Patients enrolled in clinical trials of advanced hepatocellular carcinoma (HCC) are usually required to have good liver reserve and organ function. However, their outcomes are still highly variable. We aimed to examine whether current staging systems can predict the survival of these highly selected patients.
Patients from clinical trials involving first-line anti-angiogenic therapy were assigned to different stage groups using the American Joint Committee on Cancer (AJCC), Barcelona Clinic Liver Cancer (BCLC), China integrated score, Cancer of the Liver Italian Program (CLIP) score, Chinese University Prognostic Index (CUPI), Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (GETCH), Japan Integrated Staging (JIS) score, Okuda, Tokyo score, and a new staging system recently proposed. Survival prediction by the 10 systems was then compared by both univariate and multivariate analyses.
A total of 157 patients were selected for this study. In univariate analysis, all staging systems can predict patient survival except AJCC, BCLC, and JIS score. Concordance indexes for CLIP score, CUPI, and GETCH (0.752, 0.775, and 0.791, respectively) were significantly higher than those obtained for other staging systems. In multivariate analysis, the CLIP score and CUPI (P<0.001 and 0.009, respectively) predicted survival more accurately than did the other tested staging systems. Hepatitis B infection and poor performance status were also associated with poor survival.
Several HCC staging systems, especially the CLIP score and CUPI, can predict prognosis of patients who are enrolled in clinical trials of advanced HCC.
clinical trials; hepatocellular carcinoma; prognosis; staging; survival
Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population.
Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg–1 on day 1 and capecitabine 800 mg m–2 twice daily on days 1–14 every 3 weeks as first-line therapy.
A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand–foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score ⩽3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients.
The bevacizumab–capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.
bevacizumab; capecitabine; hepatocellular carcinoma
biliary tract carcinoma; gemcitabine; 5-fluorouracil; leucovorin
Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such correlation is unclear in sorafenib resistance of HCC.
Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R; derived from sorafenib-sensitive Huh-7) were used. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured. A subcutaneous xenograft mouse model was used for in vivo efficacy.
The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity (R2=0.9067, among sorafenib-naive cell lines; P=0.003, compared between Huh-7 and Huh-7 R). DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4±8.4% vs 13±2.9% Huh-7 R, 25.3± 5.7% vs 4.3±1.5% each P<0.0001), whereas siRNA of HK2 did not. Sorafenib (10 mg kg−1 per day) plus DCA (100 mg kg−1 per day) also resulted in superior tumour regression than sorafenib alone in mice (tumour size: −87% vs −36%, P<0.001).
The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity, and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.
glycolysis; oxidative phosphorylation; sorafenib; dichloroacetate; hepatocellular carcinoma
Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression.
ASXL1 mutation; myelodysplastic syndrome; sequential analyses; prognosis
Transforming growth factor-α (TGF-α)-induced proliferation and transforming growth factor-β (TGF-β)-mediated quiescence are intricately balanced in normal lung-tissue homeostasis but are deregulated during neoplastic progression of lung cancer. Here, we show that Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a novel MYC-interacting transcriptional modulator, responds to TGF-α induction and TGF-β suppression to orchestrate cellular proliferation and quiescence, respectively. Upon TGF-α induction, CITED2 was induced by MYC and further modulated MYC-mediated transcription in a feed-forward manner. CITED2 recruited p300 to promote MYC-p300-mediated transactivation of E2F3, leading to increased G1/S cell cycle progression. Moreover, CITED2 inhibited cellular quiescence by enhancing MYC-mediated suppression of p21CIP1. CITED2 interacted with histone deacetylase 1 (HDAC1) and potentiated MYC–HDAC1 complex formation. TGF-β stimulation provoked downregulation of CITED2, which abrogated MYC-HDAC1-mediated p21CIP1 suppression, causing cellular quiescence. Ectopic CITED2 expression enhanced tumor growth in nude mice; furthermore, CITED2 knockdown caused tumor shrinkage and increased overall host mouse survival rates. Expression of CITED2/MYC/E2F3/p21CIP1 signaling molecules was associated with poor prognosis of lung cancer patients. Thus, CITED2 functions as a molecular switch of TGF-α and TGF-β-induced growth control, and MYC-CITED2 signaling axis provides a new index for predicting clinical outcome.
CITED2; MYC; cytokine; transcriptional modulator; lung cancer
PMID: 22529236 CAMSID: cams2324
A variety of aetiologies may cause third nerve palsy (TNP), and some manifestations may herald neurological emergencies. This article describes and illustrates various diseases that lead to TNP.
This study compared the odds ratio (OR) of surgical site infection (SSI) within 30 days after operation with general anaesthesia (GA) or neuraxial anaesthesia (NA) in Taiwanese women undergoing Caesarean delivery (CD).
