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Vol 8, No 6 (December 2017) /
A phase 2 trial of personalized cytotoxic therapy based on tumor immunohistochemistry in previously treated...
A phase 2 trial of personalized cytotoxic therapy based on tumor immunohistochemistry in previously treated metastatic pancreatic cancer patients
Ramesh K. Ramanathan1,2,3, Glen J. Weiss1,3, Richard G. Posner3, N.V. Rajeshkumar4,5, Gayle Jameson1, Meraj Aziz3, Antje Hoering5, Vanessa Bolejack6, Anirban Maitra4,7, Monica Fulk1, Edward C. Stites3, William S. Hlavacek3, Zoran Gatalica8, Joanne Xiu8, Manuel Hidalgo9,10, Daniel D. Von Hoff1,3, Michael T. Barrett2,3
1Honor Health Research Institute, Scottsdale, AZ, USA; 2Mayo Clinic Cancer Center, Phoenix, AZ, USA; 3Translational Genomics Research Institute, Phoenix, AZ, USA; 4Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5Human Therapeutics Division, Intrexon Corporation, Germantown, MD, USA; 6Cancer Research And Biostatistics(CRAB)®, Seattle, WA, USA; 7Sheikh Ahmed Pancreatic Cancer Research Center, UT MD Anderson Cancer Center, Houston, TX, USA; 8Caris Life Sciences, Phoenix, AZ, USA; 9Beth Israel Deaconess Medical Center, Boston, MA, USA; 10Centro Nacional de Investigaciones Oncológicas and Hospital de Madrid, Madrid, Spain
Contributions: (I) Conception and design: RK Ramanathan, DD Von Hoff, NV Rajeshkumar, A Hoering, M Hidalgo, MT Barrett; (II) Administrative support: RK Ramanathan, DD Von Hoff; (III) Provision of study materials or patients: RK Ramanathan, GJ Weiss, G Jameson, M Fulk; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Correspondence to: Ramesh K. Ramanathan, MD. Mayo Clinic Cancer Center, 5777 East Mayo Blvd, Phoenix, AZ 85054, USA. Email: ramanathan.ramesh@mayo.edu.
Background: The choice of a regimen in metastatic pancreatic cancer patients following progression on 1st line therapy is empiric and outcomes are unsatisfactory. This phase II study was performed to evaluate the efficacy of therapy selected by immunohistochemistry (IHC) in these patients following progression after one or more therapies.
Methods: Eligible patients underwent a percutaneous biopsy of a metastatic lesion and treatment selection was determined by IHC. The study required 35 evaluable patients (power of 86%) for detecting a true 1-year survival rate of >20%.
Results: A tumor biopsy was performed in 48 of 49 accrued patients. Study therapy was not given (n=13) either due to insufficient tumor on biopsy (n=8) or due to worsening cancer related symptoms after biopsy (n=5). The demographics of evaluable patients (n=35) are male/female (59%/41%), with age range 34–78 years (median 63 years). Patients had 1–6 prior regimens (median of 2). The most common IHC targets were topoisomerase 1 or 2, thymidylate synthase, excision repair cross-complementation group 1 protein (ERCC1), and osteonectin secreted protein acidic and rich in cysteine (SPARC). Commercially available treatment regimens prescribed included FOLFIRI, FOLFOX, irinotecan, and doxorubicin. The response (RECIST) was 9%, the median survival was 5.6 months (94% CI, 3.8–8.2), and the 1-year survival was 20% (95% CI, 7–33%).
Conclusions: In all patients, IHC assays resulted in identification of at least two targets for therapy and a non-cross resistant regimen could be prescribed for therapy with evidence of some benefit. An IHC based treatment strategy is feasible and needs validation in larger studies.
Keywords: Array comparative genomic hybridization (aCGH); phase II clinical trial; molecular profiling (MP); immunohistochemistry (IHC); pancreatic cancer
Submitted Jul 26, 2017. Accepted for publication Sep 14, 2017.
doi: 10.21037/jgo.2017.09.05
Metastatic pancreatic adenocarcinoma (mPC) continues to have a poor outcome despite recent advances with systemic chemotherapy. Gemcitabine until recently was widely used as a single agent to treat patients with mPC and results in a median survival of approximately 6 months and 1-year survival of 20% (1). Recently two new regimens have been developed, a combination of 5-FU, leucovorin, oxaliplatin, and irinotecan commonly called FOLFIRINOX and nab-paclitaxel combined with gemcitabine (2,3). Selected patients with a good performance status treated with either of these regimens have a median survival of about 8–11 months and a one-year survival of 30–35% (2,3). Until recently, there was no established or approved regimen for second line therapy (4,5). Following progression after first line therapy some patients with mPC will have a rapid decline in performance status, but 30–50% are candidates for subsequent therapy (4-7). Numerous phase II studies have been reported in the literature with median survival times for this population of 2–5 months, and <5% surviving for more than a year (8-10). The combination of 5-FU and oxaliplatin (OFF or FOLFOX) as second line therapy after treatment with gemcitabine has been evaluated in two randomized studies but has marginal activity (11,12). The combination of 5-FU with a nanoliposomal formulation of irinotecan (MM-398) has emerged as a new standard 2nd line regimen after treatment with a gemcitabine or a gemcitabine based combination regimen. In this study (NAPOLI-1), 417 patients were randomized to either 5-FU/MM398, monotherapy with MM398 or 5-FU alone. The median overall survival (OS) in patients receiving 5-FU/MM398 was superior, 6.1 months (95% CI, 4.8–8.9) compared to 4.2 months (95% CI, 3.3–5.3) in the 5-FU arm (HR: 0.67; 95% CI, 0.49–0.92; P=0.012) (13).
The choice of a treatment regimen for mPC remains empiric and is at the discretion of the physician and patient. Molecular profiling (MP) of tumors is now widely available from commercial vendors using multiple platforms including immunohistochemistry (IHC), gene expression microarray (MA), FISH, and next generation sequencing (14). Using one or more of these assays, most tumors will have an "actionable target" for which a chemotherapeutic agent can be selected as therapy (15-17). The first study to be published in patients who were treated by an MP based selection provides support for continued investigation of this approach. In that study 66 patients with various advanced refractory solid tumors underwent a biopsy of a metastatic lesion and targets were identified using a Clinical Laboratory Improvement Amendment (CLIA)-validated IHC assays. Commercially available agents were prescribed based on the MP. The study met its primary endpoint with 27% of patients having a longer progression-free survival (PFS) with the MP suggested regimen compared to the PFS on the last unselected prior therapy before entering the study (16). The response rate was 10% and the treating physician's empiric choice of the next treatment regimen without the availability of MP was very different, suggesting the clinical utility of this approach (18). The phase II study presented here was designed to evaluate the benefits of IHC based therapy in a cohort of mPC patients who had progressed ≥1 prior therapy with 1-year survival as the primary endpoint.
Eligible patients (≥18 years of age) had mPC and had received ≥1 prior therapy for the treatment of metastatic disease. One or more metastatic tumors had to be measurable by computed tomography (CT) scan and accessible for a tumor biopsy. Other pertinent eligibility criteria were acceptable bone marrow, kidney and liver function, prior therapy must have been completed ≥3 weeks before starting study and side effects of prior therapy must have resolved to ≤ grade 1. A Karnofsky performance status (KPS) ≥70 was required. All patients were required to sign an institutional review board approved consent form prior to participating in any study-related activities.
MP of tumors
Patients who met eligibility criteria underwent a percutaneous biopsy using an 18-gauge needle with at least three passes. The tumor sample was divided into three cores after keeping one for pathological confirmation of malignancy and then flash frozen and shipped on dry ice to the destinations below. Priority was given for IHC for its superior ability to visually assess the presence of a biomarker in targeted cell population (cancer cells), and was performed at a CLIA certified laboratory by experienced board-certified pathologists (Caris Life Sciences, Phoenix, AZ, USA) where up to 17 markers were assayed (representative IHC data is presented for the interested reader as Table S1). One of the other two samples was sent to the Translational Genomics Research Institute (TGen, Phoenix, AZ, USA) for flow sorting and array comparative genomic hybridization (aCGH). The other sample was sent to the Johns Hopkins University (Baltimore, MD, USA) for MA analysis.
Table S1 Representative IHC data
Selection of therapy
The study broadly followed previously published guidelines in a pilot study of MP in refractory solid tumors (16). Only commercially available agents were recommended for therapy. In cases of combination therapy, only published regimens could be prescribed. The IHC results were expected within ten business days from date of biopsy. A tumor board consisting of the study investigators and the treating oncologist met weekly. Treatment recommendations were made on the basis of the CLIA certified IHC assay. The tumor board (which included RK Ramanathan, MT Barrett, R Posner, NV Rajeshkumar, M Aziz, EC Stites, WS Hlavacek, M Hidalgo, DD Von Hoff) reviewed the patient's prior therapy and other relevant clinical factors such as performance status, comorbidities, and organ function. Publications for treatment regimens were also reviewed and discussed. Therapy was selected using the following principles: (I) combination therapy had preference over single agent if there was no contraindication; (II) avoid prior agents that patient had received; (III) if more than one agent or agents are options, then the toxicity profile and efficacy was taken into consideration. Based on the tumor board recommendations the principal investigator (RK Ramanathan) approved the treatment recommendation including a published reference which was communicated in writing to the treating physician. If no suitable standard agents were identified on MP, then the patient could be treated at the physician's discretion.
