Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer.

Background: There is no standard treatment after progression on second-line chemotherapy for metastatic breast cancer (MBC). We compared vinflunine with physician's choice of alkylating agent (AA) for patients with heavily pretreated MBC. Patients and methods: In this open-label phase III trial, patients with MBC were included if they had received at least two prior chemotherapy regimens for MBC and had received anthracycline, taxane, antimetabolite and vinca alkaloid therapy. Patients were no longer candidates for these chemotherapies because of resistance and/or intolerance. Patients were randomised to either vinflunine 280 mg/m2 intravenously every 3 weeks (q3w) or AA monotherapy q3w. Stratification factors were performance status, number of prior chemotherapy lines for MBC, disease measurability and study site. The primary end point was overall survival (OS). Results: A total of 594 patients were randomised (298 to vinflunine, 296 to AA). There was no difference between treatment arms in OS (hazard ratio 1.04, P = 0.67; median 9.1 months for vinflunine versus 9.3 months for AA), progression-free survival (hazard ratio 0.94, P = 0.49; median 2.5 versus 1.9 months, respectively) or overall response rate (6% versus 4%, respectively). However, the disease control rate was significantly higher with vinflunine than AA (44% versus 35%, respectively; P = 0.04). The most common adverse events (any grade) were haematological and gastrointestinal disorders and asthenia in both arms. The most common grade 3/4 adverse events were neutropenia (19% versus 11% with vinflunine versus AA, respectively) and asthenia (10% versus 4%). Conclusions: Vinflunine 280 mg/m2 q3w did not improve OS compared with the physician's choice of AA as third- or later-line therapy for MBC. Vinflunine demonstrated an acceptable safety profile, suggesting that vinflunine 320 mg/m2 merits evaluation. ClinicalTrials.gov: NCT01091168.

Comparative electrophysiology of retinal Müller glial cells-A survey on vertebrate species.

Müller cells are the dominant macroglial cells in the retina of all vertebrates. They fulfill a variety of functions important for retinal physiology, among them spatial buffering of K+ ions and uptake of glutamate and other neurotransmitters. To this end, Müller cells express inwardly rectifying K+ channels and electrogenic glutamate transporters. Moreover, a lot of voltage- and ligand-gated ion channels, aquaporin water channels, and electrogenic transporters are expressed in Müller cells, some of them in a species-specific manner. For example, voltage-dependent Na+ channels are found exclusively in some but not all mammalian species. Whereas a lot of data exist from amphibians and mammals, the results from other vertebrates are sparse. It is the aim of this review to present a survey on Müller cell electrophysiology covering all classes of vertebrates. The focus is on functional studies, mainly performed using the whole-cell patch-clamp technique. However, data about the expression of membrane channels and transporters from immunohistochemistry are also included. Possible functional roles of membrane channels and transporters are discussed. Obviously, electrophysiological properties involved in the main functions of Müller cells developed early in vertebrate evolution. GLIA 2017;65:533-568.

Developing a tool for identifying high-risk employers for inspection.

BACKGROUND: Workers' Compensation Board (WCB) data and other information are sometimes used to calculate an 'Occupational Health and Safety (OHS) index' as a way of identifying businesses considered 'high risk' to be inspected as part of enforcement work. However, no evidence on the validity of this index exists. AIMS: To evaluate the performance of the Alberta OHS index, a 'score' based largely on WCB claims data, and to see if an index calculated using different information could perform better. METHODS: Data from the Alberta Compliance Management Information System database, 2011-2015, and WCB claim database, 2007-2014, were retrieved. Issuing 'stop work' or 'stop use' orders in inspections was defined as a proxy of high-risk outcome. The performance of the current and a modified OHS index were assessed using receiver operating characteristics (ROC) and regression analyses. RESULTS: In large employers, neither the current nor the modified OHS index was particularly effective in identifying 'high risk' employers with the area under the ROC curve (AROC) of 0.55 (95% confidence interval [CI] 0.52-0.57; P < 0.001) and 0.59 (95% CI 0.57-0.62; P < 0.001), respectively. In small employers, neither index seemed very effective with an AROC of 0.54 (95% CI 0.53-0.56; P < 0.001) and 0.55 (95% CI 0.53-0.56; P < 0.001), respectively. These results were consistent in subgroup analyses of assignments without specific initiatives, both in large and small employers. CONCLUSIONS: Neither the current nor a modified OHS index seemed to effectively identify high-risk employers. Heterogeneous results in large and small employers suggest that approaches to different-sized employers are appropriate.