An epidemiologic design was used. The study population was based on the records of all deliveries in hospitals or obstetric clinics between January 2002 and December 2006 in Taiwan. Anonymized claim data from the Taiwan National Health Insurance Research Database (NHIRD) were analysed. Women who received CD were identified from the NHIRD by Diagnosis-Related Group codes. The mode of anaesthesia was defined by order codes. Multivariate logistic regression was used to estimate the OR and associated 95% confidence interval (CI) of post-CD SSIs for GA when compared with NA. The outcome was whether a woman had been diagnosed as having an SSI during the hospitalization or was re-hospitalized within 30 days after CD for the treatment of SSIs using five or 81 International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.
Among the 303 834 Taiwanese women who underwent CD during the 5 yr observation period, the 30 day post-CD SSI rate was 0.3% or 0.9% based on five or 81 ICD-9-CM codes. The multivariate-adjusted OR of having post-CD SSIs in the GA group was 3.73 (95% CI, 3.07–4.53) compared with the NA group (P<0.001) using five ICD-9-CM codes for the definition of SSI.
GA for CD was associated with a higher risk of SSI when compared with neuraxial anaesthesia.
anaesthesia; Caesarean section; general anaesthesia; neuraxial anaesthesia; surgical site infection
This study investigated the stroke risk in patients with head and neck cancers (HNCs) using population-based data.
From claims collected in the Taiwan National Health Insurance database, we identified 13 390 HNC patients with diagnosis made in 2000–2002. A reference cohort of 53 517 non-cancer individuals matched for age, gender, and stroke risk factors was used for assessing stroke risk in follow-up to 2008.
The overall stroke incidence was 1.44-fold higher in the HNC than in the reference cohort (11.4 vs 7.9 per 1000 person-years). Adjusted hazard ratios (HRs) were 1.54 (95% confidence interval (CI): 1.40–1.68) for ischaemic stroke and 1.36 (95% CI: 1.09–1.69) for haemorrhagic stroke. The cancer-to-reference stroke incidence rate ratio was age dependent and the highest in the age group younger than 40 years (5.45, 95% CI: 3.78–7.87) and decreased with aging. Comparing different therapeutic modalities, HNC patients receiving both radiotherapy (RT) and chemotherapy (CT) had the highest stroke risk (HR: 1.46, 95% CI: 1.22–1.74), followed in sequence by those who had CT alone, RT alone, and without therapy.
Patients with HNC are at increased risk of developing stroke, especially in the young age group and in those who received both RT and CT.
epidemiology; head and neck cancers; incidence; population-based study; stroke
Genetically engineered lymphocytes hold promise for the treatment of genetic disease, viral infections and cancer. However, current methods for genetic transduction of peripheral blood lymphocytes rely on viral vectors, which are hindered by production and safety-related problems. In this study, we demonstrated an efficient novel nonviral platform for gene transfer to lymphocytes. The Sleeping Beauty transposon-mediated approach allowed for long-term stable expression of transgenes at ~50% efficiency. Utilizing transposon constructs expressing tumor antigen-specific T-cell receptor genes targeting p53 and MART-1, we demonstrated sustained expression and functional reactivity of transposon-engineered lymphocytes on encountering target antigen presented on tumor cells. We found that transposon- and retroviral-modified lymphocytes had comparable transgene expression and phenotypic function. These results demonstrate the promise of nonviral ex vivo genetic modification of autologous lymphocytes for the treatment of cancer and immunologic disease.
Sleeping Beauty transposon; TCR gene therapy; adoptive immunotherapy; nonviral vector; T-cell gene transfer
Angiogenic factors have an essential role in normal and pathologic angiogenesis. However, the clinical implication of angiogenic factor expression in myelodysplastic syndromes (MDS) remains unclear.
In this study, we sought to investigate the prognostic impact of the expression of genes encoding angiopoietin-1 (Ang-1), Ang-2, the receptor Tie2, vascular endothelial growth factor-A (VEGF-A) and VEGF-C in the bone marrow (BM) in 208 patients with newly diagnosed primary MDS.
BM Ang-1 expression was significantly higher in MDS patients, especially those with higher-risk subtypes, than in normal controls. With a median follow-up time of 32.9 months, the disease transformed to acute leukaemia more frequently in the patients bearing higher Ang-1 expression than in those with lower expression (31.5% vs 18.6%, P=0.023). The MDS patients with higher Ang-1 expression had shorter overall survival than those with lower expression (median 20.8±4.5 months vs 63.3±17.8 months, P<0.001). Multivariate analyses showed that higher Ang-1 expression was an independent unfavourable prognostic factor for overall survival. There was no impact of the expression of other angiogenic factors on survival.
