tbuckley/cabot-search huggingface dataset:
Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group.
Authors: S B Kaye, J Paul, J Cassidy, C R Lewis, I D Duncan, H K Gordon, H C Kitchener, D J Cruickshank, R J Atkinson, M Soukop, E M Rankin, J A Davis, N S Reed, S M Crawford, A MacLean, D Parkin, T K Sarkar, J Kennedy, R P Symonds
Journal: Journal of Clinical Oncology (1996)

PURPOSE In 1992, we reported the first results of a randomized study in ovarian cancer, comprising two doses of cisplatin and indicated a significant difference (P = .0008) in median survival. Four years later, we now describe the results of this trial. PATIENTS AND METHODS After a median follow-up of 4 years and 9 months, 115 of 159 cases of advanced ovarian cancer, originally randomized to receive six cycles of cyclophosphamide 750 mg/m2 and either a high dose (HD) of 100 mg/m2 cisplatin or a low dose (LD) of 50 mg/m2 (LD) cisplatin, have now died. RESULTS The overall survival for HD and LD patients is 32.4% and 26.6%, respectively, and the overall relative death rate is 0.68 (P = .043). This represents a reduction in overall benefit with longer follow-up compared with the first 2 years (relative death rate of 0.52). Toxicity, particularly neurotoxicity, is still evident in the fourth year (10/31 on HD compared with 1/24 on LD). CONCLUSION Our recommended dose of cisplatin in combination schedule is therefore 75 mg/m2, representing the optimal balance between efficacy and toxicity.
Thyroid transcription factor-1 and matrix metalloproteinase-9 in the prognostic assessment of patients with lung adenocarcinoma
Authors: S. J. Martins, N. Ho, V. L. Capelozzi, T. Y. Takagaki
Journal: Journal of Clinical Oncology (2005)

7207 Background: The thyroid transcription factor-1 (TTF-1) is a tissue-specific transcription factor that could play an important role in cell differentiation, morphogenesis, and clinical behaviour of lung tumors. Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease present in low quantities in the healthy adult lung, but much more abundant in non-small cell lung cancer. Methods: The prognostic value of TTF-1 and MMP-9 was evaluated by immunohistochemical methods and Cox regression in 51 patients with advanced or metastatic lung adenocarcinoma treated with platinum regimens. Results: The median expression of TTF-1 was 30.0% (range: 0% to 85.9%). All tumors expressed MMP-9 (median: 78.7%; range: 15.2% to 96.1%). Median survival was 41.6 weeks, with estimated 1-year and 2-year survival rates of 45% and 22%, respectively. Poor performance status (Karnofsky’s scale) - hazards ratio (HR): 1.03, 95% confidence interval (CI): 1.01 to 1.06; low TTF-1 expression (< 40%) - HR: 4.00, 95% CI: 1.75 to 9.09; and high MMP-9 expression (≥ 80%) - HR: 2.82, 95% CI: 1.30 to 6.08 were independent prognostic factors. Patients were stratified in three risk groups according to markers expression: low risk (TTF-1 ≥ 40% and MMP-9 < 80%; median survival: 127.6 weeks), intermediate risk (TTF-1 < 40% or MMP-9 ≥ 80%; median survival: 39.0 weeks); and high risk (TTF-1 < 40% and MMP-9 ≥ 80%; median survival: 16.4 weeks). Conclusions: Initial immunohistochemical evaluation of TTF-1 and MMP-9 may allow us to identify different, clinically meaningful, prognostic groups of lung adenocarcinoma patients, when treated with platinum regimens. Heterogeneity on histological subtypes of lung adenocarcinoma may confound efficacy evaluation of clinical trials in this disease. No significant financial relationships to disclose.
Ireland is to install supervised injecting rooms
Authors: Muiris Houston
Journal: BMJ (2016)

Drug users in Ireland will be able to use supervised injecting rooms later this year, starting in Dublin, followed afterwards by other major cities, the Irish government has said.