A percutaneous needle biopsy technique for sampling the supraclavicular brown adipose tissue depot of humans.

Brown adipose tissue (BAT) has been proposed as a potential target tissue against obesity and its related metabolic complications. Although the molecular and functional characteristics of BAT have been intensively studied in rodents, only a few studies have used human BAT specimens due to the difficulty of sampling human BAT deposits. We established a novel positron emission tomography and computed tomography-guided Bergström needle biopsy technique to acquire human BAT specimens from the supraclavicular area in human subjects. Forty-three biopsies were performed on 23 participants. The procedure was tolerated well by the majority of participants. No major complications were noted. Numbness (9.6%) and hematoma (2.3%) were the two minor complications noted, which fully resolved. Thus, the proposed biopsy technique can be considered safe with only minimal risk of adverse events. Adoption of the proposed method is expected to increase the sampling of the supraclavicular BAT depot for research purposes so as to augment the scientific knowledge of the biology of human BAT.

Partial Protection from Metabolic Syndrome in Chronic Hepatitis C Elderly Subjects Due to Lower Triglyceride Level.

BACKGROUND: In Taiwan, persons over 65 years old have higher prevalence of hepatitis C. Among these patients, around 50% have non-alcoholic fatty liver disease (NAFLD). Since cardiovascular diseases and diabetes are main causes of death in this age group, in this cross-sectional study, we tried to evaluate the effects of NAFLD and hepatitis C on the risk of metabolic syndrome (MetS). METHODS: In total, 25 116 subjects over 65 years old who presented for routine health check-ups were enrolled. From the results of seropositivity for hepatitis C and abnormal echogenicity, they were classified into four groups: normal (N), subjects with only hepatitis C (C), subjects with only abnormal echogenicity (E) and subjects with both hepatitis C and abnormal echogenicity (CE). RESULTS: Subjects in both groups E and CE had higher abnormal MetS components than group C. Among all five components, triglyceride (TG) was the one having the highest odds ratio (OR) in determining the incidence of MetS in groups C and E. Finally, compared to group N, both groups E and CE had significantly higher OR for having MetS. However, after adjusting for confounding factors, only the significance between groups E and N remained. In other words, higher MetS was noted in group E compared to group N and there was no difference in incidence of MetS between group CE and group N. CONCLUSIONS: Chronic hepatitis C is a protective factor against having MetS and this effect might be due to lower TG level in the elderly. Further studies are warranted for the underlying mechanisms.

Rapid molecular diagnosis of the Gilbert's syndrome-associated exon 1 mutation within the UGT1A1 gene.

Gilbert's syndrome is suspected in patients with unconjugated hyperbilirubinemia caused by decreased activity of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene in the absence of abnormal liver function and hemolysis. The major genetic variants underlying Gilbert's syndrome are TATA-box repeats of the promoter region and exon 1 G211A of the coding region, particularly in Asians. The efficacy of DNA melting curve analysis, however, has not been established for the G211A mutation. For rapid and accurate molecular diagnosis of Gilbert's syndrome, DNA melting curve analysis was evaluated for its genotyping capability not only for TATA-box repeats of the UGT1A1 promoter, but also for G211A of UGT1A1 exon 1. TA repeats within the TATA-box sequence and the exon 1 G211A mutation of the UGT1A1 gene were analyzed by DNA melting curve analysis. To evaluate the assay reliability, direct sequencing or polyacrylamide gel electrophoresis was used as a comparative method. All homozygous and heterozygous polymorphisms of A(TA)7TAA within the TATA-box allele and of exon 1 G211A mutants of the UGT1A1 gene were successfully identified with DNA melting curve analysis. DNA melting curve analysis is, therefore, an effective molecular method for the rapid diagnosis of Gilbert's syndrome, as it detects not only TATA-box polymorphisms but also the exon 1 G211A mutation located within the UGT1A1 gene.