BM Ang-1 expression may serve as a new biomarker to predict clinical outcome in MDS patients.
angiopoietin; vascular endothelial growth factor; myelodysplastic syndromes; prognosis
Pathological features of amyotrophic lateral sclerosis (ALS) include, in addition to selective motor neuron (MN) degeneration, the occurrence of protein aggregates, mitochondrial dysfunction and astrogliosis. SOD1 mutations cause rare familial forms of ALS and have provided the most widely studied animal models. Relatively recent studies implicating another protein, TDP-43, in familial and sporadic forms of ALS have led to the development of new animal models. More recently, mutations in the valosin-containing protein (VCP) gene linked to the human genetic disease, Inclusion Body Myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD), were found also to be associated with ALS in some patients. A heterozygous knock-in VCP mouse model of IBMPFD (VCPR155H/+) exhibited muscle, bone and brain pathology characteristic of the human disease. We have undertaken studies of spinal cord pathology in VCPR155H/+ mice and find age-dependent degeneration of ventral horn MNs, TDP-43-positive cytosolic inclusions, mitochondrial aggregation and progressive astrogliosis. Aged animals (∼24–27 months) show electromyography evidence of denervation consistent with the observed MN loss. Although these animals do not develop rapidly progressive fatal ALS-like disease during their lifespans, they recapitulate key pathological features of both human disease and other animal models of ALS, and may provide a valuable new model for studying events preceding onset of catastrophic disease.
motor neuron; SOD1; TDP-43; amyotrophic lateral sclerosis; animal models
The field of phenomics has been investigating network structure among large arrays of phenotypes, and genome-wide association studies (GWAS) have been used to investigate the relationship between genetic variation and single diseases/outcomes. A novel approach has emerged combining both the exploration of phenotypic structure and genotypic variation, known as the phenome-wide association study (PheWAS). The Population Architecture using Genomics and Epidemiology (PAGE) network is a National Human Genome Research Institute (NHGRI)-supported collaboration of four groups accessing eight extensively characterized epidemiologic studies. The primary focus of PAGE is deep characterization of well-replicated GWAS variants and their relationships to various phenotypes and traits in diverse epidemiologic studies that include European Americans, African Americans, Mexican Americans/Hispanics, Asians/Pacific Islanders, and Native Americans. The rich phenotypic resources of PAGE studies provide a unique opportunity for PheWAS as each genotyped variant can be tested for an association with the wide array of phenotypic measurements available within the studies of PAGE, including prevalent and incident status for multiple common clinical conditions and risk factors, as well as clinical parameters and intermediate biomarkers. The results of PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation. The PAGE network has developed infrastructure to support and perform PheWAS in a high-throughput manner. As implementing the PheWAS approach has presented several challenges, the infrastructure and methodology, as well as insights gained in this project, are presented herein to benefit the larger scientific community.
genetic epidemiology; high throughput; phenomics; genetics; PheWAS
The role of surgery in clinical stage T3 prostate cancer (cT3 PCa) is still subject to debate. We reviewed the records of 139 consecutive patients who underwent a radical prostatectomy (RP) for cT3 PCa with a mean follow-up of 8 years. All data related to surgical and perioperative complications were collected. Continence and erectile function were assessed at 12 months postoperatively and long-term oncologic outcomes were analyzed. Rectal injury and injury of the obturator nerve occurred both in 0.7% of cases. No serious in-hospital complications were noted and no reintervention was needed. Lymphatic leakage was noted in 2.2% of patients and 1.4% experienced prolonged drainage of urine. In 7.2%, wound-related problems occurred. Anastomotic stricture occurred in 2.9%. These complication rates were not different compared to surgical series of RP in localized PCa. At 12 months, complete continence was 87.8% and erectile function had fully recovered in 6% and 10% of patients who underwent a non-nerve sparing or unilateral nerve-sparing procedure, respectively. 10-year estimated biochemical PFS, clinical PFS, CSS and OS were 51.8%, 85.6%, 94.6% and 85.9%, respectively. In cT3 PCa, RP is technically feasible with morbidity comparable to RP in clinically localized PCa. Long-term oncologic control was excellent.
Literature indicates a relationship between selenium supplementation and risk of diabetes. However, since these data are inconclusive we investigated the effect of selenium supplementation on serum glucose levels in men with prostate cancer enrolled in a clinical trial testing of the effect of selenium on prostate cancer progression.
Subjects were randomized to receive placebo (N = 46), selenium 200 µg/day (N = 47) and selenium 800 µg/day (N = 47). Serum glucose levels were obtained every six months for up to five years. Longitudinal analysis was carried out to assess if rate of change of serum glucose levels was significantly different in the selenium supplemented groups as compared to placebo. Sensitivity analyses were performed to assess the robustness of findings.
Changes in serum glucose levels during the course of the trial were not statistically significantly different as compared to placebo for the selenium 200 µg/day (p = 0.56) or selenium 800 µg/day (p = 0.91) treatment groups.