Announcing the decision in a speech to the London School of Economics before Christmas, the minister in charge of national drug policy, Aodhan O Riordain, said that he did not see injecting rooms as “free for all” facilities for …
Adjuvant chemotherapy for resected biliary tract cancer: A retrospective analysis.
Authors: M. Lucchesi, E. Vasile, M. Lencioni, C. Caparello, S. Caponi, L. Ginocchi, U. Boggi, F. Mosca, F. Filipponi, M. Seccia, M. Chiarugi, M. Andreuccetti, S. Ricci, A. Falcone
Journal: Journal of Clinical Oncology (2011)

e14614 Background: There are no well-conducted randomized studies regarding the role of adjuvant chemotherapy for patients with radically resected biliary tract cancers and there is no standard accepted adjuvant treatment for these patients, even if the majority of them suffers from recurrent disease. Methods: We retrospectively reviewed the outcome of patients who underwent radical surgical resection for biliary tract cancer from 2005 to 2009 and who received adjuvant treatment or were followed up at our institution. The aim of our analysis was to evaluate the correlation between prognostic factors and disease-free survival (DFS) using Chi-square test and Cox regression analysis, and to explore the role of adjuvant treatment in these patients. The indication for adjuvant chemotherapy was based upon discussion of its role with every single patient. Results: Eighty-one evaluable patients, 44 (54%) women and 37 (46%) men, all ECOG performance status 0-1, were identified; median age was 67 years (range 30-81). The site of biliary cancer was intrahepatic in 19 patients, perihilar in 12, distal tree in 20, gallbladder in 11, ampullary carcinoma in 19 cases. Fifty-three patients (65%) had T3 or T4 tumors and 34 (42%) had positive nodes; 29 tumors (37%) were of grade 3-4; perineural or vascular invasion was present in 34 (42%) and 15 (19%) cases. Thirty-two (39%) patients received adjuvant chemotherapy with gemcitabine or fluoropyrimidines. On univariate analysis tumor extension, node status, grading, vascular invasion and adjuvant chemotherapy significantly correlated with DFS. In particular, patients with N1 tumour had a median DFS of 12.4 months versus 25.2 months of N0 patients. Patients who received adjuvant chemotherapy after surgery had a median DFS of 29.0 months compared to 17.5 months of patients treated with surgery alone (p=0.04). Multivariate analysis confirmed the negative prognostic role of lymph node involvement (p=0.04) and the positive impact of adjuvant chemotherapy (p=0.001). Conclusions: Adjuvant chemotherapy seems effective in prolonging DFS in radically resected biliary tract cancer patients. A phase III randomized trial should prospectively evaluate the role of adjuvant therapy.
Response of Hyperplastic Alveolar Nodule Outgrowth-Line D1 to Mammary Tumor Virus, Nodule-Inducing Virus, and Prolonged Hormonal Stimulation Acting Singly and in Combination&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Daniel Medina, K. B. DeOme
Journal: JNCI Journal of the National Cancer Institute (1969)

This paper presents evidence that the nodule-inducing virus (NIV) can participate in the production of neoplastic cell variants within the hyperplastic alveolar nodules in the mammary glands of BALB/c mice. The transplanted D1 nodule outgrowth had an increased tumor incidence and a decreased mean age of onset after infection with NIV. An additional increase in tumor incidence was achieved when D1 nodule outgrowths were infected with both NIV and the mammary tumor virus (MTV). Although prolonged hormonal stimulation produced by pituitary isografts, in the absence of MTV and NIV infection, failed to increase the tumor incidence in D1 nodule outgrowth, it exerted a synergistic effect when acting in conjunction with either MTV or NIV.
Metabolic aspects of protection by glycine against hypoxic injury to isolated proximal tubules.
Authors: J M Weinberg, D N Buchanan, J A Davis, M Abarzua
Journal: Journal of the American Society of Nephrology (1991)

To clarify the roles of butyrate and acylglycine formation in hypoxic proximal tubule cell injury and protection by glycine and to test the contribution of iodoacetate-suppressible metabolism to protection, (1) it was determined whether protection by glycine is fully expressed when glucose, lactate, alanine, and butyrate are replaced by alpha-ketoglutarate as the sole substrate for the tubules, (2) butyrate metabolism and acylglycine formation were directly measured in control and hypoxic preparations, and (3) it was assessed whether injury produced by iodoacetate, a potent inhibitor of glycolytic metabolism, is subject to protection by glycine. Susceptibility to hypoxic injury in medium with alpha-ketoglutarate as the sole substrate was similar to that seen in medium containing glucose, lactate, alanine, and butyrate. Tubules in alpha-ketoglutarate medium showed high degrees of protection by glycine against injury produced by 30-min of hypoxia, by iodoacetate alone, and by iodoacetate combined with hypoxia. Protection did not require preservation of cell ATP or glutathione. In glucose-lactate-alanine-butyrate medium, butyrate, measured by gas chromatography, was rapidly metabolized by oxygenated tubules and fully accounted for basal rates of oxygen consumption. Butyrate utilization stopped during hypoxia. Neither aspect of butyrate metabolism was altered by glycine. Formation of acylglycines was assessed by gas chromatography/mass spectroscopy. In preparations treated with glycine, butyrylglycine was detected under both oxygenated and hypoxic conditions; the quantities, however, were small and no other acylglycines were found. These observations indicate that protective effects of glycine are independent of short-chain acylglycine formation and glycolytic metabolism.
Vow to impose contract means further action is “inevitable,” says junior doctors’ leader
Authors: Gareth Iacobucci
Journal: BMJ (2016)

The BMA has said that further action against the government is “inevitable” after the health secretary for England’s controversial decision to impose a new contract on junior doctors.

