A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer.

BACKGROUND: Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown. PATIENTS AND METHODS: ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1 : 1 to receive GEMOX (800 mg/m(2) gemcitabine and 85 mg/m(2) oxaliplatin) or C-GEMOX (500 mg/m(2) cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR). RESULTS: The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P = 0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P = 0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS. CONCLUSIONS: Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status. CLINICAL TRIALS NUMBER: This study is registered at ClinicalTrials.gov (NCT01267344). All patients gave written informed consent.

Neuroprotective effects of minocycline on double-stranded RNA-induced neurotoxicity in cultured cortical neurons.

1. Minocycline, memantine,and glycoconjugate were assessed for their ability to protect cultured primary cortical neurons against double-stranded RNA-induced neurotoxicity. 2. Minocycline but not memantine or glycoconjugate protected cultured cells and warrants further investigation.

Removal of a nasal bone intraosseous venous malformation and primary reconstruction of the surgical defect using open rhinoplasty.

Primary intraosseous venous malformations are rare benign tumors that account for approximately 1% of all primary osseous tumors. They are rarely found in the midface. The authors report a case of an intraosseous venous malformation in a 28-year-old woman who presented with a bony lesion in the nasal bone. Treatment involved surgical excision via open rhinoplasty. Histopathology indicated an intraosseous venous malformation. 16 months postoperatively, there was no evidence of recurrence, the functional and cosmetic results were good, and the patient was satisfied with the treatment outcome.

Phase II study of docetaxel and irinotecan combination chemotherapy in metastatic gastric carcinoma.

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.

Analysis of particle laden flow and heat transfer in cascade and rocket nozzle.

This paper presents results for the calculation of particle trajectories in a cascade and a rocket nozzle using a Lagrangian method. When the floating particles collide to the components, the component surface is damaged severely. The surface erosion rate is strongly dependent on a particle size, a particle impact angle and a surface material. For a compressor cascade, the particle impact rate increases proportionally with the flow inlet angle and the erosion rate on the pressure side surface of blade are related to the surface or coating materials. For a solid rocket nozzle, the particle free zone in the nozzle divergent section increases quickly with increasing particle size and the maximum heat transfer density occurs at the starting region of nozzle convergent section. The Al2O3 droplet breaks up around the nozzle throat due to the high velocity difference between the droplet and gas stream, resulting in the big change of particle free zone.

Hereditary nonpolyposis colorectal cancer with gynecologic malignancies: report of two families in Taiwan.

Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, is characterized by germline and somatic mutations of DNA mismatch repair genes with dominant inheritance of site-specific colorectal cancer or colorectal cancer plus cancers of extracolonic sites. We describe two Taiwanese HNPCC families with members who had predominantly gynecologic malignancies. In one family, the 53-year-old proband was found to have five synchronous and metachronous tumors of the genitourinary system, which included endometrial adenocarcinoma, cervical squamous cell carcinoma, ureteral and bladder transitional cell carcinoma, and ovarian teratoma. Fourteen of her first- and second-degree relatives were victims of genitourinary and gastrointestinal malignancies. The other family was characterized by four sisters who developed endometrial adenocarcinomas at young ages (36-42 yr). Their father died of both stomach cancer and colon cancer at age 47. The diagnosis of HNPCC was confirmed in this family by genetic analysis. A heterozygous germline mutation (G5 to G6 frame-shift at 183-187) of the hMSH2 (human MutS homolog 2) gene was identified in white blood cells of all the affected family members. The frequent presentation of genitourinary cancers in HNPCC highlights the importance of family-history taking in patients with gynecologic cancers and a genetic diagnosis of HNPCC.

[Treating cicatricial baldness with scalp expanding and hair autografting].

OBJECTIVE: To investigate the effective method to treat cicatricial baldness. METHODS: From 1993 to 1998, 21 cases with multi-region or great-dimensional cicatricial baldness were treated with scalp expanding and hair autografting. Among them, there were 17 males and 4 females, aged from 14 to 49 years old. The operation was divided into two stages, stage one meaned to embed the expander under the scalp and stage two meaned to sow the autogenous hair. RESULTS: All cases, no matter what the position and area, were repaired successfully. The biggest dimension of repaired baldness was 340 cm2, one expander exposed and one failed in expanding after operation and be corrected immediately. The normal hair direction changed in two cases. CONCLUSION: Combined use of scalp expanding and hair autografting is an effective method to treat multi-region or great dimensional cicarticial baldness.