Response and toxicity assessments
The treating physician followed published guidelines for follow-up, assessments, and dose modification. Serious adverse events were evaluated at every patient visit. Patients were evaluated for tumor response every 8 weeks by RECIST 1.1 criteria (19).
A percutaneous computed tomography (CT) or ultrasound (US)-guided biopsy was performed of an accessible metastatic lesion.
IHC assays
Formalin-fixed paraffin-embedded tumor samples were analyzed with up to 17 commercially available antibodies against protein biomarkers using automated staining techniques (Benchmark XT, Ventana, Tucson, AZ, USA; and AutostainerLink 48, Dako, Carpinteria, CA, USA).
HER2/CEP17 fluorescent in-situ hybridization (FISH) assay
FISH was used for evaluation of the HER2 [HER2/CEP17 (chromosome 17 centromere) probe, Abbott Molecular/Vysis, Abbott Park, IL, USA]. HER2/CEP17 ratio ≥2.2 was considered amplified [based on guidelines from the College of American Pathology (CAP)/American Society of Clinical Oncologists (ASCO) 2007].
Sanger sequencing
Mutation analysis using Sanger sequencing of selected regions of KRAS was performed using M13-linked polymerase chain reaction (PCR) primers designed to amplify targeted sequences. PCR products were bidirectionally sequenced using the BigDye Terminator v1.1 chemistry (Applied Biosystems, Grand Island, NY, USA), and analyzed using the 3,730 DNA Analyzer (Applied Biosystems). Sequence traces were analyzed using Mutation Surveyor software v3.25 (Soft Genetics, San Francisco, CA, USA).
Flow cytometry and aCGH
Biopsies were thawed then minced in the presence of NST buffer and DAPI according to published protocols (20). Nuclei were disaggregated then filtered through a 40 µm mesh prior to flow sorting with an Influx cytometer (Becton-Dickinson, San Jose, CA, USA) with ultraviolet excitation and DAPI emission collected at >450 nm. DNA content and cell cycle were analyzed using the software program MultiCycle (Phoenix Flow Systems, San Diego, CA, USA). DNA was extracted from each sorted sample using Qiagen micro kits (Qiagen Valencia, CA, USA). For each hybridization 100 ng of genomic DNA from each sample and of pooled commercial 46XX reference (Promega) were amplified using the GenomiPhi amplification kit (G.E. Healthcare, Piscataway, NJ, USA). Subsequently, 1 µg of amplified sample and 1µg of amplified reference template were digested with DNaseI then labeled with Cy-5 dUTP and Cy-3 dUTP respectively, using a BioPrime labeling kit (Invitrogen, Carlsbad, CA, USA). All labeling reactions were assessed using a Nanodrop assay (Nanodrop, Wilmington, DE, USA) prior to mixing and hybridization to CGH arrays with 400,000 oligonucleotide features (Agilent Technologies, Santa Clara, CA, USA). After hybridization, all aCGH slides were scanned using an Agilent 2565C DNA MA scanner. Images were analyzed using Agilent Feature Extraction software version 10.7 (FE 10.7) with default settings. These data have been deposited in the GEO database under the accession number GSE64462. All aCGH experiments were evaluated using a series of quality control (QC) metrics. These include background noise, signal intensities, and signal to noise ratios for each dye-specific channel, the reproducibility of a series of replicate control probes on the arrays, and a measure of the spread of the distribution of the log2 ratios reported in each experiment. The data from arrays were analyzed in Genome Workbench using an aberration detection algorithm (ADM2) to define and rank all amplicons and deletions (21).
MA was performed using the Affymetrix GeneChip® (Santa Clara, CA, USA; data not shown).
This was an open label phase II study. The primary objective was to determine the 1-year survival from start of registration for patients who received at least one dose of therapy. The goal was to improve the 1-year survival of patients receiving 2nd line or more salvage therapy from the historical rate of 5% to ≥20% by means of IHC-based therapy. Assuming the number of patients alive at 1 year was binomially distributed, this design had a one-sided significance level, alpha, of 0.03 and a power of 86% for detecting a true survival rate of at least 20% versus the null hypothesis survival rate of 5% or less. If 5 or more patients of the 35 evaluable patients enrolled were alive at 1 year, this would be considered adequate evidence of promising activity. Secondary objectives were to determine the response rate (according to RECIST 1.1), PFS, and correlation of molecular profiles and outcomes. PFS were assessed using the method of Kaplan Meier. Cox regression was used to determine the effect of MP on survival. Because subjects received therapy with commercially available agents, toxicity data were not collected.
Patient characteristics
Forty-nine patients were accrued at the Virginia G. Piper Cancer Center, Scottsdale, AZ between September 2010 and January 2012. One patient withdrew consent prior to a biopsy, and 48 were scheduled and underwent a biopsy without any major complications (Figure 1). Thirteen patients did not start protocol therapy either due to insufficient tumor for analysis on biopsy (n=8) or due to worsening cancer related symptoms after biopsy which precluded further treatment (n=5). Table 1 describes demographics of evaluable patients (n=35), males (55%), the majority had KPS of 70–80 and age range is 34–78 years (median 63 years). Time from the first diagnosis of mPC to biopsy on this protocol ranged from 5.8–26.7 months (median 16.1 months). All patients had prior gemcitabine-based therapy and had a median of 2 prior regimens (range, 1–6). The time from patient signing consent to performing the biopsy was a median of 4 days (range, 1–9 days) and from biopsy to availability of the IHC report was a median of 13 days (range, 4–16 days).
Figure 1 Flow diagram. IHC, immunohistochemistry.
Table 1 Baseline patient characteristics
IHC results
In the 40 patients who had adequate tissue for IHC analysis, the most common targets identified were overexpression of topoisomerases (TOPO) 1 (73%) and TOPO2A (63%), under-expression of thymidylate synthase (TS) (63%), overexpression of SPARC (48%), and under-expression of excision repair cross-complementation group 1 protein (ERCC1) (40%). Most patients had at least two IHC targets which were actionable (Table 2).
Table 2 Summary of treatment characteristics and outcomes
Mutation status
KRAS codon 12 mutations by sequencing were seen in 33 of the 38 tested samples (87%). When 5 samples which had tested initially negative for a KRAS mutation were resequenced using DNA from flow sorted purified samples, 3 additional Kras codon 12 mutations were identified with another one sample having an uncommon Q61H mutation.
aCGH
A total of 39 biopsies were processed with flow cytometry and aCGH. In seven cases there was no tumor detected whereas two additional cases failed QC metrics in the aCGH analysis. The 30 tumor samples that were successfully sorted and profiled included 24 patients who received treatment. The use of flow sorted samples enabled objective thresholds for the identification of gains and losses and the discrimination of homozygous loss (log2ratio <−3.0) and focal amplicons (<7.0 Mb and log2ratio >1.0) in each tumor. This high-resolution analysis identified multiple copy number aberrations in known drivers of pancreatic cancer and the genes targeted by the IHC assays (Table 3). The most frequent aberrations were copy number losses of 9p21.3 and 18q21.1. These included homozygous deletions targeting CDKN2A and SMAD4; two tumor suppressor genes with known roles in pancreatic cancer. Strikingly, we detected a novel homozygous deletion affecting RASA1, a negative regulator of wild type (WT) KRAS, in the one confirmed case that was KRAS WT.
Table 3 Copy number aberrations
Treatment selection
Based on the IHC results, patients received therapy with commercially available single agents or combination therapy. Prior agents on which patients' cancers had progression were avoided. Therapy was modified by the treating physician in four cases (Table 2). Patient #006 was prescribed capecitabine, in this case mitomycin was added to the regimen. Patient #020 was prescribed FOLFOX, but FOLFIRINOX was chosen for therapy. Patient #043 was prescribed irinotecan and received therapy on a phase I clinical trial with a pegylated form of irinotecan. Patient #049 had doxorubicin as the prescribed regimen and was treated with a combination of doxorubicin and bortezomib (22). Common treatments prescribed were FOLFIRI (n=31%), single agent irinotecan or other irinotecan combinations excluding fluorouracil (23%), FOLFOX (17%), doxorubicin (17%), erlotinib combinations (11%), and nab-paclitaxel based combination (9%).
Efficacy results