These results do not support a relationship between selenium supplementation and changes in serum glucose levels. Recommendations regarding selenium supplementation and risk of diabetes will require more definitive studies.
Selenium supplementation; serum glucose; prostate cancer
Increasing evidence supports a putative link between LRRK2 function and the MAP kinase cascades. We recently demonstrated that LRRK2 binds to MKK6, −3, and −7. Previous studies demonstrated that scaffold proteins are essential in the regulation of subcellular localization of stress kinase complexes. The c-jun NH2-terminal kinase (JNK)-interacting proteins (JIPs) are a group of scaffold proteins that play an important role in the regulation of MAP kinase signaling cascades. JIP1–3 are known to regulate the specificity and localization of the JNK pathway, while JIP4 is a specific scaffolding protein for the p38 pathway. We demonstrate that LRRK2 binds to JIP1–4, and is associated with increased levels of total JIP1, −3, −4, oligomeric JIP and ubiquitinated JIP. These results are consistent with a putative role of LRRK2 in regulating the stress kinase cascade.
MAP kinase; c-jun NH2-terminal kinase; Scaffold proteins; Parkinson's disease; Immunoprecipitation
New pathway databases generally display pathways by retrieving information from a database dynamically. Some of them even provide their pathways in SBML or other exchangeable formats. Integrating these models is a challenging work, because these models were not built in the same way. Pathways integration Tool (PINT) may integrate the standard SBML files. Since these files may be obtained from different sources, any inconsistency in component names can be revised by using an annotation editor upon uploading a pathway model. This integration function greatly simplifies the building of a complex model from small models. To get new users started, about 190 curated public models of human pathways were collected by PINT. Relevant models can be selected and sent to the workbench by using a user-friendly query interface, which also accepts a gene list derived from high-throughput experiments. The models on the workbench, from either a public or a private source, can be integrated and painted. The painting function is useful for highlighting important genes or even their expression level on a merged pathway diagram, so that the biological significance can be revealed. This tool is freely available at http://csb2.ym.edu.tw/pint/.
The adapter protein SH2 domain-containing leukocyte protein of 76 kDa (SLP-76) is an essential mediator of signaling from the T-cell antigen receptor (TCR). We report here that SLP-76 also mediates signaling downstream of integrins in T cells and that SLP-76-deficient T cells fail to support adhesion to integrin ligands. In response to both TCR and integrin stimulation, SLP-76 relocalizes to surface microclusters that colocalize with phosphorylated signaling proteins. Disruption of SLP-76 recruitment to the protein named LAT (linker for activation of T cells) inhibits SLP-76 clustering downstream of the TCR but not downstream of integrins. Conversely, an SLP-76 mutant unable to bind ADAP (adhesion and degranulation-promoting adapter protein) forms clusters following TCR but not integrin engagement and fails to support T-cell adhesion to integrin ligands. These findings demonstrate that SLP-76 relocalizes to integrin-initiated signaling complexes by a mechanism different from that employed during TCR signaling and that SLP-76 relocalization corresponds to SLP-76-dependent integrin function in T cells.
A new Parasitorhabditis species with males and females was discovered from the southern pine beetle Dendroctonus frontalis and its galleries in loblolly pine, Pinus taeda, growing in Mississippi. Females of the new species have a cupola-shaped tail with a small spike; males possess a 2 + (3+2) + 3 ray pattern on the tail fan with ray 10 reaching the margin, and a distinctive stomatal tooth. Parasitorhabditis frontali n. sp. has some similarities to P. hylurgi Massey, 1974 from Hylurgops pinifex in New York, USA, P. terebranus Massey, 1974 from D. terebrans (Olivier, 1795) in Texas USA, P. ligniperdae Fuchs, 1915 from Hylergops ligniperda (Fabricius, 1787) and P. dendroctoni Rühm, 1956 from D. micans (Kugelann, 1794) in Europe, P. ateri Fuchs, 1915 isolated from the beetle Hylastes ater (Paykull, 1800) in Germany, and P. malii Devdariani and Kakulia,1970 from Scolytus mali (Bechstein, 1805) within the republic of Georgia. Morphometrics for 44 species of Parasitorhabditis are provided to update older keys. Parasitorhabditis frontali n. sp. was initially grown on Malt Extract (ME) agar with its own microbial contaminants that included a bacterium and fungus. The nematode also grew and reproduced after slices of ME agar with nematodes and microbial contaminants were transferred to water agar. It was killed by E. coli on NGM agar plates commonly used to raise other Rhabditida. Drawings of diagnostic anatomy and low-temperature SEM images of bodies, heads, and tails are provided for cultured specimens from pine beetle frass.
morphology; nematode; Parasitorhabditis frontali n. sp.; SEM; southern pine beetle; taxonomy; trophic interaction
maxillofacial injury; penetrating wound