Metal content and biochemical analyses of a recombinant collagenase PrtV from Vibrio parahaemolyticus.

PrtV is an extracellular metalloprotease of Vibrio parahaemolyticus and regarded as a collagenase. Inductively coupled plasma-optical emission spectrometry analysis indicated that the recombinant PrtV contains 1 mol of zinc per mol of the native enzyme. On the basis of a kinetic study using 2-furanacryloyl-Leu-Gly-Pro-Ala (FALGPA, the specific substrate for bacterial collagenase) as a substrate, it was suggested that metal ions may play a significant role in the binding and catalytic steps of the substrate. PrtV hydrolyzed type I, II, III, and IV collagens; however, it did not hydrolyze type V. In addition, the hydrolysis of native proteins and synthetic substrates revealed that PrtV possesses higher activity toward collagen and collagen-like sequences. The result of the thermal stability study indicated that PrtV was thermostable up to 40 C; at 50 C, stability gradually decreased. In addition, PrtV showed higher storage stability at -20 and 4 C, respectively, than at 25 C. Compared with collagenases from Clostridium histolyticum and Vibrio alginolyticus, PrtV was immunologically different and had no significant effect on the growth of CHO, HeLa, and Vero cells. Taken together, the results of the studies described in this paper advance our knowledge concerning the metal content and biochemical properties of PrtV.

Lindane (gamma-hexachlorocyclohexane) induces internal Ca2+ release and capacitative Ca2+ entry in Madin-Darby canine kidney cells.

The effect of lindane (gamma-hexachlorocyclohexane), an organochlorine pesticide, on Ca2+ mobilization in Madin-Darby canine kidney cells was examined by fluorimetry using fura-2 as a Ca2+ indicator. Lindane (5-200 microM) increased [Ca2+]i concentration-dependently. The [Ca2+]i signal comprised an immediate initial rise followed by a persistent phase. Ca2+ removal inhibited the [Ca2+]i signal by reducing both the initial rise and the sustained phase. This implies lindane-triggered Ca2+ influx and Ca2+ release. In Ca2+ -free medium, 0.15 mM lindane increased [Ca2+]i after pretreatment with carbonylcyanide m-chlorophenylhydrazone (CCCP, 2 microM), a mitochondrial uncoupler, and two endoplasmic reticulum Ca2+ pump inhibitors, thapsigargin and cyclopiazonic acid. Conversely, pretreatment with lindane abolished CCCP- and thapsigargin-induced Ca2+ release. This suggests that 0.15 mM lindane released Ca2+ from the endoplasmic reticulum, mitochondria and other stores. La3+ (1 mM) partly inhibited 0.1 mM lindane-induced [Ca2+]i increase, confirming that lindane induced Ca2+ influx. Addition of 3 mM Ca2+ increased [Ca2+]i after pretreatment with 0.15 mM lindane for 750 sec. in Ca2+ -free medium, which indicates lindane-induced capacitative Ca2+ entry. Lindane (0.15 mM)-induced Ca2+ release was not reduced by inhibiting phospholipase C with 2 microM U73122, but was inhibited by 70% by the phospholipase A2 inhibitor aristolochic acid (40 microM).

Impact on maternal parenting stress of receipt of genetic information regarding risk of diabetes in newborn infants.

Our objective was to investigate whether notification of high-risk status for type 1 diabetes in newborn infants results in an increased maternal-parenting stress level when compared with notification of low-risk status for type 1 diabetes. Maternal parenting stress level was assessed at 5-7 weeks postpartum (baseline) and was reassessed 4-5 months after parents were informed of their newborn infants' genetic screening results (follow-up). Parenting stress level was measured using the total stress score (TSS) of the Parenting Stress Index/Short Form. The outcome variable, change in TSS, was calculated by subtracting the baseline TSS from the follow-up TSS. Demographic variables such as maternal race, maternal age, maternal education level, maternal marital status, child's birth order, and total family income were assessed through a structured phone interview at the time of baseline assessment. The risk factor of interest was the child's human leukocyte antigen (HLA) status for type 1 diabetes, i.e., whether child was at a high or moderate (combined into "high") genetic risk or at a low genetic risk for type 1 diabetes. A sample of 88 mothers (23 with a high-risk child and 65 with a low-risk child) was evaluated. Baseline median TSSs were 65 and 74 for mothers of low-risk infants and mothers of high-risk infants, respectively. Both groups' median TSS decreased between baseline and follow-up. No significant differences were found between change in TSS and maternal age, race, education level, marital status, total family income, or child's birth order. Although the median decrease in TSS was smaller in mothers with a high-risk child when compared with mothers of a low-risk child, this difference was not statistically significant. We did not find an association between newborn's HLA status and change in maternal TSS. The results of this study suggest that notification of high-risk status for type 1 diabetes in newborn infants may not result in an increased level of parenting stress among mothers.