Laparoscopic versus robotic TAPP/TEP inguinal hernia repair: a multicenter, propensity score weighted study.

PURPOSE: The objective of this retrospective study was to assess safety and comparative clinical effectiveness of laparoscopic inguinal hernia repair (LIHR) and robot-assisted inguinal hernia repair (RIHR) from multi-institutional experience in Taiwan. METHODS: Medical records from a total of eight hospitals were retrospectively collected and analyzed. Patients primarily diagnosed of inguinal hernia, recurrent inguinal hernia or incarceration groin hernia patients who either underwent laparoscopic or robot-assisted inguinal hernia repair between January 2018 and December 2022 were included in the study. Baseline characteristics, intra-operative and post-operative results were analyzed. To compare two cohorts, overlap weighting was employed to balance the significant inter-group differences. We also conducted subgroup analyses by state of a hernia (primary or recurrent/incarceration) and laterality (unilateral or bilateral) that indicated complexity of surgery. RESULTS: A total of 1,080 patients who underwent minimally invasive inguinal hernia repair from 8 hospitals across Taiwan were collected. Following the application of inclusion criteria, there were 279 patients received RIHR and 763 patients received LIHR. In the baseline analysis, RIHR was more often performed in recurrent/incarceration (RIHR 18.6% vs LIHR 10.3%, p = 0.001) and bilateral cases (RIHR 81.4 vs LIHR 58.3, p < 0.001). Suturing was dominant mesh fixation method in RIHR (RIHR 81% vs LIHR 35.8%, p < 0.001). More overweight patients were treated with RIHR (RIHR 58.8% vs LIHR 48.9%, p = 0.006). After overlap weighting, there were no significant difference in intraoperative and post-operative complications between RIHR and LIHR. Reoperation and prescription rates of pain medication (opioid) were significantly lower in RIHR than LIHR in overall group comparison (reoperation: RIHR 0% vs. LIHR 2.9%, p = 0.016) (Opioid prescription: RIHR 3.34 mg vs LIHR 10.82 mg, p = 0.001) while operation time was significantly longer in RIHR (OR time: RIHR 155.27 min vs LIHR 95.30 min, p < 0.001). CONCLUSIONS: This real-world experience suggested that RIHR is a safe, and feasible option with comparable intra-operative and post-operative outcomes to LHIR. In our study, RIHR showed technical advantages in more complicated hernia cases with yielding to lower reoperation rates, and less opioid use.

Can surgeons accurately identify mesh type when interpreting computed tomography scans after ventral hernia repair?

BACKGROUND: Recurrent ventral hernia repair can be challenging due to scarred tissue planes and the increasing complexity of disease related to multiple recurrences. Given the challenges of acquiring complete and accurate prior operative reports, surgeons often rely on computed tomography (CT) scans to obtain information and plan for re-operation. Still, the contribution of CT scans and the ability of surgeons to interpret them is controversial. Previously, we examined the ability of surgeons to determine prior operative techniques based on CT scans. Here, we assessed the accuracy of expert abdominal wall reconstruction (AWR) surgeons in identifying the type of prior mesh using CT imaging. METHODS: A total of 22 highly experienced AWR surgeons were asked to evaluate 21 CT scans of patients who had undergone open ventral hernia repair with bilateral transversus abdominis release utilizing mesh. The surgeons were required to identify the mesh type from a multiple-choice selection. Additionally, negative controls (patients without a history of prior laparotomy) and positive controls (patients with laparotomy but no ventral hernia repair) were incorporated. The accuracy of the surgeons and interrater reliability was calculated. RESULTS: The accuracy rate of the surgeons in correctly identifying the mesh type was 46%, with heavy-weight synthetic mesh (HWSM) being identified only 35.4% of the time, Strattice mesh and medium-weight synthetic mesh (MWSM) were identified at 46.3%, and 51.8%, respectively. The interrater reliability analysis found a moderate level of agreement 0.428 (95% CI 0.356-0.503), and the repeatability measure was poor-0.053 (95% CI 0-0.119); this indicates that surgeons cannot reliably replicate the identification process. CONCLUSIONS: Surgeons' ability to accurately identify the type of previous mesh using CT scans is poor. This study underscores the importance of documenting the type of mesh used in the operative report and the need for standardized operative notes to improve the accuracy and consistency of documentation.

