PTEN is one of the most frequently mutated or deleted tumor suppressors in human cancers. NEDD4-1 was recently identified as the E3 ubiquitin ligase for PTEN; however, a number of important questions remain regarding the role of ubiquitination in regulating PTEN function and the mechanisms by which PTEN ubiquitination is regulated. In the present study, we demonstrated that p34, which was identified as a binding partner of NEDD4-1, controls PTEN ubiquitination by regulating NEDD4-1 protein stability. p34 interacts with the WW1 domain of NEDD4-1, an interaction that enhances NEDD4-1 stability. Expression of p34 promotes PTEN poly-ubiquitination, leading to PTEN protein degradation, whereas p34 knockdown results in PTEN mono-ubiquitination. Notably, an inverse correlation between PTEN and p34/NEDD4-1 levels was confirmed in tumor samples from colon cancer patients. Thus, p34 acts as a key regulator of the oncogenic behavior of NEDD4-1 and PTEN.
p34; NEDD4-1; PTEN; ubiquitination
Cellular senescence is an important mechanism for preventing tumor progression. The elevated expression of Bcl-2-interacting cell death suppressor (BIS), an anti-apoptotic and anti-stress protein, often correlates with poor prognosis in several cancers including glioblastoma; however, the role of BIS in the regulation of senescence has not been well defined. Here, we describe for the first time that the depletion of BIS induces G1 arrest and cellular senescence through the accumulation of p27 that is independent of p53, p21 or p16. The increase in p27 expression in BIS-depleted cells was attributable to an impairment of the ubiquitin-mediated degradation of p27, which was caused by a decrease in S-phase kinase-associated protein 2 (SKP2) at the transcriptional level. As an underlying molecular mechanism, we demonstrate that the loss of activity of signal transducer and activator of transcription 3 (STAT3) was specifically linked to the suppression of SKP2 expression. Despite a reduction in phospho-STAT3 levels, total STAT3 levels were unexpectedly increased by BIS depletion, specifically in the insoluble fraction. Our results show that 14-3-3ζ expression is decreased by BIS knockdown and that 14-3-3ζ depletion per se significantly induced senescence phenotypes. In addition, the ectopic expression of 14-3-3ζ blocked senescence caused by BIS depletion, which was paralleled with a decrease in insoluble STAT3 in A172 glioblastoma cells. These findings indicate that the impairment of the protein quality control conferred by BIS and/or 14-3-3ζ is critical for BIS depletion-induced senescence. Moreover, BIS knockdown also induced senescence along with an accumulation of total STAT3 and p27 in several different cell types as well as embryonic fibroblasts derived from Bis-knock out mice with/without variations in 14-3-3ζ levels. Therefore, our findings suggest that a downregulation of BIS expression could serve as a potential strategy for restricting tumor progression via an induction of senescence through the regulation of STAT3/SKP2/p27 pathway.
Following DNA damage, p53 translocates to the cytoplasm and mitochondria, where it triggers transcription-independent apoptosis by binding to Bcl-2 family proteins. However, little is known about how this exonuclear function of p53 is regulated. Here, we identify and characterize a p53-interacting protein called Hades, an E3 ligase that interacts with p53 in the mitochondria. Hades reduces p53 stability via a mechanism that requires its RING-finger domain with ubiquitin ligase activity. Hades polyubiquitinates p53 in vitro independent of Mdm2 and targets a critical lysine residue in p53 (lysine 24) distinct from those targeted by Mdm2. Hades inhibits a p53-dependent mitochondrial cell death pathway by inhibiting p53 and Bcl-2 interactions. These findings show that Hades-mediated p53 ubiquitination is a novel mechanism for negatively regulating the exonuclear function of p53.
p53; ubiquitination; E3 ligase
We assessed the efficacy and safety of solifenacin compared with tolterodine for treatment of overactive bladder (OAB) in Korean patients.
Materials and methods:
The study was randomised, double-blind, tolterodine-controlled trial in Korea. Patients had average frequency of ≥ 8 voids per 24 h and episodes of urgency or urgency incontinence ≥ 3 during 3-day voiding diary period. Patients were randomised to 12-week double-blind treatment with either tolterodine immediate release (IR) 2 mg twice daily (TOL4) or solifenacin 5 mg (SOL5) or 10 mg (SOL10) once daily. The outcome measure was mean change in daily micturition frequency, volume, daily frequency of urgency incontinence, urgency and nocturia from baseline to week 12. Quality of life was assessed using the King’s Health Questionnaire.