Laparoscopic loop ligatures for bladder repair during laparoscopic surgery.

In this paper, we report a case where a bladder perforation occurred during a laparoscopically assisted vaginal hysterectomy and was repaired by laparoscopic loop ligatures. This is the first case report of using the laparoscopic loop ligatures to close the bladder perforations. The loop ligature is an easy and quick procedure, which can be performed by most surgeons who take the time to learn the endoscopic suturing techniques.

Nesidioblastosis, myelodysplastic syndrome and nodular diabetic glomerulosclerosis in an elderly nondiabetic woman: an autopsy report.

Nesidioblastosis as the cause of hyperinsulinaemic hypoglycaemia in an adult is rare. We report here an additional case of nesidioblastosis, which resulted in fatal hyperinsulinaemic hypoglycaemia in a 72-year-old woman with an underlying myelodysplastic syndrome. The diagnosis of nesidioblastosis was established only after post-mortem examination with a careful exclusion of minute insulinoma. To our surprise, the renal pathology disclosed typical diabetic nodular glomerulosclerosis in the same patient who had no previous history of diabetes mellitus (DM). Nesidioblastosis has been reported to cause 'reversal' of Type 1 DM and insulinoma causing 'reversal' of Type 2 disease. We therefore hypothesize that our patient might have had an undiagnosed DM in the past, which resulted in the typical diabetic nodular glomerulosclerosis. The nesidioblastosis caused a 'reversal' of DM and even the ultimate development of hyperinsulinaemic hypoglycaemia.

Oral ciprofloxacin as antibacterial prophylaxis after allogeneic bone marrow transplantation: a reappraisal.

The efficacy of ciprofloxacin as antibacterial prophylaxis for allogeneic bone marrow transplantation has been well documented, and it virtually eliminated bacteremias caused by gram-negative pathogens in early reports. Ciprofloxacin was therefore incorporated into the prophylactic antibiotic regimen during allogeneic bone marrow or peripheral blood stem cell transplantation at Veterans General Hospital, Kaohsiung from February 1997. In 12 consecutive patients receiving allogeneic bone marrow or peripheral blood stem cell transplantation, ciprofloxacin-resistant Escherichia coli bacteremia developed in three (25%). In addition to our data, increasing evidence suggests that the widespread use of a fluoroquinolone is associated with the emergence of resistant isolates as well as documented infections caused by these resistant strains. The incidence of Escherichia coli bacteremia in our transplant patients was 25%, which was similar to that in patients not receiving preventive therapy or in those receiving trimethoprim-sulfamethoxazole prophylaxis. The prophylactic efficacy of ciprofloxacin in allogeneic bone marrow transplant or peripheral blood stem cell transplant recipients should therefore be reassessed.

HPV-associated cervical cancers show frequent allelic loss at 3p14 but no apparent aberration of FHIT mRNA.

The genetic aberration involved in the loss of heterozygosity (LOH) at 3p14 has recently been attributed to the disruption of the FHIT gene in many cancers. This study analyzed HPV DNA and allelic status of 5 microsatellite markers spaning 3p13-3p25 in 57 cases of cervical cancer. With no homozygous deletion found in any case, a 39% overall frequency of LOH was noted. The presence of tumorigenic HPV DNA (91%) did not correlate with the allelic loss at any marker, including THRB (3p22-24) and D3S1228 (3p14) which were found with high LOH rates of 43% (12/28) and 37% (11/30), respectively. Further analysis of FHIT mRNA in 29 cancers by reverse transcription (RT)-PCR showed a full-length transcript in all cases. However, additional minor transcripts were occasionally observed in cancer tissues (9/29) as well as in normal tissues (12/31) by nested PCR of the RT products. Sequence analysis of these transcripts showed exclusive internal exon deletions, suggesting a source of minor splicing variants. No apparent mutation of the mRNA sequences was found in 8 transcripts examined, except for a silent polymorphism and a site of alternative splicing. The results suggest that, although frequently reported to be abrogated in several cancers, the mRNA of FHIT remains intact in cervical cancer. Other genes closely linked to FHIT may be responsible for frequent LOH at 3p14 observed in cervical cancer.