Distant metastasis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) relapses more frequently than hormone receptor-positive subtypes and is often associated with poor outcomes. This retrospective study reviewed the pattern of distant metastasis with regard to survival in patients with TNBC. A total of 205 TNBC patients were analyzed. TNBC patients with lung metastases had the longest median post-metastatic OS (with 95% confidence interval) of 16.6 (10.3-22.9) months, followed by the bone, 16.3 (11.7-20.8) months, the liver, 8.9 (3.5-14.4) months, the pleura, 7.5 (2.8-12.3) months, and the brain, 4.3 (0.6-8.0) months. Kaplan-Meier plots indicated that TNBC patients with metastatic spread to brain, liver, and pleural had poorer post-metastatic OS rate than patients with lung metastases (p = 0.001, 0.004, and 0.029, respectively). Moreover, brain and liver metastases correlated significantly with poorer post-metastatic OS as compared to bone metastasis (p = 0.004 and 0.011, respectively). Route of first metastasis correlated significantly with survival of TNBC patients with brain metastases being the poorest survival indicator, followed by metastases to liver, pleura, bone, and lung.

Kidney-targeting Smad7 gene transfer inhibits renal TGF-ß/MAD homologue (SMAD) and nuclear factor κB (NF-κB) signalling pathways, and improves diabetic nephropathy in mice.

AIMS/HYPOTHESIS: The TGF-ß/MAD homologue (SMAD) and nuclear factor κB (NF-κB) signalling pathways have been shown to play a critical role in the development of renal fibrosis and inflammation in diabetic nephropathy. We therefore examined whether targeting these pathways by a kidney-targeting Smad7 gene transfer has therapeutic effects on renal lesions in the db/db mouse model of type 2 diabetes. METHODS: We delivered Smad7 plasmids into the kidney of db/db mice using kidney-targeting, ultrasound-mediated, microbubble-inducible gene transfer. The histopathology, ultrastructural pathology and pathways of TGF-ß/SMAD2/3-mediated fibrosis and NF-κB-dependent inflammation were evaluated. RESULTS: In this mouse model of type 2 diabetes, Smad7 gene therapy significantly inhibited diabetic kidney injury, compared with mice treated with empty vectors. Symptoms inhibited included: (1) proteinuria and renal function impairment; (2) renal fibrosis such as glomerular sclerosis, tubulo-interstitial collagen matrix abundance and renal inflammation, including Inos (also known as Nos2), Il1b and Mcp1 (also known as Ccl2) upregulation, as well as macrophage infiltration; and (3) podocyte and endothelial cell injury as demonstrated by immunohistochemistry and/or electron microscopy. Further study demonstrated that the improvement of type 2 diabetic kidney injury by overexpression of Smad7 was associated with significantly inhibited local activation of the TGF-ß/SMAD and NF-κB signalling pathways in the kidney. CONCLUSIONS/INTERPRETATION: Our results clearly demonstrate that kidney-targeting Smad7 gene transfer may be an effective therapy for type 2 diabetic nephropathy, acting via simultaneous modulation of the TGF-ß/SMAD and NF-κB signalling pathways.

Effects of spiked metals on the MSW anaerobic digestion.