A total of 357 were randomised and 329 were evaluated for efficacy. All voiding parameters recorded in micturition diary improved after treatment in all three groups. Mean changes in volume voided were 19.30 ml (26.69%) in TOL4, 30.37 ml (25.89%) in SOL5 and 37.12 ml (33.36%) in SOL10 group (p = 0.03). Speed of onset of SOL10 efficacy on urgency incontinence was faster than that of SOL5 and TOL4. Quality of life improved in all three groups. Dry mouth was the most common adverse event; its incidence was the lowest in SOL5 group (7.63%, compared with 19.49% and 18.64% in SOL10 and TOL4 groups respectively).
Solifenacin succinate 5 and 10 mg once daily improve OAB symptoms with acceptable tolerability levels compared with tolterodine IR 4 mg. Solifenacin 5 mg is a recommended starting dose in Korean patients with OAB.
mutation; BRAF; RAS; non-Hodgkin's lymphoma; oncogene
There has been no standard therapy for patients with metastatic colorectal cancer who have failed to first-line fluorouracil-based treatment. The present study was designed to assess the efficacy and toxicities of a combination of oxaliplatin, 5-fluorouracil (5-FU) and leucovorin in fluoropyrimidine-pretreated patients with metastatic colorectal cancer. Chemotherapy consisted of oxaliplatin 85 mg/m2 on day 1, followed by leucovorin 20 mg/m2 and 5-FU 1,200 mg/m2 on days 1 and 2. Treatment courses were repeated every two weeks. Thirty-nine patients were enrolled in this study. All patients previously received fluoropyrimidine-based chemotherapy. Thirty-one patients were assessable for response and 33 for treatment toxicity. Six patients required dose reduction of 5-FU due to grade III/IV cytopenia. Nausea/vomiting and peripheral neuropathy were common non-hematologic toxicities. Overall response rate was 42.0% including 3 complete response and 10 partial response. The median response duration was 91 days (range, 28-224+). The median duration of progression-free survival was 132 days (range, 40-308). A combination of oxaliplatin, 5-FU, and leucovorin showed high response rate in fluoropyrimidine-pretreated patients with metastatic colorectal cancer, but the duration of response was relatively short. It may be worthwhile to explore its therapeutic potential in the first-line treatment setting.
Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are commonly prescribed because of their therapeutic and preventive effects on cardiovascular diseases. Even though they have been occasionally reported to have antitumour activity, it is unknown whether statins have anti-angiogenic effect in human colorectal cancer (CRC).
A total of 11 human CRC cell lines were used to test the effects of bevacizumab, statins, and bevacizumab plus statins on human umbilical vein endothelial cell (HUVEC) viability and invasion in vitro. To determine the molecular mechanism of statins as anti-angiogenic agents, we performed an angiogenesis antibody array and proteomics analysis and confirmed the results using immunoblot assay, HUVEC invasion rescue assay, and siRNA assay. The antitumoural effects of bevacizumab and statins were evaluated in xenograft models.
A conventional dose of statins (simvastatin 0.2 μM, lovastatin 0.4 μM, atorvastatin 0.1 μM, and pravastatin 0.4 μM) in combination with bevacizumab directly reduced the cell viability, migration, invasion, and tube formation of HUVECs. The culture media of the CRC cells treated with bevacizumab or statins were also found to inhibit HUVEC invasion by suppressing angiogenic mediators, such as angiopoietin2, binding immunoglobulin protein (BiP), and Hsp90α. The combined treatment with bevacizumab and simvastatin significantly reduced the growth and metastases of xenograft tumours compared with treatment with bevacizumab alone.