The chair of the BMA’s Junior Doctors Committee, Johann Malawana, said that the BMA had received “a tidal wave of calls” from the profession since the announcement by Jeremy Hunt on 11 February that he would push through a deal after negotiations between the BMA and NHS Employers broke down.1

Hunt’s announcement followed a second day of industrial action by junior doctors in as many months on Wednesday 10 February.2 Junior doctors took to the streets again after the announcement, with a protest outside the Department of Health headquarters in Whitehall on the evening of 11 February.

Malawana, who said that the government had “alienated a generation of junior doctors” with its action, added that the BMA would now …
Gemcitabine (G) plamsa and intracellular pharmacokinetics in E6201: Greater metabolite levels using fixed dosing rate (FDR) delivery
Authors: L. Liebes, D. E. Levy, E. Poplin, S. Mendoza, D. Fry, M. Buckley, A. Zoloratov, A. Benson, H. Hochster
Journal: Journal of Clinical Oncology (2006)

2024 Background: Gemcitabine (G) is an antimetabolite which requires activation by the rate-limiting enzyme dCK to its active metabolite, dFdCTP. FDR delivery of G at 10 mg/m 2 /minute may allow greater formation of active metabolite and improved activity. E6201 randomly assigned first line pancreatic cancer patients to three arms: A (G 1000 mg/m 2 over 30 minutes), B FDR G (1500 mg/m 2 over 150 minutes), and C GemOx (1000 mg/m 2 over 100 minutes with oxaliplatin 100 mg/m 2 ). Methods: Investigators from 18 centers contributed 23 sample sets on the first dose of G. Five time points over 4 hrs were sampled (baseline, mid infusion, end infusion, 1–2 post and 4 hrs). Plasma fractionation along with the PBMC purification and subsequent perchloric acid extraction were conducted locally with THU 1 mg (cytidine deaminase inhibitor). Samples were shipped overnight to the central lab where G and its metabolite dFdU were quantified from deproteinized plasma by reverse phase HPLC. dFdCTP was quantified by ion-exchange HPLC in neutralized PBMC extracts after removal of ribonucleotide triphosphates. Data were fit to nonlinear models (WinNonLin, v4.1) and comparisons amongst dosing groups employed the non-parametric, 2-sided Mann-Whitney test. Results: For Arms A, B and C the plasma AUCs were respectively (median ± SD): 4542 ± 2472 (N=9), 8603 ± 2608 (N=8) and 9130 ± 8788 (N=6) ng/ml x hr. The difference between group A and B (p=0.003) and A and C (p=0.05) were statistically different. Intracellular dFdCTP AUCs for groups A, B, and C were: 1862 ± 794 (N=8); 3725 ± 7763 (N=8) and 5024 ± 2113 (N=5) and significantly different for both A vs. B (p=0.05) and borderline significant for A vs C (p=0.065). The latter comparison is limited by a small number of samples. Conclusions: When studied in a multi-centered, randomized cooperative group setting, FDR delivery of G results in higher plasma AUC, and increased intracellular levels of active metabolite dFdCTP. These data support the concept that fixed dose rate delivery of G results in greater intracellular metabolite production at similar and equitoxic doses. Supported by ECOG NYU620HH04–00, NCI CA16087, CA2115, and from Eli Lilly. No significant financial relationships to disclose.
Impact of NHS Direct on demand for immediate care
Authors: J. McInerney
Journal: BMJ (2000)

