1A1*6, UGT1A6*2, and UGT1A7*3), grade 3/4 febrile neutropenia (UGT1A1*6), and grade 3 abdominal pain (UGT1A1*6). CONCLUSIONS: The TIROX regimen induced marked tumor reduction and promising survival with a manageable toxicity profile in MGC patients. UGT1A genotype may be predictive of TIROX toxicity.

Plasma total homocysteine and the methylenetetrahydrofolate reductase 677C>T polymorphism do not contribute to the distribution of cervico-cerebral atherosclerosis in ischaemic stroke patients.

OBJECTIVE: To evaluate the effects of plasma total homocysteine (tHcyt) and the MTHFR 677C>T polymorphism on determining the intracranial- (IC) and extracranial (EC) locations of atherosclerosis. METHODS: Brain MR angiography was performed on 463 patients with symptomatic ischaemic stroke to detect significant atherosclerosis (more than 50% stenosis of vessel diameter) in the IC- and EC arteries. Relationships between IC- or EC atherosclerosis and plasma tHcyt level and/or MTHFR 677C>T genotypes were analyzed after adjusting for vascular risk factors. RESULTS: The odd ratios (ORs) of plasma tHcyt were not significantly higher in patients with either IC- or EC atherosclerosis than in patients with no atherosclerosis. When the study subjects were stratified into three subgroups according to their plasma tHcyt levels, neither the crude ORs nor adjusted ORs of each IC- and EC atherosclerosis in highest and middle plasma tHcyt tertile were significantly different from those in lowest plasma tHcyt tertile. The ORs of the MTHFR 677TT genotype in IC- and EC atherosclerosis were not significantly different from those in no atherosclerosis. There was no dose-dependent effect of MTHFR 677T allele on either IC- or EC atherosclerosis. CONCLUSION: Plasma tHcyt level and the MTHFR 677C>T polymorphism do not contribute to the distribution of cervico-cerebral atherosclerosis in ischaemic stroke patients.

Osteonecrosis of the jaw induced by oral administration of bisphosphonates in Asian population: five cases.

SUMMARY: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) can occur irrespective of race. Old age and long-term use of corticosteroid may be a more reliable risk factor than racial characteristics. INTRODUCTION: BRONJ is an increasingly common problem. Most BRONJ occurs following an intravenous administration of bisphosphonate treatment for malignant bone disease and metastatic cancer. As the incidence of BRONJ caused by oral administration of bisphosphonate is quite low, it is believed that this medication is relatively safe and effective in preventing complications of osteoporosis, such as hip or spine fractures. The many known risk factors for BRONJ can be classified as drug-related, local, demographic, and systemic. One demographic and systemic risk factor is race. Most of the case reports of BRONJ present elderly, white women. METHODS: In this report, we describe five cases of BRONJ caused by oral administration of bisphosphonate in Asian population. RESULTS: All the patients were female and over 65 years old. Three patients had been prescribed with corticosteroids for rheumatoid arthritis. CONCLUSION: Irrespective of race, elderly women undergoing steroid therapy have an increased incidence of BRONJ even with oral administration of bisphosphonate.

Biomarker analysis in stage III-IV (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy: epidermal growth factor receptor (EGFR) associated with favourable survival.

The aim of this study was to analyse the impact of epidermal growth factor receptor (EGFR), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), aurora kinase (ARK) A/B, and excision repair cross-complementing gene 1 (ERCC1) on the efficacy of adjuvant chemotherapy with 5-fluorouracil and cisplatin (FP) after curative gastric resection. Normal and cancer tissue were separately obtained from gastrectomy samples of 153 patients with AJCC stage III-IV (M0) who subsequently treated with adjuvant FP chemotherapy. TS, DPD, TP, ERCC1, and ARK proteins were measured by immunohistochemistry (IHC). EGFR expression was investigated using a standardized IHC with the EGFR PharmDx assay. Amplification of EGFR gene was analysed using fluorescent in situ hybridisation (FISH). In multivariate analysis, stage, ratio of positive to removed lymph nodes, and EGFR expression were significant prognostic factors for overall survival. Patients with higher EGFR expression had better overall survival than those with lower expression (relative risk: 0.475 (95% confidence interval, 0.282-0.791, P=0.005). Low EGFR expression might be a predictive marker for relapse in curative resected stage III-IV (M0) gastric cancer patients who received adjuvant FP chemotherapy.

Effective second-line chemotherapy for extranodal NK/T-cell lymphoma consisting of etoposide, ifosfamide, methotrexate, and prednisolone.

BACKGROUND: Many patients with extranodal natural killer/T-cell lymphoma (NTCL) fail to the front-line therapy and need an effective second-line chemotherapy. PATIENTS AND METHODS: This was single-institutional, phase II study. The primary end point was response rate and secondary end points were toxicity, time to treatment failure (TTF), and overall survival (OS). Patients with relapsed or refractory NTCL were eligible. They received the chemotherapy consisting of ifosfamide, methotrexate, etoposide, and prednisolone and it was repeated every 3 weeks. RESULTS: Thirty-two patients were enrolled and 15 patients had achieved partial remission (PR) or complete remission (CR) after the front-line chemotherapy. The International Prognostic Index scores were 0-1 in thirteen, 2 in five, 3 in five, and 4-5 in nine patients. Twelve and two patients achieved CR and PR, respectively. Median OS and TTF of all patients were 8.2 and 3.7 months, respectively. Non-hematologic toxic effects were well tolerated, but grade 3/4 leukopenia occurred in 11.7% of all cycles. Four patients developed febrile neutropenia and one patient died due to pneumonia. CONCLUSIONS: This chemotherapy regimen was moderately effective for relapsed/refractory extranodal NTCL, nasal type. Toxic effects were moderate, but caution should be exercised to prevent severe infection.

Phase I/II study of S-1 combined with weekly docetaxel in patients with metastatic gastric carcinoma.

We designed a phase I/II trial of S-1 combined with weekly docetaxel to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in metastatic gastric carcinoma (MGC). Patients with measurable disease received S-1 orally b.i.d. on days 1-14 and docetaxel intravenously on days 1 and 8 every 3 weeks. In phase I (n=30), each cohort received escalating doses of S-1 (30-45 mg m(-2) b.i.d.) and docetaxel (25-40 mg m(-2)); MTD was 45 mg m(-2) b.i.d. S-1/35 mg m(-2) docetaxel and RD was 40 mg m(-2) b.i.d. S-1/35 mg m(-2) docetaxel. Dose-limiting toxicities included grade 3 elevated liver enzymes, gastric perforation, grade 3 diarrhoea/fatigue, febrile neutropenia with grade 3 anorexia/fatigue, and neutropenic infection with grade 3 stomatitis/anorexia. In phase II (n=52), the overall response rate was 66.7% (95% confidence interval (CI): 53.8-79.6%) and the median time to progression and overall survival were 6.5 months (95% CI: 4.9-8.1) and 13.7 months (95% CI: 9.9-17.5), respectively. The most common grade 3/4 toxicity was neutropenia (29.4%), and febrile neutropenia/neutropenic infection occurred in 19.6% of patients. Non-haematological toxicities were generally mild. There was one treatment-related death due to pneumonitis. S-1 combined with weekly docetaxel is active in MGC with moderate toxicities.