The addition of simvastatin at a dose used in patients with cardiovascular diseases (40–80 mg once daily) may potentiate the anti-angiogenic effects of bevacizumab on CRC by suppressing angiopoietin2, BiP, and Hsp90α in cancer cells. A clinical trial of simvastatin in combination with bevacizumab in patients with CRC is needed.
colorectal cancer; statins; angiogenesis; bevacizumab
This study intended to compare the productive performance of three different layer raising systems; conventional cage (CC), barn (BR) and aviary (AV). The AV is welfare bestowed housing that allows free locomotion for birds within the BR. The BR allows bird’s free locomotion inside BR but without multilevel structures. Both pullets and cockerels were housed together in both AV and BR, but only pullets in CC. Seventeen weeks old Lohmann Brown Lite (n = 800) pullets were housed in AV during this study. The same age layer pullets were simultaneously assigned to either at CC or BR to compare egg production performance with AV. The duration of experiment was 40 weeks (from 21st to 60th week). There were no remarkable differences in egg production, hen day egg production (HDEP) and average egg weight among three rearing systems. First 20 weeks (phase-1) average HDEP (%) of AV, CC, and BR were 85.9, 88.8, 87.1 and average egg weights (g) were 57.5, 59.9, and 56.9 respectively. Those of the remaining 20 weeks (phase-2) were 87.1, 87.9, 85.5 and 64.2, 63.0 62.1, respectively. Daily feed intakes (122 g, 110 g, 125 g); feed conversion ratio (2.4, 2.1, 2.5) and daily egg mass (53.9 g, 54.4 g, 52.8 g) data from AV, CC, and BR were not influenced significantly by the respective raising systems. Daily feed intake of layers in both AV (124 g) and BR (127 g) tended to be higher than that in CC (113 g) during phase-2. Overall, exterior egg quality (dirty and cracked eggs) in both phases was superior in BR compared with AV and CC, whereas CC generated intermediate results. This study indicated that the HDEP per se in AV and BR were not significantly different from that in CC. The study implied that the facility depreciation cost for AV and cost for increased feed intake in AV compared to CC are believed to be critical to evaluate the cost effectiveness of egg production in AV.
Chicken Welfare; Aviary System; Poultry Housing; Productive Performance; Egg Traits
Based on a quantitative traits locus (QTL) study using a F2 intercross between Landrace and Korean native pigs, a significant QTL affecting teat numbers in SSC7 was identified. The strong positional candidate gene, TBC1D21, was selected due to its biological function for epithelial mesenchymal cell development. Sequence analysis revealed six single nucleotide polymorphisms (SNPs) in the TBC1D21 gene. Among these, two SNP markers, one silent mutation (SNP01) for g.13,050A>G and one missense mutation (SNP04) for c.829A>T (S277C), were genotyped and they showed significant associations with teat number traits (p value = 6.38E-05 for SNP01 and p value = 1.06E-07 for SNP04 with total teat numbers). Further functional validation of these SNPs could give valuable information for understanding the teat number variation in pigs.
QTL; SNP; SSC7; TBC1D21; Teat Number; Pig
The objective of this study was to determine the incidence of typical and
atypical enhancement patterns of hepatocellular carcinomas (HCCs)
on multiphasic multidetector row CT (MDCT) and to correlate the
enhancement patterns and morphological image findings of HCC with the degree
of tumour differentiation.
MDCT images of 217 patients with 243 surgically proven HCCs were evaluated
through consensus reading by two radiologists. Our MDCT protocol was composed
of precontrast, arterial, portal and delayed phases. The reviewers analysed
the CT images for degree of attenuation; relative timing of washout; presence
of dysmorphic intratumoral vessels, aneurysms and necrosis; tumour size; tumour
margin; presence of pseudocapsule; intratumoral heterogeneity; and determined
enhancement pattern. The imaging features were correlated with tumour differentiation
using Fisher's exact test or the χ2
Among 243 HCCs, 137 (56.4%) showed the typical enhancement
pattern of HCC, which is arterial enhancement and washout on portal or equilibrium
phase images. In the arterial phase, 190 of 243 (78.2%) HCCs
showed hypervascularity, with approximately three quarters of poorly differentiated (PD) (34
of 45, 75.6%) and moderately differentiated (MD) HCCs (92
of 123, 74.8%) showing washout during the portal or delayed phases, vs
only 50% of well-differentiated (WD) HCCs (11 of 22; p<0.048).
The presence of intratumoral vessels and aneurysms, tumour necrosis, attenuation
of precontrast, the relative timing of washout, intratumoral attenuation heterogeneity,
tumour margin and tumour size were correlated with the pathological differentiation
of HCCs (p<0.05).
A typical enhancement of HCCs on MDCT was not unusual (43.6%)
and WD and PD HCCs account for most of the atypical enhancement patterns.