Impact of NHS Direct on demand for immediate care Target communities show poor awareness of NHS DirectEditor-Munro et al found that NHS Direct had no discernible effect on the use of emergency ambulances or accident and emergency departments in the first year of operation, leading to a suggestion that this service may not prove cost effective. 1 The study is limited by an assumption that the population studied had complete awareness of the service.Six months after the introduction of East Midlands NHS Direct we had anecdotal evidence to suggest that many patients attending our accident and emergency department were unaware of the telephone advisory service.Consequently we undertook a survey of 300 consecutive ambulatory patients (or their parents) who referred themselves to the accident and emergency department and had not contacted NHS Direct.We wanted to find out whether they were aware of the service.Altogether 266 (89%) questionnaires were completed, with 166 (62%) patients claiming to have had no previous awareness of NHS Direct.Furthermore, of the 100 patients who were aware of the service, only 36 were aware of the telephone charge while 51 thought that calls were taken by doctors.Only eight "aware" patients, however, said that they would distrust advice given by a nurse, a finding that supports a study by O'Cathain et al. 2 The survey also determined which sections of the community were unaware of NHS Direct.Patients aged over 65 (all 9), patients from ethnic minorities (41/59; 69%), patients from predominantly less affluent postcodes (101/129; 78%), and young men (20/28; 71%) were overrepresented.The survey also found that 240 (90%) patients claimed to have access to a telephone and that 56 (21%) might have been redirected away from our department by NHS Direct.In the light of these findings we would say that NHS Direct has failed to market its existence to those members of the community who frequently access urgent health care.The results of NHS Direct impact studies have consequently been confounded by this oversight.Whether a proper national publicity campaign can improve the impact of this beleaguered service remains to be seen.
Aurora kinase A inhibition in combination with proapoptotic BH3-mimetic for treatment of pancreatic cancer.
Authors: Edward Jae-hoon Kim, Danielle C. Chinn, Thomas John Semrad, Philip C. Mack
Journal: Journal of Clinical Oncology (2015)

316 Background: BH3-mimetics were designed to inhibit the anti-apoptotic members of the Bcl-2 family of proteins. BH3-mimetics in clinical development do not inhibit the Bcl-2 protein Mcl1, which is often active in pancreatic cancer. However, Mcl1 level can be decreased by mitotic arrest. Therefore, drugs that cause mitotic arrest may augment apoptosis induced by BH3-mimetics. Aurora Kinase A (AKA), also commonly overexpressed in pancreatic cancer, regulates mitotic spindle assembly and centrosome maturation and its inhibition leads to M-phase arrest. We hypothesized that inhibiting AKA would increase sensitivity of pancreatic cancer cells to BH3-mimetic-induced apoptosis. Methods: Pancreatic cancer cell lines (AsPC-1, PANC-1, MIA PaCa-2, HPAF-II) were evaluated for AKA protein expression by Western blot (WB). Baseline cell cycle distribution was evaluated by flow cytometry. All four cell lines were treated with a BH3-mimetic (ABT-263) alone, an AKA inhibitor (MLN8237) alone, or the combination in comparison to untreated controls. Cell viability was measured using the Celltiter-Fluor assay. Apoptosis was evaluated by WB for cleaved PARP and caspase 3. Percentage of cells undergoing apoptosis was quantitated using flow cytometry of annexin V and propidium iodide stained cells. Results: AKA expression varied between cell lines but correlated with percentage of cells in G2/M. Level of AKA expression did not appear to correlate with response to MLN8237. However, MLN8237 did induce mitotic arrest resulting in an increase in the G2/M fraction. Cell viability assays revealed limited sensitivity to MLN8237 or ABT-263 alone. MIA PaCa-2 cells were the most sensitive to MLN8237 with IC 50 ~0.09µM and HPAF-II cells were the most sensitive to ABT-263 with IC 50 0.6µM. MLN8237 lowered the IC 50 of ABT-263 in all 4 cell lines. Chou-Talalay plots exhibited a combination index &lt; 1 in each cell line, confirming synergy. WB for cleaved PARP and caspase 3 showed increased apoptosis with the combination. The percentage of cells undergoing apoptosis also increased with the combination in each cell line. Conclusions: Inhibition of AKA synergistically augments BH3-mimetic-induced apoptosis in pancreatic cancer cells.
A phase I study of E7070, a chloroindolyl-sulfonamide, in combination with irinotecan in gastrointestinal and thoracic carcinomas
Authors: D. P. Ryan, J. P. Eder, L. Appleman, P. Fidias, B. Johnson, J. Lucca, J. Aluri, T. Owa, F. G. Renshaw, G. Shapiro
Journal: Journal of Clinical Oncology (2005)