[Applied anatomic study of the posterior interosseous artery in forearm].

The posterior interosseous artery (PIA) is the nutritive artery of the dorsal forearm flap. This article describes the dissection study for PIA in 40 cases. The results are as follows: 1. PIA is classified into different types; 2. the external diameter of PIA at the inferior margin of the supinator, the length of PIA and the distance between the artery and external epicondyle of the humerus are described; 3. the course of the artery and its neighboring structures are defined. The above study provides the foundation of designing of the posterior forearm pedicled flap in the repair of defects situated on the forearm and hand.

An angiogenic factor from human bladder cancer: the investigation of purification and biological activities.

An angiogenic factor from human transitional cell cancer of bladder has been purified by protein extraction, cation exchange chromatography, gel filtration high-performance liquid chromatography (GE-HPLC) and reversed-phase high-performance liquid chromatography (RP-HPLC). The purified substance was named bladder cancer angiogenic factor (BCAF). Biological activity of the BCAF was assessed by the method of chick embryo chorioallantoic membrane (CAM) assay and 3H-TdR incorporation into DNA in Balb/C 3T3 cells. The BCAF displayed the potent activities of neovascularization in CAM and DNA synthesis in Balb/C 3T3 cells. The ultrastructural features of blood vessels induced by the BCAF were similar to the blood vessels in tumors. The BCAF contained a protein with an approximate molecular weight of 15,000 D which was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and silver staining. Amino acid compositions of the BCAF were also analysed by acid hydrolysis.

Immunohistochemical detection of Newcastle disease virus in chickens.

An immunoperoxidase histochemical technique utilizing a monoclonal primary antibody was developed for detection of Newcastle disease virus (NDV) antigen in tissues from chickens. The technique was applied to trachea, lung, spleen, Harderian gland, and cecal tonsil harvested from specific-pathogen-free (SPF) chickens at 2, 5, 7, 10, and 14 days postinoculation (PI) with NDV, and to corresponding tissues from commercial broiler chickens representing 30 cases of spontaneous respiratory disease. Positive staining occurred in the cytoplasm of respiratory epithelial cells in the trachea or bronchi of NDV-inoculated SPF chickens at 5 and 7 days PI. Staining also occurred in the respiratory epithelium of the trachea and bronchi of commercial broilers from seven of 30 cases of spontaneous respiratory disease. These results indicate that the immunoperoxidase technique has value as a rapid diagnostic test for Newcastle disease.

Morphogenetic and regulatory effects of mutations in the envelope proteins of an avian hepadnavirus.

The envelope gene of the avian hepadnavirus, duck hepatitis B virus, was mutated in order to dissect the functions of the two major envelope proteins pre-S/S and S. Both envelope proteins were found to be required for virus particle assembly and secretion. The placement of stop codons after each of the first three AUG codons in the pre-S region allowed efficient translational initiation at downstream AUG codons to produce novel N-terminally truncated pre-S/S proteins. These proteins could substitute for pre-S/S protein in the production of enveloped virus production, but not in the production infectious virus. A mutant defective in myristylation of the pre-S/S protein produced reduced amounts of enveloped virus, and this virus was not infectious. Mutants defective in the pre-S/S protein accumulated high levels of covalently closed circular viral DNA (cccDNA) compared with the wild type or with a mutant defective in only the S protein. Hyperamplification of cccDNA resulted in high levels of viral RNA, consistent with the proposed role of cccDNA as the transcriptional template. Myristylation of the pre-S/S protein was not required for control of cccDNA amplification, and mutants that produced N-terminally truncated pre-S/S proteins displayed higher levels of cccDNA. We concluded that the pre-S/S protein, but not the S protein, is required for control of cccDNA amplification and persistent infection.