This study aimed to investigate the effects of eight metals on the anaerobic digestion of the organic fraction of municipal solid waste (OFMSW) in bioreactors. Anaerobic bioreactors containing 200 mL MSW mixed completely with 200 m L sludge seeding. Ca and K (0, 1000, 2000 and 6,000 mg L(-1)) and Cr, Ni, Zn, Co, Mo and W (0, 5, 50 and 100 mg L(-1)) of various dose were added to anaerobic bioreactors to examine their anaerobic digestion performance. Results showed that except K and Zn, Ca (~728 to ~1,461 mg L(-1)), Cr (~0.0022 to ~0.0212 mg L(-1)), Ni (~0.801 to ~5.362 mg L(-1)), Co (~0.148 to ~0.580 mg L(-1)), Mo (~0.044 to ~52.94 mg L(-1)) and W (~0.658 to ~40.39 mg L(-1)) had the potential to enhance the biogas production. On the other hand, except Mo and W, inhibitory concentrations IC(50) of Ca, K, Cr, Ni, Zn and Co were found to be ~3252, ~2097, ~0.124, ~7.239, ~0.482, ~8.625 mg L(-1), respectively. Eight spiked metals showed that they were adsorbed by MSW to a different extent resulting in different liquid metals levels and potential stimulation and inhibition on MSW anaerobic digestion. These results were discussed and compared to results from literature.

Physisorbed surface coatings for poly(dimethylsiloxane) and quartz microfluidic devices.

Surface modifications of microfluidic devices are of essential importance for successful bioanalytical applications. Here, we investigate three different coatings for quartz and poly(dimethylsiloxane) (PDMS) surfaces. We employed a triblock copolymer with trade name F(108), poly(L-lysine)-g-poly(ethylene glycol) (PLL-PEG), as well as the hybrid coating n-dodecyl-ß-D-maltoside and methyl cellulose (DDM/MC). The impact of these coatings was characterized by measuring the electroosmotic flow (EOF), contact angle, and prevention of protein adsorption. Furthermore, we investigated the influence of static coatings, i.e., the incubation with the coating agent prior to measurements, and dynamic coatings, where the coating agent was present during the measurement. We found that all coatings on PDMS as well as quartz reduced EOF, increased reproducibility of EOF, reduced protein adsorption, and improved the wettability of the surfaces. Among the coating strategies tested, the dynamic coatings with DDM/MC and F(108) demonstrated maximal reduction of EOF and protein adsorption and simultaneously best long-term stability concerning EOF. For PLL-PEG, a reversal in the EOF direction was observed. Interestingly, the static surface coating strategy with F(108) proved to be as effective to prevent protein adsorption as dynamic coating with this block copolymer. These findings will allow optimized parameter choices for coating strategies on PDMS and quartz microfluidic devices in which control of EOF and reduced biofouling are indispensable.

Clinical presentations of thyroid cancer patients with multiple primary cancers.

BACKGROUND: In thyroid cancer patients with multiple primary cancers, primary cancers tend to be more aggressive. AIMS: We analyzed multiple primary cancers in thyroid cancer patients and determined the differences between the incidence and the characteristics of primary cancers. MATERIALS AND METHODS: A total of 3070 patients with thyroid cancer underwent a thyroidectomy and follow-up examination at a single medical center. The times of diagnosis of the primary cancers were categorized as antecedent, synchronous, or subsequent to the diagnosis of thyroid cancer. RESULTS: After a mean follow-up period of 8.8 ± 0.5 yr, the presence of multiple primary cancers was histopathologically confirmed in 163 patients (5.3%). Patients with multiple primary cancers had a lower female-to-male ratio, an older mean age, advanced tumor-node-metastasis (TNM) stage, higher total mortality, and higher therapeutic radioactive iodide (131I) doses than patients without multiple primary cancers. Hematological malignancy and renal cell carcinoma, neither of which are among the 10 most common cancers observed in the general population of Taiwan, were the most common multiple cancers among women and men with thyroid cancer. Patient age, thyroid cancer tumor size, and thyroid cancer mortality in the antecedent, synchronous, and subsequent groups were not significantly different. CONCLUSIONS: Patients with multiple primary cancers in advanced stages had shorter disease-free survival period after treatment. Thyroid cancer patients with multiple primary cancers should be closely followed up for the occurrence of other secondary cancers in order to improve total mortality.

Lack of modulatory function of coding nucleotide polymorphism S100A2_185G>A in oral squamous cell carcinoma.