Early washout favoured MD and PD HCCs rather than WD HCCs, whereas in our
study the presence of intratumoral aneurysm was a highly specific finding
for PD HCC.
Docetaxel is widely used as a chemotherapeutic agent for gastric cancer treatment. A
combined regimen with sunitinib demonstrated a synergistic antitumour effect in a
preclinical model. The aim of this study was to evaluate the efficacy and safety of this
combination in patients with unresectable or metastatic advanced gastric cancer
following failure of treatment with a fluoropyrimidine and platinum combination.
This open-label, phase II, randomised trial enrolled patients with unresectable or
metastatic gastric cancer. Patients were assigned to either a docetaxel monotherapy arm
(D only arm: 60 mg m−2, every 3 weeks) or a combination
arm (DS arm: docetaxel+sunitinib 37.5 mg every day). The primary end point
of the study was time to progression and the secondary end points were overall response
rate, disease control rate, overall survival, and toxicity profile. A pharmacokinetic
study was also performed.
A total of 107 patients were entered into the study. The TTP was not significantly
prolonged in the DS arm when compared with the D only arm (DS vs D only arm:
3.9 months (95% confidence interval (CI) 2.9–4.9) vs 2.6 months
(95% CI 1.8–3.5) (P=0.206). The hazard ratio for TTP was
0.77 (95% CI 0.52–1.16). However, the objective response rate was
significantly higher in the DS arm (41.1% vs 14.3%,
P=0.002). Patients in the DS arm experienced stomatitis, diarrhoea, and
hand–foot syndrome more frequently.
The addition of sunitinib to docetaxel did not significantly prolong TTP, although it
significantly increased response.
gastric cancer; second-line chemotherapy; docetaxel; sunitinib
The purpose of this study was to review radiological images of patients with Paragonimus westermani (PW) that simultaneously involved the chest and abdomen.
Our study included four patients with serologically and histopathologically confirmed paragonimiasis. Abdomen CT (n=3) and chest CT (n=3) scans were available, and abdominal wall ultrasonography was performed in all patients. We retrospectively reviewed the clinical, radiological and histopathological findings of these patients.
The most common abdominal CT findings were ascites and intraperitoneal or abdominal wall nodules. Low-attenuated serpentine lesions of the liver were another common and relatively specific feature.
Radiologists should consider the possibility of PW when these abdominal CT findings are noted, especially with pleural effusion or subpleural nodules in patients with initial abdominal symptoms.
Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.
We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.
An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.
Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology® 2012;78:690–695
Twist1 is highly expressed in primary and metastatic non-small cell lung cancer (NSCLC), and thus acts as a critical target for lung cancer chemotherapy. In the current study, we investigated the underlying mechanism initiated by silencing of Twist1 that sensitizes NSCLC cells to cisplatin. Silencing of Twist1 triggered ATP depletion, leading to AMP-activated protein kinase (AMPK)-activated mammalian target of rapamycin (mTOR) inhibition in NSCLC cells. AMPK-induced mTOR inhibition, in turn, resulted in downregulation of ribosome protein S6 kinase 1 (S6K1) activity. Downregulation of mTOR/S6K1 reduced Mcl-1 protein expression, consequently promoting sensitization to cisplatin. Overexpression of Mcl-1 reduced PARP cleavage induced by cisplatin and Twist1 siRNA, suggesting that this sensitization is controlled through Mcl-1 expression. Interestingly, cells treated with Twist1 siRNA displayed upregulation of p21Waf1/CIP1, and suppression of p21Waf1/CIP1 with specific siRNA further enhanced the cell death response to cisplatin/Twist1 siRNA. In conclusion, silencing of Twist1 sensitizes lung cancer cells to cisplatin via stimulating AMPK-induced mTOR inhibition, leading to a reduction in Mcl-1 protein. To our knowledge, this is the first report to provide a rationale for the implication of cross-linking between Twist1 and mTOR signaling in resistance of NSCLC to anticancer drugs.