In the study population (n=35) there were 3 partial responses (PRs) (9%), these patients received FOLFOX (#023), FOLFIRI (#029), and nab-paclitaxel/capecitabine (#033); and 9 patients had stable disease (SD) for a disease control rate of 35% (95% CI, 19–54%) (Table 2). Time on study ranged from 0–8.6 months (median 1.3 months, 95% CI, 1–1.6 months). All patients have died, with survival ranging from 0.4 months to 26.8 months. The median PFS is 2.4 months (95% CI, 2.1–3.9 months) and median survival is 5.7 months (95% CI, 3.8–8.2 months). The 1-year survival rate was 20% (95% CI, 7–33%) for all 35 patients (Figure 2).
Figure 2 Overall survival.
This study illustrates the feasibility and challenges of a MP directed therapy in mPC patients following a first line therapy. At present a tumor biopsy consisting of adequate number of malignant tissue is necessary to construct a molecular profile using different technologies, In the patient population studied, we were able to do percutaneous biopsies safely and obtain tissue for IHC analysis in most cases. In all cases we were able to determine "actionable targets" in evaluable patients. It is interesting that based on the IHC results, irinotecan (TOPO1) and/or fluorouracil (TS) were common agents prescribed in the study. FOLFIRINOX is a standard first line regimen for mPC and the respective contributions of the individual therapeutic components (5FU, oxaliplatin, irinotecan) and tumor biomarkers (TOPO1, TS) to the efficacy of the regimen are not known. A number of pilot studies in mPC have suggested that FOLFIRI is active (23,24) and support for this hypothesis also comes from a recently completed study (NAPOLI-1), which established MM398 in combination with 5-FU as an effective 2nd line regimen (13). The therapeutic ratio of this combination could be enhanced if activity is increased in tumors with TOPO1 expression. Although doxorubicin was prescribed in 17% of patients based on MP, the efficacy results were disappointing. ATP-binding cassette transporter proteins mediate resistance to a number of chemotherapeutic agents (25) and in patients treated with doxorubicin, intrinsic resistance is suggested by overexpression of MDR1 and/or BRCP in all but one patient (#002), this patient had SD and had a survival of 10.7 months (Table 2). It is noteworthy that MP results ribonucleotide reductase M1 (RRM1) did not suggest gemcitabine as a treatment option for patients. All patients had prior gemcitabine before entering the study and further studies need to elucidate whether IHC markers accurately predict resistance to gemcitabine from prior exposure. KRAS mutations are seen in almost all pancreatic cancers, but still there are no treatment strategies for this mutated gene. Validation of molecular markers as a clinical tool continues to evolve. Since the study was completed, the validity of expression of the ERCC protein by the previously used batches of 8F1 antibody could not be replicated in non-small cell lung cancer and has been replaced by newer methodology (26). The usefulness of SPARC is also in question as a subset analysis of mPC patients treated with nab-paclitaxel and gemcitabine in the randomized MPACT trial did not show a benefit of treatment for SPARC overexpression (27).
Additional MP was performed, with aCGH in 24 treated patients. In addition to aberrations targeting known drivers of pancreatic cancer, we identified unique and recurring aberrations in each tumor genome (Table 3). These included high level focal amplicons targeting oncogenes (MYC, AURKC, FGFR1) and homozygous deletions of tumor suppressor genes (MAP2K4, L3MBTL4). In many cases the targeted genes are associated with specific pancreatic cancer hallmarks, including KRAS signaling (focal amplification of FNTA and homozygous deletion of RASA1) and DNA repair (focal amplification of USP47). Of significant interest are those aberrations targeting genes and pathways (e.g., AURKC, FGFR1, AKT) that may be exploited in future studies for therapeutic targeting. MA was also performed in selected samples (n=27) and the expression profile was matched to the chemosensitivity profiles of the NCI 60 cell line and an institutional database of patient derived pancreatic xenografts (28) (data not shown). However, results did not correlate to the treatment selection by IHC in this study. This approach is still worthwhile, and requires further study as pharmacogenomics modeling based on the expression profile of circulating tumor cells from mPC patients appears to predict response and outcomes to cytotoxic therapy (29).
This study is the first to prospectively biopsy tumor and treat mPC patients according to the IHC results. The study endpoint of 1-year survival of ≥20% was met and several new treatment regimens for pancreatic cancer such as irinotecan, FOLFIRI, nab-paclitaxel/capecitabine (30) have been identified as promising leads, and require validation in subsequent studies. Our study has limitations of a single arm study and has potential for selection bias. In fact, the median time from diagnosis of mPC to enter the study was surprisingly 16.1 months, which is considerably more than the expected survival of 9–12 months and these patients had a median of two prior regimens. Still a response rate of 9% and disease control rate of 34% in these heavily pretreated patients argues for some benefit of this approach. aCGH and MA were performed in this study, but were not used to make treatment decisions. Ongoing work will attempt to integrate global information into actionable pathways that can provide information for therapy (31,32). We believe it is time for randomized studies to be conducted. All pancreatic patients receive cytotoxic therapy and IHC markers, especially RRM1, ERCC, TS and TOPO1 appear to predict sensitivity in different tumor types to gemcitabine, platinum, 5-FU, and irinotecan; respectively. In mPC, a study design can stratify patients to first line therapy to gemcitabine/nab-paclitaxel or FOLFIRINOX based on these IHC markers. Similarly, in a 2nd line setting stratification can be made to gemcitabine, 5-FU, FOLFOX, FOLFIRI (or MM-398).
The use of MP assays has been increasing in clinical practice with availability of a number of different platforms. Retrospective MP results have been published in a number of different tumor types showing actionable mutations/deletions or amplifications in a number of genes (14,30). Clinical trials have been initiated. A recently reported study enrolled 25 evaluable metastatic breast cancer patients following ≥3 lines of therapy. Treatment selection was made by biopsy of an accessible lesion and "multi-omic" MP. The study met its primary endpoint with PRs noted in 5/25 (20%) and SD in 8/25 (32%) of patients (17). Thus, data is accumulating on the feasibility and usefulness of MP based therapy. In the next decade we should expect validation of increasingly sophisticated "pan-omic" assays for MP based therapy with resulting benefits to patients and improved outcomes.
Funding: Supported by a Stand Up to Cancer (SU2C-AACR) Dream Team Translational Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0509).
Conflicts of Interest: This work was presented in part at the American Association for Cancer Research; 103rd Annual Meeting (LB-221 and A 3697), 2012, Chicago, IL, USA. RK Ramanathan: meeting honorarium and travel expenses from Caris Life Sciences; DD Von Hoff: consultant and stock options, Caris Life Sciences; Z Gatalica, J Xiu: employment and stock options, Caris Life Sciences. The other authors have no conflicts of interest to declare.
Ethical Statement: The study was approved by institutional ethics board of Honor Health Research Institute/TGEN (No. WIRB 20101207) and informed consent was taken from all the patients.
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Qiu LX, Tang QY, Bai JL, et al. Predictive value of thymidylate synthase expression in advanced colorectal cancer patients receiving fluoropyrimidine-based chemotherapy: evidence from 24 studies. Int J Cancer 2008;123:2384-9. [Crossref] [PubMed]
Lee SJ, Choi YL, Park YH, et al. Thymidylate synthase and thymidine phosphorylase as predictive markers of capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Cancer Chemother Pharmacol 2011;68:743-51. [Crossref] [PubMed]
Li P, Fang YJ, Li F, et al. ERCC1, defective mismatch repair status as predictive biomarkers of survival for stage III colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy. Br J Cancer 2013;108:1238-44. [Crossref] [PubMed]
Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011;29:4548-54. [Crossref] [PubMed]
Braun MS, Richman SD, Quirke P, et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol 2008;26:2690-8. [Crossref]
Rodrigo RS, Nathalie A, Elodie T, et al. Topoisomerase II-alpha protein expression and histological response following doxorubicin-based induction chemotherapy predict survival of locally advanced soft tissues sarcomas. Eur J Cancer 2011;47:1319-27. [Crossref] [PubMed]
O'Malley FP, Chia S, Tu D, et al. Topoisomerase II alpha protein and responsiveness of breast cancer to adjuvant chemotherapy with CEF compared to CMF in the NCIC CTG randomized MA.5 adjuvant trial. Breast Cancer Res Treat 2011;128:401-9. [Crossref] [PubMed]
Cite this article as: Ramanathan RK, Weiss GJ, Posner RG, Rajeshkumar N, Jameson G, Aziz M, Hoering A, Bolejack V, Maitra A, Fulk M, Stites EC, Hlavacek WS, Gatalica Z, Xiu J, Hidalgo M, Von Hoff DD, Barrett MT. A phase 2 trial of personalized cytotoxic therapy based on tumor immunohistochemistry in previously treated metastatic pancreatic cancer patients. J Gastrointest Oncol 2017;8(6):925-935. doi: 10.21037/jgo.2017.09.05