OBJECTIVE: S100A2, a Ca(2+) -binding protein with two EF-hands, is a tumor suppressor in oral cancer. Helix III flanking the C-terminal EF-hand is implicated to participate in the interaction of S100A2 and its target(s). The aim of this study was to examine if the coding sequence polymorphism S100A2_185G>A, leading to the peptide 62 substitution of asparagine (AAC, A allele) for serine (AGC, G allele) in helix III, had modulation effects on S100A-mediated tumor suppression. SUBJECTS AND METHODS: We sequenced the coding sequence of S100A2 gene in normal oral keratinocytes (NOKs), dysplastic oral keratinocytes (DOKs), eight oral cancer lines, and 54 pairwise oral cancer specimens. We also compared the in vitro anti-tumor effect of wildtype (G allele) and variant (A allele) S100A2 expression using cell proliferation, migration, invasion, and colony formation assays. RESULTS: With the exception of CAL27 and SCC-15 cancer lines being heterozygotes of A and G alleles, the remaining oral cells were homozygotic in G alleles. No alterations of anti-growth, anti-migration, anti-invasion, and anti-colony formation were observed between variant and wildtype cells. Moreover, no minor S100A2_185A allele was detected in 54-pairwise clinical specimens. CONCLUSION: The coding sequence polymorphism S100A2_185G>A had no regulatory role in S100A2-mediated tumor suppression in oral cancer.

A rare case of the coexistence of ovarian clear cell carcinoma, mucinous cystadenoma, and endometriosis in the same ovary.

Clear cell carcinomas and endometrioid carcinomas are associated with endometriosis. The association of clear cell carcinomas with mucinous lesions has only been reported infrequently, and with mucinous cystadenoma has been rarely reported. This is the second reported case of the coexistence of ovarian clear cell carcinoma, mucinous cystadenoma, and endometriosis in the same ovary. A 57-year-old woman presented with lower abdominal pain for three weeks. Ultrasonography revealed a 16 x 14 x 10 cm mass in the left ovary with solid and cystic components. Hysterectomy and bilateral salpingo-oophorectomy were performed. Histopathological examination of the left ovary revealed the presence of clear cell carcinoma, mucinous cystadenoma, and endometriosis. Continuity between the areas of mucinous epithelium and clear cell carcinoma were noted; this may suggest that clear cell carcinoma may arise from endometriosis or mucinous cystic tumors.

Potential applications of CRISPR/Cas for next-generation biomonitoring of harmful algae blooms: A review.

Research on harmful algal and cyanobacterial blooms (HABs and CHABs) has risen dramatically due to their increasing global distribution, frequency, and intensity. These blooms jeopardize public health, ecosystem function, sustainability and can have negative economic impacts. Numerous monitoring programs have been established using light microscopy, liquid chromatography coupled to mass spectrometry (LC-MS), ELISA, and spectrophotometry to monitor HABs/CHABs outbreaks. Recently, DNA/RNA-based molecular methods have been integrated into these programs to replace or complement traditional methods through analyzing environmental DNA and RNA (eDNA/eRNA) with techniques such as quantitative polymerase chain reaction (qPCR), fluorescent in situ hybridization (FISH), sandwich hybridization assay (SHA), isothermal amplification methods, and microarrays. These have enabled the detection of rare or cryptic species, enhanced sample throughput, and reduced costs and the need for visual taxonomic expertise. However, these methods have limitations, such as the need for high capital investment in equipment or detection uncertainties, including determining whether organisms are viable. In this review, we discuss the potential of newly developed molecular diagnosis technology based on Clustered Regularly Interspaced Short Palindromic Repeats/Cas proteins (CRISPR/Cas), which utilizes the prokaryotic adaptative immune systems of bacteria and archaea. Cas12 and Cas13-based platforms can detect both DNA and RNA with attomolar sensitivity within an hour. CRISPR/Cas diagnostic is a rapid, inexpensive, specific, and ultrasensitive technology that, with some further development, will provide many new platforms that can be used for HABs/CHABs biomonitoring and research.

Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 < or =3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients. CONCLUSION: The bevacizumab-capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.

Tieg1/Klf10 is upregulated by NGF and attenuates cell cycle progression in the pheochromocytoma cell line PC12.