2031 Background: E7070 is a novel sulfonamide cell cycle inhibitor, demonstrating preclinical synergy with irinotecan. A phase I study was designed to determine the MTD of E7070 in combination with irinotecan in patients with GI and thoracic malignancies. Secondary objectives include evaluation of safety and preliminary assessment of antitumor activity.Methods: This is an ongoing study in which either 125 mg/m2 or 100 mg/m2 of irinotecan is followed by E7070 given in escalating doses (250 mg/m2 to 525 mg/m2). The combination is administered on days 1 and 8 of a 21-day cycle. Patients may have been treated with up to two prior regimens, and may have also received capecitabine or cetuximab. Toxicities are graded using NCI CTC version 2.0. Pharmacokinetic analyses have been performed. Results: Thirty-five patients have been treated. The MTD of the regimen is 125 mg/m2 irinotecan plus 325 mg/m2 E7070 or 100 mg/m2 irinotecan plus 400 mg/m2 E7070. Therapy was well tolerated with a dose limiting toxicity of neutropenia. One death occurred, secondary to neutropenic sepsis. Among 14 patients treated with 100 mg/m2 irinotecan plus 400 mg/m2 E7070, 4 have required dose reductions, omissions or delays. Notable treatment toxicities in this group include: grade 4 neutropenia (2), grade 3 diarrhea (1) and grade 3 pneumonitis (1). Of 11 patients with colorectal cancer one PR occurred in an irinotecan-naïve patient, while 6/8 who had received prior irinotecan had stable disease, with a median TTP of 18 weeks (range 12–24). Among 9 irinotecan-naïve SCLC patients, 3 achieved PR, including one with primary refractory disease, durable for 15+, 21 and 36+ weeks, respectively. Four additional SCLC patients had SD, 2 with >20% reduction in tumor burden. Preliminary pharmacokinetic analyses demonstrated decreased clearance of E7070 in the presence of irinotecan, while irinotecan pharmacokinetics were not affected by E7070. Conclusion: The combination of irinotecan with E7070 is tolerable and has promising activity in previously treated GI and thoracic malignancies. Additional cohorts are planned using 100 mg/m2 CPT-11 and E7070 escalation in a bi-weekly schedule. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Medical Research, Eisai Tsubuka AstraZeneca, Eli Lilly, Pfizer Eisai Medical Research
DUSP7 and DUSP8 promoter hypermethylations: Predictors of clinical outcomes in advanced epithelial ovarian carcinoma
Authors: S. Lim, J. A. Green, H. Wong, M. E. VanderBurg, T. Crook
Journal: Journal of Clinical Oncology (2007)

5501 Background: The Dual specificity phosphatases (DUSPs) are a subclass of the protein tyrosine phosphatase (PTP) gene family which appears to be selective for dephosphorylating the critical phosphothreonine and phosphotyrosine residues within the mitogen-activated protein kinases (MAPKs) leading to inactivation. MAPK activation is a downstream target of several oncogenes and may give rise to oncogenic transformation, and hence DUSPs are potential tumor suppressor genes. The aim of this study was to investigate if DUSPs are subject to methylation-dependent silencing in epithelial ovarian cancer. Methods: In this study, promoter methylation and gene expression of the DUSPs genes (DUSP1, DUSP2, DUSP3, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8 and DUSP10) were investigated in 9 ovarian cancer cell lines and in 74 primary epithelial ovarian tumors (Stage III/IV), using methylation specific PCR (MSP) and Reverse- transcription PCR (RT-PCR). The 74 clinical samples were retrospectively retrieved from a large Phase III RCT (the EORTC 55931/NCIC OV10) with clinical follow-up in excess of 6.5 years. Results: Ovarian Cancer Cell lines: Aberrant CpG methylation detected in DUSP1, DUSP2, DUSP4, DUSP6, DUSP7 and DUSP8. DUSP7 promoter methylation was associated with downregulation of mRNA expression. Primary Ovarian Tumors: Methylation of DUSP1, DUSP2, DUSP7 and DUSP8 was observed in 15–38% of the primary tumors. DUSP7 methylation is a predictor of adverse PFS in both univariate (median PFS 10.6 m versus 13.3m, p=0.002) and multivariate (Cox Regression HR 2.76, p&lt;0.001) analyses, and is associated with a trend for poorer OS (22.1 m versus 29.3 m, p=0.07). In contrast, DUSP8 methylation is an independent predictor of favorable PFS (median 23.7m versus 11.5m; Cox Regression HR 0.30, p=0.006) and OS (HR 0.31, p=0.013). 5-year OS for DUSP8 methylated patients was 58.3% compared with 16.1% for DUSP8 unmethylated (HR 0.277, p=0.005). Conclusion: This is the first report of DUSP methylation in epithelial ovarian cancer. The study suggests that methylation-dependent transcriptional silencing of DUSP7 in advanced epithelial ovarian cancer may represent an independent predictor of adverse PFS. DUSP8 methylation, on the other hand, is a favorable clinical outcome marker. No significant financial relationships to disclose.