redpajama_set_name: RedPajamaCommonCrawl


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Access Providers / Recently Commented
EFF Challenges Telecom Immunity Law in Court
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The Electronic Frontier Foundation (EFF) Thursday challenged the constitutionality of a law aimed at granting retroactive immunity to telecommunications companies that participated in President Bush's illegal domestic wiretapping program. In a brief filed in the U.S. District Court in San Francisco, EFF argues that the flawed FISA Amendments Act (FAA) violates the federal government's separation of powers as established in the Constitution and robs innocent telecom customers of their rights without due process of law. Signed into law earlier this year, the FAA allows for the dismissal of the lawsuits over the telecoms' participation in the warrantless surveillance program if the government secretly certifies to the court that either the surveillance did not occur, was legal, or was authorized by the president. Attorney General Michael Mukasey filed that classified certification with the court last month. more
New DPI Technology Allows ISPs to Inspect Every File, Image, and Movie Transmitted by Users
MSNBC reports that an Australian company, Brilliant Digital Entertainment Ltd., is marketing a new controversial deep packet inspection technology called CopyRouter in the U.S. cable of allowing ISPs to check every file passing through their network. More specifically, this technology can check "every image, every movie, every document attached to an email or found in a Web search," to see if it matches a list of illegal images from a law enforcement agency. more
White Spaces News… Interesting First Step
When the U.S. Digital Television Transition (DTV) transition happens in Feb. 2009, channels 2 through 51 will remain allocated for television transmission. Few of the nation's television markets actually use 49 channels. Indeed, most use less than half of that number... Today, with Congress in recess, leaving less room for last-minute-Lucy-with-the-football lobbying gambits, the Federal Communications Commission (FCC) appears to be poised to release a report saying the white spaces can be used without necessarily causing interference to existing broadcasts. There are still many questions to be answered... more
My Name is Vint Cerf, I'm a Scientist and I am Voting for Barack Obama
Vint Cerf, Google's Chief Internet Evangelist who is also credited as the co-founder of the Internet, has endorsed U.S. presidential candidate Barack Obama in a YouTube video submitted to AVoteForScience channel. In the video, Cerf discusses the importance of Net Neutrality (NN) and the fact that Obama is the candidate that supports NN. The following excerpt is a portion of what Cerf says in the video... more
CircleID Reporter
ISP Warnings Could Cut Illegal Music Downloads by 75%, Says Survey
According to a survey by European research group, Entertainment Media, 75% of music pirates would stop illegal downloads if warned by their ISPs. The research which looked at the digital habits of consumers, has also found that the abundance of online music services has played a strong role in reducing illegal music downloads. "It is quite evident that an ISP-led strategy has bite, because illegal downloaders are fairly convinced that ISPs are currently monitoring their activities and are more likely to act against them than the courts," said Russell Hart, chief executive of Entertainment Media Research. more
The Net Neutrality Conflicts in Obama vs. McCain Presidential Debates?
According to U.S. presidential candidates' position statements on the issues, John McCain is against Net neutrality and Barack Obama supports it. Glenn Derene, senior tech editor of Popular Mechanics who has put some thought into this issue in light of the current presidential race, says Net Neutrality is "one of the few technology issues on which the candidates clearly disagree." Derek explains... more
Broadband Data Improvement Act Passes Senate, House, A.K.A. Find Why U.S. is on Continuous Decline
In a major win for the public interest, the Broadband Data Improvement Act passed the Senate (on September 26th) and the House (on September 29th). Due to amendments, it now goes back to the Senate for final approval (should be pro-forma) before it lands on George Bush's desk. With the United States falling further and further behind a host of other countries, the question on many people's minds (including the folks over at Point-Topic who created this graphic) is, "Why is this happening?" more
Sascha Meinrath
Telcos, IT Companies Start $1B Promotion for Mobile Broadband as Alternative to Wi-Fi and WiMax
Some of the world's largest IT and mobile companies have teamed up to create a new category of always-connected 'Mobile Broadband' devices, delivering an alternative to WiFi. According to reports, in the first phase of this initiative lead by GSM Association (GSMA), mobile operators, PC manufacturers and chipset providers will collaborate to pre-install Mobile Broadband into a range of notebook PCs that will be ready to switch on and surf straight out of the box in 91 countries. more
European Commission on the Future of the Internet
The European Commission has just published a communication which describes the broad lines of its Internet policy in the coming years. Vint Cerf, on the Google Public Policy blog sees this as a very interesting vision. Indeed, it closely links the issue of openness of the Internet to several obvious and not-so-obvious factors. more
Patrick Vande Walle
Comcast Discloses Network Management Practices
Comcast has provided U.S. regulators details of how it plans to change the way it manages Web traffic over its high speed Internet network without blocking any applications or content. The move comes after the Federal Communications Commission (FCC) voted last month to uphold a complaint that Comcast had violated the regulator's open-Internet principles by hindering peer-to-peer traffic from applications such as BitTorrent. Comcast said on Friday that under the plan designed to give all users their "fair share" of bandwidth it would focus on managing the traffic of customers who are using most bandwidth when the network is congested. more
EFF Says Stop Illegal Surveillance; Sues NSA, President Bush, and Vice President Cheney
The Electronic Frontier Foundation (EFF) has filed a lawsuit against the U.S. National Security Agency (NSA) and other government agencies today on behalf of AT&T customers to stop the alleged illegal, unconstitutional, and ongoing dragnet surveillance of their communications and communications records. The five individual plaintiffs are also suing President George W. Bush, Vice President Dick Cheney, Cheney's chief of staff David Addington, former Attorney General and White House Counsel Alberto Gonzales and other individuals who have ordered or participated in the domestic surveillance. more
Interactive Deployment Database of Global WiMAX Deployments Released
The WiMAX Forum has released an Interactive Deployment Database, providing a resource of more than 300 WiMAX deployments across the world. Available for public use, this tool includes detailed information on each of the operators, stage and type of deployment, as well as spectrum utilized. The database is planned to be updated quarterly with the latest information. more
Comcast Sues FCC, Says Net Neutrality Order Legally Inappropriate
Comcast has filed suit against the Federal Communications Commission (FCC) today in order to block the agency's decision to sanction Comcast for blocking certain Internet traffic. Comcast has released the following statement attributed to David L. Cohen, Executive Vice President of Comcast Corporation... more
Internet Services Will be Worth Nearly $1 Trillion by 2012, Says Report
According to a report by the research firm Yankee Group, the global market for high-speed Internet services will be worth nearly $1 trillion by 2012. The broadband market, which includes revenue from services to consumers and businesses, as well as the amount spent on equipment for the underlying infrastructure, is currently worth $590 billion, according to the report. By 2012, the market will grow to more than $903 billion, it projected. The estimates are part of Yankee Group's concept of an "Anywhere" environment, where there is at least one broadband connection for every person on the planet. Emily Green, president and chief executive of Yankee Group, says it took 10 years for the Internet to reach one billion people and it will double its reach by 2012. more
Aircell vs. VoIP
Last week American Airlines launched their Aircell wireless Internet access on a limited number of flights. It didn't take long before a few folks tried to make voice and video calls (in violation of Aircell's terms-of-service according to their PR folks), and it didn't take long before someone figured a way around their voice/video blocking efforts. more
Irwin Lazar
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Taylor Spivey
World Ranking 1
World Triathlon Championship Series Ranking 25
World Triathlon Individual Olympic Qualification Ranking 4
Continental Ranking 1
Taylor Spivey was born and raised in California and spent her early years focused on surf-lifesaving, winning several national titles, before transitioning to triathlon in college. Since 2016, she's been a member of USA Triathlon's National Team and had her best ever season in 2019 with two World Triathlon Series podium placings and a 4th overall ranking in the WTS series.
At the end of the 2016 season, at the age of 25, the USA's Taylor Spivey earned herself a place inside the WTS top 50 for the first time.
In 2017, the fearless cyclist secured her first podiums on both the World Cup and WTS stage. Spivey earned silver medals at the Leeds WTS race and the Madrid and Miyazaki World Cup races. Eventually finishing 12th in the overall rankings and becoming a key part of a formidable Team USA.
In 2018, Spivey finally found the golden formula, winning her first World Cup in Weihai after producing a brilliant swim, bike and run combo. That year she also earned a silver medal for Team USA at the Edmonton Mixed Team Relay. Consistent again over the course of this season, she achieved six top ten placings in WTS racing and finished the season ranked 8th on the WTS leaderboard. Outside of the ITU circuit, also earned an the overall victory at Super League Mallorca.
In 2019, Spivey continued her upward trajectory, finishing 4th overall in the WTS series, including a 2nd place finish at WTS Abu Dhabi and a 3rd place finish at WTS Yokohama. She also competed for Team USA in the Mixed Team Relay on two occasions in 2019, including earning a silver medal with the team at WTS Abu Dhabi.
WTCS
2021 World Triathlon Championship Series Abu Dhabi
05 Nov, 2021 - Elite Women - 00:57:51
2021 World Triathlon Championship Finals Edmonton
21 Aug, 2021 - Elite Women - 01:56:16
Groupe Copley 2021 World Triathlon Championship Series Montreal
15 Aug, 2021 - Mixed Relay - 00:22:21
14 Aug, 2021 - Final Women. Stage 2 - 00:24:01
2021-11-05 - Elite Women - 00:57:51
2021-08-13 - Qualifier 2 Elite Women - 00:24:10
AJ Bell 2021 World Triathlon Championship Series Leeds
WTCS Leeds to reveal Olympic stories in crucial women's race
Zaferes eyes destiny, Learmonth, Taylor Brown and Spivey chase World title dreams
Olympic and World Champions to take the line at WTS Hamburg
Katie Zaferes powers to WTS Abu Dhabi gold as world title hunt begins in UAE
Spivey and Iden win emphatic World Cup golds in Weihai
more articles tagged with Taylor Spivey →
Given Name Taylor
Family Name Spivey
Representing USA
Place of Birth Redondo Beach
Coach Paulo Sousa
Sponsors Descente, Science In Sport, 100% Sunglasses, Jolyn, Garmin, Cadex Wheels, Scott Bicycles, New York Athletic Club
Twitter @TKSpivey
Taylor's next event
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If you missed it, this is what I'm referring to. A first for females at the Paris-Roubaix! History made, and many m… twitter.com/i/web/status/1…
04 Oct, 2021 • 06:15
Grateful for the equal gendered prize money in triathlon. twitter.com/bbculp/status/…
RT @pstriathlon: A propos, another week of @TKSpivey at the top of the @worldtriathlon ranking https://t.co/69g4r4Lu2k
29 Sep, 2021 • 10:55
2019 MS Amlin World Triathlon Bermuda Women Highlights
2019 Daman World Triathlon - Women's Highlights
2017 Miyazaki ITU World Cup - Elite Women's Highlights
2017 WTS Leeds Women's Highlights ITA
2017 WTS Leeds Women's Highlights
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The Sky Has Fallen (2009) - Zombie Horror Film Review
The Sky Has Fallen was written, produced, edited and directed by Doug Roos and has won a few awards including Best Feature at the 2009 Freak Show Horror Film Festival and Best Horror Feature at the 2009 Indie Gathering Film Festival, it was also nominated for Best FX at the 2012 Maverick Movie Awards.
One fateful night a bizarre infection sweeps the globe which decimates mankind; it turns the infected into zombie like creatures. At the same time comes the arrival of mysterious hooded figures; these sadistic killers not only hunt down the non infected but also perform sickening experiments on the dead and dying. Some months later and Lance (Carey MacLaren); a survivor is out in the woods hunting down the leader of these mysterious figures, he thinks if he can kill this one person then the madness will all end.
The Sky Has Fallen had a very different feel to it than other films of this type with an often dreamlike tone. Apart from a few flashbacks the entirity of this piece takes place out in dense woodland which while the location has a story based reason for it being where the characters are sure does save on budget. For the majority of this there are just the two characters; the brooding samurai sword wielding Lance, and Rachel (Laurel Kemper); a girl he meets who decides to team up with him on his quest. For a lot of the film there is little dialogue and plenty of action sequences, the duo are under constant attack from not only the undead but the hooded creatures. This gets into a comfortable cycle with fight scenes in the daytime, dialogue at night usually followed by dream sequences.
Mention has to go to the practical FX of which there are plenty, and wonderfully there is no CGI, not even for blood spray. Bullets thud into creatures with close ups showing the impact via squibs, limbs are cut off, heads severed, someone even gets their spine ripped out. This is one bloody film with the claret spreading everywhere. Blood is never in short supply and when the two are not fighting there is plenty of cut aways to random victims being butchered by either the ghouls or their masters. I always feel the need to mention this when it occurs but there are some scenes of children getting killed, something which is often missing in zombie films for some reason.
There are a lot of zombies here, the make up effects for them are pretty awesome looking, many are stitched up and with crude modifications done to them such as having a scythe blade stitched onto the stump of an arm, or chunks of glass sticking out the eye sockets. The hooded figures have cruel bony hands and are shown to be very powerful, snapping a wrist at one point, yet when they are dispatched they usually just stand there, their bodies substance less. A lot of the action scenes revolve around the samurai sword and reminded me loads of Michonne from The Walking Dead with Lance expertly handling the sword in fights that more resemble slow dances than fast paced encounters. There are also plenty of gun battles, though it was a bit off putting that the guns seemed to have infinite ammo.
Visually the film is a real treat, the special effects are superb and despite the wooded location the setting manages to never feel stale though variation would have been nice. Unfortunately when it comes to dialogue the problems arise. The script is pretty terrible, usually a series of unnatural sounding exchanges where neither character sounds like a real person and more like they are reading from a script, it fits with the dream like tone but with the speed and emotionless way in which the actors say their lines and the fast cuts it seems just plain weird. This isn't helped later on by some really silly and unneeded plot twists revealed via dialogue which just had me dumbfounded as to why anyone thought including them was a good idea. The films editing is different to what I'm used to also, the whole film features a lot of fast edits, usually it is only a few seconds before the shot changes leading to kinetic fast paced sequences which did get dizzying at times and left me hoping for some nice long lazy shots just to slow down the pace. I'm all for the fast edits when they are called for, but when even conversations are stuffed full of inserts and quick camera angle changes it gets slightly too much.
Saving the best till last is the wonderful score by James Sizemore, the music is simply beautiful managing to be so sorrowful and emotive throughout, loved the music and was by far the best thing about The Sky Has Fallen. In terms of plot I really liked how nothing was explained, there is no resolution as to just what or who the figures are, or why they are doing what they have done. It is inferred they could be demons, or even physical manifestations of the infection which spread the globe, and the mission Lance has set himself; to kill the figure he believes to be the leader, I love how it is never explained if it really is the leader or not.
At around 80 minutes this flew by at a rapid pace, The setting may eventually start to get bland, the characters may talk as if they are reciting lines, and the quick cuts may make you long for some slow moments but it certainly looks the part with some fantastic FX, great atmosphere, a decent enough plot, and the score is sublime. If you want to check this out for yourself head over here where the film can be purchased.
Labels: Horror Films, Screener Provided, Zombies
Jeremy [Retro] said...
watched it a few years ago, remember enjoying it... thanks for the solid review and now I have to track it down... watch it again!
Daniel Simmonds said...
It was different enough for sure :)
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Sergal's kit of the HMS Victory builds up into a fine model of the flagship to Admiral Lord Nelson during the battle of Trafalgar on 21st October 1805 and is the most famous of the great British fighting ships. She can be visited at Portsmouth dockyard where she is preserved for posterity.
Sergal's kit of the HMS Victory builds up into a fine model of the flagship to Admiral Lord Nelson during the battle of Trafalgar on 21st October 1805.