AMPK; cisplatin; mTOR; p21Waf1/CIP1; Twist1
Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) has frequently been observed in human gliomas, conferring AKT activation and resistance to ionizing radiation (IR) and drug treatments. Recent reports have shown that PTEN loss or AKT activation induces premature senescence, but many details regarding this effect remain obscure. In this study, we tested whether the status of PTEN determined fate of the cell by examining PTEN-deficient U87, U251, and U373, and PTEN-proficient LN18 and LN428 glioma cells after exposure to IR. These cells exhibited different cellular responses, senescence or apoptosis, depending on the PTEN status. We further observed that PTEN-deficient U87 cells with high levels of both AKT activation and intracellular reactive oxygen species (ROS) underwent senescence, whereas PTEN-proficient LN18 cells entered apoptosis. ROS were indispensable for inducing senescence in PTEN-deficient cells, but not for apoptosis in PTEN-proficient cells. Furthermore, transfection with wild-type (wt) PTEN or AKT small interfering RNA induced a change from premature senescence to apoptosis and depletion of p53 or p21 prevented IR-induced premature senescence in U87 cells. Our data indicate that PTEN acts as a pivotal determinant of cell fate, regarding senescence and apoptosis in IR-exposed glioma cells. We conclude that premature senescence could have a compensatory role for apoptosis in the absence of the tumor suppressor PTEN through the AKT/ROS/p53/p21 signaling pathway.
premature senescence; apoptosis; PTEN; glioma
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.
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).
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.
Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin.
cisplatin; CYP2A6; ERCC1; gastric cancer; polymorphism; S-1
Lymph node metastasis is one of the most important adverse prognostic factors for pancreatic cancer. The aim of this study was to identify novel lymphatic metastasis-associated markers and therapeutic targets for pancreatic cancer.
DNA microarray study was carried out to identify genes differentially expressed between 17 pancreatic cancer tissues with lymph node metastasis and 17 pancreatic cancer tissues without lymph node metastasis. The microarray results were validated by real-time PCR. Immunohistochemistry and western blotting were used to examine the expression of farnesoid X receptor (FXR). The function of FXR was studied by small interfering RNA and treatment with FXR antagonist guggulsterone and FXR agonist GW4064.
Farnesoid X receptor overexpression in pancreatic cancer tissues with lymph node metastasis is associated with poor patient survival. Small interfering RNA-mediated downregulation of FXR and guggulsterone-mediated FXR inhibition resulted in a marked reduction in cell migration and invasion. In addition, downregulation of FXR reduced NF-κB activation and conditioned medium from FXR siRNA-transfected cells showed reduced VEGF levels. Moreover, GW4064-mediated FXR activation increased cell migration and invasion.
These findings indicated that FXR overexpression plays an important role in lymphatic metastasis of pancreatic cancer and that downregulation of FXR is an effective approach for inhibition of pancreatic tumour progression.
pancreatic cancer; lymph node metastasis; FXR; DNA microarray; siRNA
Only a few clinical trials have been conducted in patients with advanced pancreatic cancer after failure of first-line gemcitabine-based chemotherapy. Therefore, there is no current consensus on the treatment of these patients. We conducted a randomised phase II study of the modified FOLFIRI.3 (mFOLFIRI.3; a regimen combining 5-fluorouracil (5-FU), folinic acid, and irinotecan) and modified FOLFOX (mFOLFOX; a regimen combining folinic acid, 5-FU, and oxaliplatin) regimens as second-line treatments in patients with gemcitabine-refractory pancreatic cancer.
The primary end point was the 6-month overall survival rate. The mFOlFIRI.3 regimen consisted of irinotecan (70 mg m−2; days 1 and 3), leucovorin (400 mg m−2; day 1), and 5-FU (2000 mg m−2; days 1 and 2) every 2 weeks. The mFOLFOX regimen was composed of oxaliplatin (85 mg m−2; day 1), leucovorin (400 mg m−2; day 1), and 5-FU (2000 mg m−2; days 1 and 2) every 2 weeks.
Sixty-one patients were randomised to mFOLFIRI.3 (n=31) or mFOLFOX (n=30) regimen. The six-month survival rates were 27% (95% confidence interval (CI)=13–46%) and 30% (95% CI=15–49%), respectively. The median overall survival periods were 16.6 and 14.9 weeks, respectively. Disease control was achieved in 23% (95% CI=10–42%) and 17% patients (95% CI=6–35%), respectively. The number of patients with at least one grade 3/4 toxicity was identical (11 patients, 38%) in both groups: neutropenia (7 patients under mFOLFIRI.3 regimen vs 6 patients under mFOLFOX regimen), asthaenia (1 vs 4), vomiting (3 in both), diarrhoea (2 vs 0), and mucositis (1 vs 2).