The transcription factor Tieg1/Klf10 belongs to a family of Sp1/Klf proteins that have been shown to play important roles during development and maintenance of various tissues and cell types. Upregulation of Tieg1/Klf10 has been reported for TGF-beta, BMP2, BMP4, ActivinA and GDNF as members of the TGF-beta superfamily. Moreover, estrogen, the cytostatic drugs homoharringtonine and velcade as well as nitric oxide are also able to trigger Tieg1/Klf10 transcription. Recent studies suggest a role for members of the neurotrophin family in regulating Tieg1/Klf10 transcriptional upregulation. Using semi-quantitative RT-PCR and immunoblotting, we present data describing that nerve growth factor (NGF) regulates the expression of Tieg1/Klf10 in the pheochromocytoma cell line PC12 in a TrkA-dependent manner. Moreover, we provide evidence for the existence of NGF-responsive elements in the 5'-regulatory region of Tieg1/Klf10 that contain binding sites for the transcription factors Sp1 and CREB. After treatment with NGF PC12 cells exit the cell cycle and start to differentiate towards a neuron-like phenotype indicated by neurite outgrowth. Using flow cytometry and differentiation assays we demonstrate that Tieg1/Klf10 reduces cell cycle progression in PC12 cells but fails to promote their terminal differentiation. Together, our results identify Tieg1/Klf10 as a new NGF target gene and substantiate its anti-proliferative function in the NGF signaling pathway in PC12 cells.

Genetic analysis of haemophilia A in Taiwan.

Haemophilia A (HA) is an X-linked bleeding disorder caused by mutations in the factor VIII (FVIII) gene. Identification of these mutations is becoming increasingly important in a variety of clinical settings. The purpose of this report is to describe our experience of FVIII gene mutation analysis in the largest cohort of patients in Taiwan including the discovery of 21 novel mutations. We tested 115 HA patients from 91 unrelated families, including 79 severe, 15 moderate and 21 mild types starting with an assay for the intron 22 inversion by long range-PCR followed if necessary by additional genetic studies. Intron 22 inversion accounted for 27.8% of the total and 36.7% of severe HA patients respectively while intron 1 inversion comprised 7.6% of severe patients. These were clearly different from the known data in caucasian populations. Of 75 patients without intron 22 or 1 inversion, 70 from 62 unrelated families revealed 56 different mutations by denaturing high-performance liquid chromatography (DHPLC), of which 21 were novel. Also, the only female patient with severe HA was found to have heterozygous non-sense mutation (c.6683G>A) of exon 24. Seven patients, including five without amplified PCR product and two without encoded DNA defect turned out to have exon(s) deletion or insertion by reverse transcript PCR (RT-PCR). In our study, the combination of various molecular techniques including LR-PCR, multiplex PCR, DHPLC and RT-PCR analysis enabled definitive detection of the causative FVIII gene defects in 112 of 113 (99%) HA patients.

A new hospice consulting system for terminal cancer patients in transferring to post-acute care options in Taiwan.

The terminal cancer patients increase needs for hospice care day by day. A new hospice consulting system has been developed in Taiwan to provide options for terminal cancer patients in choosing a suitable post-acute hospice care while a combined hospice care system is also given by the consulting team in the acute wards. Hereinafter is our report. From March 2005 to January 2006, 313 terminal cancer patients were analysed. These patients had signed consent forms for palliative treatment and had received consultations from the new hospice consulting system. Multivariate analysis showed that the home care patients had better performance status (P = 0.012), less shortness of breath (P = 0.006), less limbs swelling (P = 0.043), less flatulency (P = 0.000) and less constipation (P = 0.018). Among the 162 patients with regular follow-up, the symptoms/signs were significantly improved after intervention of consulting team in pain (P = 0.000), shortness of breath (P = 0.000), difficulty in sleeping (P = 0.002), nausea (P = 0.004), constipation (P = 0.008), changes in skin (P = 0.024) and adoption (P = 0.000). This new system had significant improvement in the terminal cancer patients' symptoms/signs control in acute wards and could contribute to the care quality of home care patients.