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You are watching the movie Mission: Impossible
When Ethan Hunt, the leader of a crack espionage team whose perilous operation has gone awry with no explanation, discovers that a mole has penetrated the CIA, he's surprised to learn that he's the No. 1 suspect. To clear his name, Hunt now must ferret out the real double agent and, in the process, even the score.
Director: Brian De Palma, Chris Soldo, Diana Dill, Ernest Day, Kate Hazell, Michael Stevenson, Nick Moore, Oldrich Mach, Paul F. Bernard
Actors: Emilio Estevez, Emmanuelle Béart, Henry Czerny, Ingeborga Dapkūnaitė, Jean Reno, Jon Voight, Kristin Scott Thomas, Tom Cruise, Vanessa Redgrave, Ving Rhames
Keywords:Emilio Estevez Emmanuelle Béart Free Henry Czerny Ingeborga Dapkūnaitė Jean Reno Jon Voight Kristin Scott Thomas Mission: Impossible Online sitename Tom Cruise Vanessa Redgrave Ving Rhames Watch Mission: Impossible
Ranam : Detroit Crossing
The movie narrates the story of the Indian immigrant community in Detroit, where a garage mechanic gets unwillingly involved in the criminal world as a getaway driver.
720p Web DL
Detective Mark Corley storms his way onto an alien spaceship to rescue his estranged son. When the ship crashes…
Country: Canada, China, Indonesia, Singapore, UK, USA
Genre: Action, Hollywood HD Movies, Horror, Science Fiction
Nibunan
A senior cop and his team of two are after a serial killer who is giving them nightmares. Shocked after finding who the next possible victim is going to be,…
The Men in Black have always protected the Earth from the scum of the universe. In this new adventure, they tackle their biggest, most global threat to date: a mole…
Genre: Action, Adventure, Comedy, Science Fiction
The Making of a Tomb Raider
This feature length film will follow renowned BASE jumper, climber and mountain biker Clair Marie as she attempts real-world Lara Croft challenges that show what it takes to become a…
Genre: Action, Adventure
Imaikkaa Nodigal
A CBI officer goes in search of a ruthless serial killer. Things get worse when the murderer targets the former and her family
Genre: Action, Romance, Thriller
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Looper (2012)
In the futuristic action thriller Looper, time travel will be invented but it will be illegal and only available…
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Aragorn is revealed as the heir to the ancient kings as he, Gandalf and the other members of the broken…
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Wanted by the mafia, a New York City bike messenger escapes into the world of parkour after meeting a beautiful stranger.
Wastelander (2018)
In a post-apocalyptic landscape, an ex-soldier wanders in search of his lost home and family…
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1999, Serbia is bombed and Kosovo region is left for plunder by bandits under command of Albanian warlord, Smuk. The removal of the human organs take place within the territories…
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Long before he even met Shrek, the notorious fighter, lover and outlaw Puss in Boots becomes a hero when he sets…
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Everyday teen hero Kim Possible and her best friend Ron Stoppable embark on their freshman year of high school, all while saving the world from evil villains. While Kim and…
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The Prey
An innocent man sentenced to rot in a Cambodian jail is released for the sadistic pleasure of twisted trophy hunters and forced to fight – or die.
Genre: Action, Adventure, Crime
A grieving mother transforms herself into a vigilante following the murders of her husband and daughter, eluding the authorities to deliver her own personal brand of justice.
Disaster strikes when a criminal mastermind reveals the identities of all active undercover agents in Britain. The secret service can now rely on only one man — Johnny English. Currently…
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Phantom 2015
Phantom is an action thriller that unfolds across various countries around the world. The plot revolves around protagonist Daniyal…..
Genre: Action, Bollywood HD Movies, Thriller
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Your umbrella will probably be useless in one of these.
It's called a wet microburst -- but when you see it on video like this, there's nothing "micro" about it.
This time-lapse footage captured by Tucson photographer Brian Snider shows a microburst absolutely unloading on an area near the city.
It seems as if a giant nozzle has been turned on in the sky, sending a blast of water straight down, which then quickly fans out.
"Notice how the ball of rain falls from the sky and starts separating before hitting the ground," wrote Snider. "Once it hits the ground you can see the power of microburst as it expands similar to the ripple you would see when you drop a stone in water."
While the video contains a slow-motion section highlighting the microburst, Snider also posted a complete slow-motion version here.
And for more incredible weather footage, check out his Vimeo page.