Both mFOLFIRI.3 and mFOLFOX regimens were tolerated with manageable toxicity, offering modest activities as second-line treatments for patients with advanced pancreatic cancer, previously treated with gemcitabine.
second-line chemotherapy; pancreatic cancer; irinotecan; oxaliplatin; gemcitabine
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.
S-1; docetaxel; metastatic gastric carcinoma; phase I/II study
Phosphorylated AKT (pAKT) is a major contributor to radioresistance in human cancers. The aim of this study was to investigate the association of pAKT expression and radiation resistance in cervical cancer. A retrospective review was made of the records of 27 women who received primary radiation therapy due to locally advanced cervical cancer (LACC) with FIGO stage IIB–IVA. Nine patients regarded as radiation resistant developed local recurrences with a median progression free interval of 9 months. Eighteen patients did not show local recurrences, and were regarded as a radiation-sensitive group. Using pretreatment paraffin-embedded tissues, we evaluated pAKT expression by immunohistochemistry. A significant association was found between the level of pAKT expression and local recurrence. Immunohistochemical staining for pAKT was significantly more frequent in the radiation-resistant than in the radiation-sensitive group (P=0.004). The mean progression-free survival was 86 months for patients with pAKT-negative staining (19 cases) and 44 months for patients with pAKT-positive expression (eight cases) (P=0.008). These results suggest that signalling from phosphatidylinositide 3-kinase/pAKT can lead to radiation resistance, and that evaluation of pAKT may be a prognostic marker for response to radiotherapy in LACC.
cervical neoplasms; radiation resistance; pAKT; PI3K; immunohistochemistry
The current treatment for metastatic gastric cancer (MGC) consists of cisplatin and/or fluorouracil (5-FU) based combination chemotherapy, but cisplatin-based regimens are associated with considerable toxicity. We evaluated the efficacy and safety of a noncisplatin-, non-5-FU-containing regimen, docetaxel/irinotecan in MGC. Chemo-naive patients with MGC received docetaxel (30 mg m−2) and irinotecan (70 mg m−2) on days 1 and 8 every 3 weeks. The 48 eligible patients (median age 56 years) received a median of four cycles of docetaxel/irinotecan (range 1–18). Of the 46 patients in whom efficacy could be evaluated, 21 showed a partial response (response rate=45.7%; 95% confidence interval (CI) 31.3–60.1%). At a median follow-up of 15.0 months, the median time to progression was 4.5 months (95% CI 3.8–5.2 months) and overall survival was 8.2 months (95% CI, 5.8–10.6 months). Grade 3/4 neutropenia developed in 57.4% of patients, and febrile neutropenia/neutropenic infection in 19.1%. Nonhaematological toxicities were moderate; grade 3/4 diarrhoea occurred in 19.1% of patients, however, was manageable by a dose reduction. There was one possible treatment-related death. In conclusion, weekly docetaxel/irinotecan is a promising outpatient regimen in MGC, with appropriate dose modification.
docetaxel; gastric cancer; irinotecan
mitral regurgitation; ventricular function; systolic dimension
Aim: To determine the prevalence and identify associated risk factors for dry eye syndrome in a population in Sumatra, Indonesia.
Methods: A one stage cluster sampling procedure was conducted to randomly select 100 households in each of the five rural villages and one provincial town of the Riau province, Indonesia, from April to June 2001. Interviewers collected demographic, lifestyle, and medical data from 1058 participants aged 21 years or over. Symptoms of dry eye were assessed using a six item validated questionnaire. Presence of one or more of the six dry eye symptoms often or all the time was analysed. Presence of pterygium was documented.
Results: Prevalence of one or more of the six dry eye symptoms often or all the time adjusted for age was 27.5% (95% confidence interval (CI) 24.8 to 30.2). After adjusting for all significant variables, independent risk factors for dry eye were pterygium (p<0.001, multivariate odds ratio (OR) 1.8; 95% CI 1.4 to 2.5) and a history of current cigarette smoking (p=0.05, multivariate OR 1.5; 95% CI 1.0 to 2.2).
Conclusions: This population based study provides prevalence rates of dry eye symptoms in a tropical developing nation. From our findings, pterygium is a possible independent risk factor for dry eye symptoms.
dry eye symptoms; pterygium; smoking; population based study
amniotic membrane transplantation; conjunctival ulceration; atropine