SAFETY HARBOR, FLORIDA – NOVEMBER 2016: Vahagn Stepanyan is a talented music producer, arranger, composer, and keyboard player from Armenia who has fully embraced the promise of long-distance collaboration. He regularly collaborates with Turkish mixing engineer Alen Konakoglu. He and Vahagn completed projects with musicians from nearly fifteen different countries, including Eric Marienthal, Nathan East, Eric Moore, Anthony Crawford, Mark Lettieri, Adam Hawley, and Jack Thammarat. In addition, he handles the YouTube post-production for Chaka Khan's bassist Melvin Lee Davis and works with Grammy-winning mastering engineer, Evren Goknar and some others. Vahagn is also a Grammy Recording Academy voting member and recently signed on to score and arrange soundtracks for sixteen documentaries produced by Armenian Public Television.
SAFETY HARBOR, FLORIDA – NOVEMBER 2016: Vahagn Stepanyan is a talented music producer, arranger, composer, and keyboard player from Armenia who has fully embraced the promise of long-distance collaboration. He regularly collaborates with Turkish mixing engineer Alen Konakoglu. He and Vahagn completed projects with musicians from nearly fifteen different countries, including Eric Marienthal, Nathan East, Eric Moore, Anthony Crawford, Mark Lettieri, Adam Hawley, and Jack Thammarat. In addition, he handles the YouTube post-production for Chaka Khan's bassist Melvin Lee Davis and works with Grammy-winning mastering engineer, Evren Goknar and some others. Vahagn is also a Grammy Recording Academy voting member and recently signed on to score and arrange soundtracks for sixteen documentaries produced by Armenian Public Television.


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Can anyone describe the nearby public parking? Is there a chance it will be full? What is the price? Are the cars safe there? Thanks!
I am parked there now. Very safe. 20euro per day but you can get a 2 day pass for 30 euro and come and go as many times as you like thru the day. Lots of car parks so won't be full. Well signposted too so easy to find.


A couple of shots of the Vulcan Hotel on Nab Lane. The top photo is taken from the Blakey Moor side and the photographer was probably stood by the railings at the side of the Technical School (Victoria Centre of Blackburn College) and at a guess, I would estimate the date at being late 1960's or maybe sometime in the 1970's.
The second photo was taken lower down Nab Lane, approximately where the motorbikes are parked in the first photo, and was taken in 1950, as they cleared the site to build the first phase of the new Municipal Technical College (The Feilden Centre nowadays).
Everyone has their own memories of the Vulcan, mine date from the mid 1970's - 1980's. Always a great (and very loud) jukebox throughout the years. I can remember being in there during power cuts and drinking from bottles (the pumps were off) by candlelight. Health & Safety regs would never permit that now.
For quite a number of years, the Vulcan, the Courts, the Peel and the Queens had their own, very unique clientele. People that just seemed to wander between those four pubs all night and then ventured up to the Millstone (above the Dirty Duck / Castle) after hours.
TOP PHOTO COURTESY OF COTTONTOWN AND THE COMMUNITY STUDIES DEPT. BLACKBURN LIBRARY.
Yeah Colin like yourself spent many a happy night and indeed day in The Vulcan.
In fact when I was at Blackburn College, I think I spent more time in there than actually in College!
That was the route we used to take every weekend on our nights out. ohh how how i loved those times.
I go right back to the 'birth' of the Vulcan, as when we first ventured there it was not what it became to be!
Myself and about 5 or 6 others most notably Brian Rossall and Chris Howarth, started going in as we got a bit miffed at waiting a fair old time getting re-fills at Courts, Ribby, Queens, Peel etc.
Memory is fading now but, the new landlord was Mike Mc Goldrick (pretty sure it was Mike), ex landie of the Dolphin (next t'fishmarket sidings up Foundry Hill) My first ever pub pint place! He was also an ex near neighbour of mine from Wensley Fold, ex Telecom man I seem to recall.
Anyways, at that time there were only a couple of tables in there and a few chairs. There probably was limited wall seating as well. More of a front/parlour room with a bar top. But, there was a Juke box with an awful selection on it. Because we loved beer AND good music, we asked him if we could add 'our own'. He said sure why not, as we were pretty much his only regular clientele (virtually all 'passing trade' heading for the above).
At that time we always perused what was on offer at the record exchange on the 3 day market, and this was the time of the 45 rpm disc where the centre could be 'popped out' for a mandrel mounting (as on a jukebox). More importantly, also imports.
Pretty quickly we 'replaced' all of the old original 'crap' and had our own personal cool vibes pub!
Only trouble was, being then allowed to crank it up 'a few notches', volume wise, it then caught the attention of the 'passing trade', and over about 6 months or so we found that we then were sharing 'our pub' with throngs of newcomers. Then within maybe 12 months we were back to queuing for re-fills once again!
I don't recall Mike complaining much though!
Once it was really up and running, he sold on/made way to a guy, I cant remember the name of, but was busy buying the more 'lively' places in town.
From there on it achieved legendary status, and quite right too.
As for us, we then started using more often, the then lesser busy Courts, Ribby, Peel etc. (Queens by then unfortunately declining).
I am guessing that our first 'visit' would be approx. 72 ish.
Thanks for that Bernie. Interesting stuff. I didn't start drinking until 1974 (when I was 16), but the Vulcan and Peel were always among the the pubs we visited, along with the ones on the Barbary Coast. I started my apprenticeship when I was 16 too and we were sent to the college on day release one day a week and we used to go into the Vulcan after college too, as well as in the little cafe that was just a bit further up Nab Lane.
I was never a regular in the Vulc, but we would always include it in a crawl around town on a Friday or Saturday night, right from 1974 when I was 16, through to when it closed in 93 (?). Though I have to admit, I thought it had gone a bit crap in the year or two before it finally closed.
It was a brilliant pub throughout the 70's and the 80's though, that's for sure and it will always remain one of my favourite pubs. I'm sure it remains one of the best pubs in town in lots of people's memories.
Yeah the Queens was on the decline when I was 16 - 19 ish. We would still pop in from time to time, but it wasn't a regular inclusion on a Fri / Sat. It was included sometimes (intermittently) a bit later, when it had a revamp. We went in a bit more often then, but we soon got fed up with it again.
I've got 5 yrs on you then!
My first pint was on my 14th! as advertised above (with I recall two mates, one being Rob Rolands. Mike never let on he knew me, but when I asked for a pint of beer, he asked with a put on stern face and said 'Fine, what kind'?
When I blurted out 'a pint of bitter', he said that's ok, but I want you lads out by 7. It was a well known pub for under age drinking, and I at least did not look remotely 15 even.
Two pints later we rolled out chuckling like idiots back to our neighbourhood.
Forward to 70's and unlike like you, infrequently in Vulcan, I might as well have bunked there. I would not like to calculate just how much Wonga I put over that bar and others mentioned, pretty much a 7 night week man. At w'end it was day and night.
But so many happy, if not blurry memories.
As said, our town was one hell of a place to be a young lad into ale and music circa 70 - 85. For me it sort started to taper off (for the worst) around about mid 80's.
But then again, that was just maybe me getting older and more sensible!
For me a night out in the seventies was Peepers, the Vulcan and the Regent for pub bands.Remember Manc Group james appearing with a huge folllwing of Mancs filling the Regent ..Then came punk at the Lodestar,an early days venue for Sexpistols and the Boomtown rats.but for me it was therVulcan..Remember the posters and the jukebox.I would like to make a download compliation of reords fromthe Vulcan jukebox and Peepers..Anyone remember the tracks..?..
If you go onto Facebook and find a group called 'I drank in the Vulcan', I'm sure someone the other year was compiling a CD of tracks that were on the Vulcan jukebox at one time or another, tracks from the early 70's right through to the early 90's when it closed down. I'm not a member of that particular group, but I'm sure if you went on there and asked, someone would point you in the right direction for the person that was putting the CD together. I think they were making it for a reunion 'do' and making copies for people.


The South Alabama Radio Club was formed on July 29, 1995 to provide a community service and to have available emergency communications during the event of a disaster. Additional information about the club can be found on the Club History page.
Our net is called Thursday evening at 7:30 PM Central time on the WC4M repeater 147.260 + (100 Hz tone). The alternate frequency of 147.260 simplex is used as a backup frequency when needed. There is no net called on club meeting night which is the third Thursday of the month. If you are passing through the Andalusia, Alabama area we'd love to chat with you! Some one is usually jawboning on these frequencies especially in the evening hours!
During severe weather, the Covington County SKYWARN group uses the 147.26 repeater. Check the ARES/RACES page or the preamble for more information about ARES/RACES. For information about other nets in the area check out the Local Nets page.
The South Alabama Radio Club vanity call sign, WC4M, was issued by the FCC on April 19, 2002.
Our meeting are held at 7:00 PM Central time in the Dixon Room Annex of Andalusia Public Library on the third Thursday of each month. Occasionally it may be necessary to change the starting time of some club meetings to accommodate out of town guest speakers. These time changes will be announced on the local nets and posted on the Club Events page. Additional meetings will be called as needed. Time and location will be made on the Thursday night SARC 2-Meter Net.
The December club meeting date is the Annual Business meeting when Election of new officers takes place.


SINGAPORE, May 24 (Reuters) - Singapore's first quarter economic growth was revised higher, with firm expansion in the city-state's manufacturing sector, data showed on Thursday.
The economy grew 1.7 percent in the January-March quarter from the previous three months on an annualised and seasonally adjusted basis, revised final figures from the Ministry of Trade and Industry showed.
The government's initial estimate, released on April 13, had showed the economy grew 1.4 percent.
Gross domestic product grew 4.4 percent in the first quarter from a year earlier, faster than the advance estimate of 4.3 percent growth.
The MTI also revised its GDP forecast range for 2018 to 2.5 to 3.5 percent, from 1.5 to 3.5 percent previously.
The median forecast of 11 analysts in a Reuters poll predicted 1.4 percent quarter-on-quarter growth and a 4.3 percent annual expansion.


text:
Abelardo Antonio Ríos Osorio, né à Alejandría (département d'Antioquia), le , est un coureur cycliste colombien des années 1970 et 1980, professionnel de 1985 à 1988.

En 1973, il fait partie de sa sélection nationale qui dispute le Tour de l'Avenir. Il le terminera neuvième, en échouant deux fois à la deuxième place lors d'arrivées d'étape. Il a, également, participé aux Jeux olympiques de 1976 à Montréal.

Il a été intégré à la première équipe cycliste colombienne (amateur) invitée à participer à un grand tour, le Tour de France 1983.

Équipes
 Amateur :
 1983 :  Colombie - Piles Varta
 1984 :  Colombie - Piles Varta
 Professionnelles :
 1985 :  Piles Varta - Café de Colombia - Mavic
 1986 :  Café de Colombia - Piles Varta
 1987 :  Pony Malta - Bavaria
 1988 :  Pony Malta - Bavaria - Avianca

Palmarès
 Clásico RCN
 2 fois sur le podium ( en 1975 et  en 1974).
 10 fois dans les 10 premiers au classement général final entre 1971 et 1981.
 4 victoires d'étape en 1974, en 1978, en 1980 et en 1981.
 Tour de Colombie
 6 victoires d'étape en 1973, en 1976, en 1979, en 1981, en 1986 et en 1987.

Résultats sur les grands tours

Tour de France
2 participations.
 1983:  du classement général.
 1984: non partant au matin de la .

Tour d'Italie
1 participation.
 1985:  du classement général.

Tour d'Espagne
Aucune participation.

Résultats sur les championnats

Jeux olympiques
1 participation.
 1976 : abandon.

Championnats du monde amateurs
2 participations.
 Montjuich 1973 :  au classement final.
 Prague 1981 :  au classement final.

Championnats nationaux

 1975 :  Médaillé de bronze de la course en ligne.
 1976 :  Médaillé d'argent de la course en ligne.
 1977 :  Champion de Colombie sur route.

Notes et références

Liens externes

Coureur cycliste colombien
Coureur cycliste aux Jeux olympiques d'été de 1976
Naissance en janvier 1952
Naissance dans le département d'Antioquia

redpajama_set_name: RedPajamaWikipedia


The Tyk Dashboard allows multi-tenant and granular user access. Users can be assigned specific permissions to ensure that they only have very specific access to the dashboard pages, and to the underlying API.
From v2.7 you can now assign users to a user group if you are an admin user or have the User Group permission assigned to you. See User Groups for more details. This feature is available to all our Cloud and Multi-Cloud users. For On-Premises installations, this feature is available only for customers with an "Unlimited" license.
It is important to note that all user roles are defined and enforced at the API level, and the UI is merely reactive.
Selecting the Account is Admin checkbox from the Dashboard gives the user full access (the same as the IsAdmin property).
If it contains no properties, the user is assumed to be an admin.
If it contains even just one property, it acts as a white list, and only that one property is allowed.
Any non-listed properties are denied.
Values for each section are: read or write, remove the property altogether to deny access.
Permissions are enforced at the Dashboard API level.
Each of the object categories will also have an effect on the dashboard navigation, however side-effects can occur if pages that make use of multiple APIs to fetch configuration data cross over e.g. policies and API Definition listings.


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SANDWICH – John T. Foster Jr., 81, of Sandwich, and Naples, FL, formerly of Concord, Mass., retired Lieutenant, Concord Police Department died Wednesday, Nov. 21, 2018, in Barnstable. He was the loving husband for 57 years of Linda (Baker) Foster.
CHICOPEE ~ Robert L. "Bob" Beaulieu, 90, of the Aldenville section of Chicopee, was Called Safely Home on Tuesday, November 20, 2018. He passed into Eternal Life at his home surrounded by the care and comfort of his loving family.
Webster/Dudley Marsha I. (Hanson) Stockley, 81, passed away Thursday, November 22, 2018 at home surrounded by her loving family. Her husband of 51 years, Raymond A. Stockley died March 25, 2011. Arrangements are in the care of the ROBERT J.
Vina A. Ronan of Roslindale, November 22, 2018. Complete notice to follow.


Thanks to everyone who stopped by on release day and made my contest so much fun! I had a ball celebrating the release of TEMPTED with all of you!
And to say thank you…here are the winners!
Comment #12 – Lisa B.
Comment #26 – Yadira A.
Congrats to all the winners! Winners, I sent you an email with instructions on how to claim your prize, but just to reiterate…email your snail mail addy to me at elisabeth (at) elisabethnaughton (dot) com and I'll forward your info to the appropriate authors.
In the meantime…if you haven't gotten your copy of TEMPTED yet…RUN OUT AND BUY IT TODAY!!
CONGRATS to all of the other Winners!!!
Congrats on the release of Tempted.
I do hope you do this again it was fun!!!
Thanks so much, Elisabeth. Congrats again on the new release. Congrats to the winners.
😀 Thank you Elisabeth & Kris Kennedy for the book win!
Congrats to all of the other winners also! Enjoy!
Thank you for holding such a great contest, enjoyed reading everyone else's comments.
And congrats on the new release!
Congratulations to all the winners and All the best for the rest.


text:
SAN DIEGO COMIC-CON: Warner Brothers/DC reveal Aquaman and Shazam!
HomeAll PostsFilm TalkSAN DIEGO COMIC-CON: Warner Brothers/DC reveal...
Film Talk, Nick on July 21, 2018 357Views 0Likes 0Comments
San Diego Comic-Con is currently underway and with Marvel Studios essentially skipping the convention this year, Warner Brothers and the DC film universe hit the ground running with two highly anticipated films releasing trailers today. While technically "teaser" trailers, the footage shown from Aquaman (2018) and Shazam! (2019) offered up plenty of spectacular material.
Aquaman stars Jason Momoa as Arthur Curry, the half-human, half-Atlantean would-be king. Directed by James Wan, the film certainly doesn't appear to delve into dark territory like Wan's resume of horror films has (and Zack Snyder's DC films have been heavily criticized for). There is plenty of awe-inspiring images of Atlantis and the myriad of sea creatures that the hero will have at his disposal. Co-starring Amber Heard, Patrick Wilson and Nicole Kidman, Aquaman simply looks like a blast; a solid action-adventure story with massive spectacle and Momoa's surfer-dude/rock star charm. Count me in!
P.S. How cool is the gold suit he wears? We've already seen production art that heavily suggests Aquaman will have a more comic-accurate wardrobe compared to what Momoa wore in Justice League (2017).
Not being satisfied with only one massive trailer reveal, DC/WB also showed a kick-ass trailer for Shazam! The film stars Asher Angel and Zachary Levi as Billy Batson/Shazam: a teenage boy who is given superpowers by an ancient wizard. Upon uttering the magic word "Shazam", Billy Batson (Angel) transforms into a hulking caped-crusader who rivals Superman in both size and abilities. The film clearly plays on the comedic angle of having a 12-year-old boy behind the wheel of the adult-sized hero and both Angel and Levi show considerable charm as the character. This one looks like a riot for both the comedy and the action. Sign me up.
Aside from Warner Brothers bringing their A-game with their DC properties, they also released a new trailer for Fantastic Beasts: The Crimes of Grindelwald (2018); set in the "Wizarding World" created by Harry Potter author, J.K. Rowling.
M. Night Shyamalan's highly anticipated sequel to both Unbreakable (2000) and Split (2016) was shown. The film titled Glass (2019) unites Samuel L. Jackson, Bruce Willis and James McAvoy in this non-comic-book superhero film. Once again, McAvoy displays absolute brilliance as Kevin Wendell Crumb / The Horde: a supervillain suffering from dissociative identity disorder who possesses 23 personalities and whose body chemistry changes with each personality, resulting in a 24th personality known as "The Beast". McAvoy's performance(s) in Split were nothing sort of brilliant and I can't wait to see the conclusion to this saga nearly 2 decades in the making.
Nick Maylor
Nick is an actor/writer/comedian/musician from Hamilton, ON Canada. Having been a film nut since the early days of his life, Nick has had an obsession with cinema and popular entertainment. Nick has written for thecinemaholic.com and is the current Foote & Friends "expert" on all things geek/superhero/comic-book related. Nick met John when studying acting at the Toronto Film School, for which John H. Foote was director and Film History professor. The two have been arguing ever since.
Follow Nick on Twitter @NickMaylor
Tags: Coming Soon, Nick
Fosse and his Films
2018 TIFF FIRST ANNOUNCEMENTS
Alan, Film Talk, Lists
Julie Andrews: A Look Back at Her Essential Performances
on December 5, 20180
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Revisiting V FOR VENDETTA (2005)
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PODCAST #001
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text:
Spirited Away (Dubbed)
2001
Action/Adventure, Animation, Family
2 h 4 min
English audio
CC PG
Winner of the Academy Award for Best Animated Feature, Hayao Miyazaki's wondrous fantasy adventure is a dazzling masterpiece from one of the most celebrated filmmakers in the history of animation.
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Bundles containing this item
Studio Ghibli 6-Film Collection
Winner of the Academy Award for Best Animated Feature, Hayao Miyazaki's wondrous fantasy adventure is a dazzling masterpiece from one of the most celebrated filmmakers in the history of animation. Chihiro's family is moving to a new house, but when they stop on the way to explore an abandoned village, her parents undergo a mysterious transformation and Chihiro is whisked into a world of fantastic spirits ruled over by the sorceress Yubaba. Put to work in a magical bathhouse for spirits and demons, Chihiro must use all her wits to survive in this strange new place, find a way to free her parents and return to the normal world. Overflowing with imaginative creatures and thrilling storytelling, Spirited Away became a worldwide smash hit, and is one of the most critically-acclaimed films of all time.
English (CC)
Released year
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3.5 GB (SD)
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text:
Walk This Way to Game 3 … Mets Beat Padres to Take NL Wild Card Series to its Limit
NBC San Diego 10/9/2022 Derek Togerson
NEW YORK, NEW YORK – OCTOBER 08: Francisco Lindor #12 of the New York Mets hits a solo home run during the first inning against the San Diego Padres in game two of the Wild Card Series at Citi Field on October 08, 2022 in New York City. (Photo by Dustin Satloff/Getty Images)
Blake Snell is usually really good in the post-season. On Saturday night he was anything but good. Of course, neither was anyone else on the Padres pitching staff (with the exception of Steven Wilson) and now we have a winner-take-all situation on Sunday.
The Mets beat the Padres 7-2 in Game 2 of their best-of-3 NL Wild Card series at Citi Field, thanks in large part to the nine walks (and one hit batter) the Friars staff issued.
Snell had all kinds of trouble finding the plate. He walked six batters and worked a ton more 3-ball counts before getting pulled after just 3.1 innings. He needed 90 pitches to get 10 outs and even some of those were hit awfully hard right at fielders.
The trouble started in the 1st inning when Francisco Lindor launched a solo home run to left field off Snell to give the Mets a 1-0 lead. However, give the Padres offense credit for doing some damage against one of the best pitchers on earth.
Jacob deGrom was throwing 102-MPH fastballs most of the night but in the 3rd inning Trent Grisham continued his resurrection with another home run, his 2nd of the playoffs, this time an opposite field shot to tie it 1-1.
In the 4th Snell's lack of control hurt him again. He walked the first two batters of the inning and Brandon Nimmo lined a single to left field to bring one of them home with a 2-1 lead. That's when manager Bob Melvin went to his bullpen. Nick Martinez came in and got out of the inning on just three pitches to keep it from getting completely out of hand.
Amazingly the Padres offense bailed out their starter with another run in the top of the 5th. Jurickson Profar singled down the first base line to bring home Grisham (who drew a walk from deGrom to lead off) and tie it up 2-2. That tie did not last long. Pete Alonso hit the first pitch he saw from Martinez out of the yard to put the Mets on top 3-2.
In the 7th inning things got completely out of hand. Adrian Morejon came on and gave up a leadoff single to Lindor. Then he walked Alonso and Mark Canha, both on the 10th pitch of their at-bats. Clearly laboring, Melvin left the lefty in to face left-handed hitting Jeff McNeil. It was one hitter too many. McNeil laced a 2-run double to right-centerfield and New York was up 5-2. Pierce Johnson came in to try and clean up Morejon's mess.
He gave up an RBI single to Eduardo Escobar and a sac fly to Daniel Vogelbach to make it 7-2 and we should give a shoutout to Steven Wilson for throwing a perfect 8th inning with two punchouts in his post-season debut. His ability to keep it there actually, inexplicably, allowed the tying run to come to the plate.
Adam Ottavino had control issues of his own. He walked three, including Manny Machado with the bases loaded to make it 7-3 and bring up Josh Bell. But, Seth Lugo got him to ground out to end it.
So, it all comes down to Sunday. San Diego's own Joe Musgrove takes the mound against Chris Bassitt. Winner goes to the National League Division Series in Los Angeles. Loser goes home until pitchers and catchers report in 2023.
LISTEN: With NBC 7 San Diego's Darnay Tripp and Derek Togerson behind the mic, On Friar will cover all things San Diego Padres. Interviews, analysis, behind-the-scenes...the ups, downs, and everything in between. Tap here to find On Friar wherever you listen to podcasts.
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Kia Ora, talofa lava, malo e lelei, fakaalofa lahi atu, kia orana, bula vinaka, namaste and greetings!! It's Pasifika week in Aotearoa, this means it's a week long celebration of all things Pacific. This includes the birthday dance we had with Mrs Tele'a! Part of the celebration is the Polyfest! This Thursday we are planning to travel to Manukau to take part in some workshops and then visit stages. The two stages we will be visiting will be the Maori and Diversity stages. Did you know that this event - the Polyfest celebrates 40 years since it's beginning? Awesome isn't it!
whanau and young kids participate in these stages because it is there culture.Performers go through hard things to get people to watch them, Learn the dance, Know the song to the dance, learn how to move and know where you're gonna be positioned and remember who you're next to, they had to learn all that to get perfect.
Polyfest promote our different culture because it shows creativity and responsibility in the dances.
I'm looking forward to polyfest because I want to see different dance culture because some are fast and some are slow.


Did you read the Jason Brinn Article and thread? Please do and then join in the fun.
What the hell is Mala Vidyea?
What is the best martial art IN THE WILD!?!!
The rank or the experience?
Uh, guys? I'm torn beween BJJ and MT.
whats the most important thing in martial arts?
Anderson Silva training with....Steven Seagal?!
BJJ America: trian under own supervision, be graded by John Will and David Meyer.
Fat Guy Fights Over Cheezburger!
what style does Cody Diesbourg do?
This JKD School for real? Help.
Got into ANOTHER street fight...!
Mayweather has got teh deadly.
Charlies Combat Club or Gracie Barra Everett?


The eagerly anticipated Batman Vs Superman movie will be titled Batman Vs Superman: Dawn Of Justice, it has been confirmed.
The film will open in cinemas in 2016, with a post on the official Facebook page yesterday (May 21) confirming the title. Shooting has begun with director Zack Synder filming at Michigan Motion Picture Studios and on location in and around Detroit, Michigan, Illinois, Africa and the South Pacific.


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text:
Margaret Joan Beazley (nascida em 23 de julho de 1951) é uma jurista australiana que é a 39ª e atual governadora da Nova Gales do Sul, atuando desde 2 de maio de 2019. Foi presidente do Tribunal de Apelação de Nova Gales do Sul, a primeira mulher a ocupar o cargo, de 2013 a fevereiro de 2019.

Governadores da Nova Gales do Sul