tbuckley/cabot-search huggingface dataset:
Effect of Lopinavir/ritonavir protease inhibitor on the pharmacokinetics of Irinotecan in HIV-infected patients with advanced Kaposi’s sarcoma
Authors: G. Corona, E. Vaccher, G. Di Gennaro, U. Tirelli, G. Toffoli
Journal: Journal of Clinical Oncology (2006)

9558 Background: Irinotecan (CPT11) in combination with HAART has been found active in patients with advanced AIDS-related Kaposi’s sarcoma [Vaccher E et al. AIDS 2005]. Dose-limiting toxicity consisted of persistent leukopenia, suggesting the potential for pharmacokinetic interactions between CPT11 and lopinavir boostered with ritonavir, the protease inhibitor component of HAART. Methods: Six HIV-infected patients with advanced Kaposi’s sarcoma were prospectively treated with CPT11 at a dose of 150 mg/m 2 , given as a 90-min infusion on days 1 and 10, in absence and in combination with 400mg/100mg LPV/rtv. Pharmacokinetic parameters of the CPT11, the active metabolite (SN38), its glucoronide derivative (SN-38G), and the APC metabolite were investigated over a 50 h time interval at the first day of chemotherapy cycle. A 2-day LPV/rtv washout was allowed before the evaluation of pharmacokinetics of CPT11 alone. The pharmacokinetics of CPT11 in combination with LPV/rtv was determined at day-10 (paired cross over). Results: The mean (± SD) clearance of CPT11 was found significantly lower when CPT11 was administered in combination with LPV/rtv (13.39±3.39 l/h/m 2 vs 23.55±7.16 l/h/m 2 , p&lt;0.05 for CPT11+ LPV/rtv and CPT11 alone respectively). This was associated with a 94.3% reduction of AUC APC oxidized metabolite and with 2.9 and 1.8-fold increase of SN38 and SN38G AUC, respectively. During the CPT11+ LPV/rtv, the ratio SN38/CPT11 AUC was higher (0.031±0.008 vs 0.019±0.006, p&lt;0.05) while the glucoronidation ratio (the AUC ratio of SN38G and SN38) was found significantly lower (5.50±1.43 vs 9.03±2.49, p&lt;0.05) as compared to the administration of CPT11 alone. Conclusions: This preliminary investigation indicates that CPT11 pharmacokinetics can be strongly influenced by the co-administration of LPV/rtv. This leads to a significant increase of AUC SN38 active metabolite, likely associated to an increase of CPT11 activation and in a reduction of SN38 glucoronidation paths, which may have profound effects on pharmacodynamic of CPT11 when used in combination with LPV/rtv -based HAART. No significant financial relationships to disclose.
Anticancer effects on aurora kinase A and TACC3 protein complex
Authors: Jeong-Hoon Bae, Eun-Mi Ho, Eun-Kyoung Yim, Jong-Sup Park
Journal: Clinical Cancer Research (2007)

B61   The serine/threonine kinase Aurora A localizes to centrosomes and in required for centrosome maturation and spindle assembly. Transforming acidic coiled coil (TACC) proteins stabilize microtubules during mitosis by recruiting minispindles to centrosomes. TACC proteins can be phosphorylation in vitro by Aurora A kinases. We identified TACC3 as a novel protein that is down-regulated with paclitaxel treatment by proteomic analysis including 2-DE and MALDI-TOF-MS. TACC3 levels after paclitaxel treatment decreased as a time- and dose dependent manner in cervical carcinoma cells. Paclitaxel treated cervical carcinoma cells are unable to proceed normally through the cell cycle and are arrested in G2-M phase. However, the expression of Aurora kinase A was not influenced by paclitaxel treatment. Furthermore, we confirmed that  in vitro  immunoblotting analysis of Aurora kinas A and TACC3 co-immunoprecipitates showed that Aurora kinase A was associated with TACC3. Also, Aurora A kinase and TACC3 interaction using immunofluorescence analysis in cervical carcinoma cell, and these two proteins were mainly co-localized to the nucleus during mitosis, however, knockdown of Aurora kinase A by RNAi had no significant effect on expression of TACC3. These results suggest that the biological functions of these proteins are different, although they have overlapping subcellular co-localizations. But, further detailed investigation is needed to understand the mutual relation and molecular function of Aurora kinas A and TACC3 complex by treatment of paclitaxel in cervical carcinoma cells.
Metoclopramide versus setrons in delayed emesis in moderate emetogenic chemotherapy: A meta-analysis
Authors: K. Jordan, F. Mueller, A. Hinke, T. Behlendorf, P. Feyer, F. Roila, H. J. Schmoll
Journal: Journal of Clinical Oncology (2009)

e20538 Background: In the actual antiemetic ASCO and MASCC guidelines 5-HT 3 -RAs but not metoclopramide (MCP) are recommended as prophylaxis option for delayed emesis (DE) in moderate emetogenic chemotherapy (MEC). However, MCP was part of the former guidelines in this setting. As there are no clear study results showing a consistent advantage of 5-HT 3 -RAs over MCP in delayed emesis a metaanalysis would give more conclusive informations. Methods: In a Medline search 15 potential studies comparing a 5-HT 3 -RA vs. MCP in DE in patients receiving MEC were identified. Efficacy was classified as complete delayed response (no vomiting 24h-120h after chemotherapy). In 4 studies insufficient data for discrimination of acute and delayed emesis were given and in 5 studies additional antiemetics in one arm or MCP/ 5-HT 3 -RA were administerd only on demand. For each indivudual study odds ratio was calculated. Combined odds ratios were generated according to the methods developed by the Peto group. Results: Six studies (N=700) could be included in the final analysis. The comparison of 5-HT 3 -RAs and MCP revealed similar efficacy in the prevention of DE in patients receiving MEC (OR fixed 1.01, 95% CI: 0.75, 1.36, OR random 1.26, 95% CI: 0.64, 2.46). A second analysis (N=895) including the study with additional dexamethasone application in the DE phase confirms no advantage of one drug over the another (OR fixed 1.02, 95% CI: 0.79, 1.22, OR random 1.19, 95% CI: 0.70, 2.04). Conclusions: This is the first meta-analysis of all available randomized trials comparing 5-HT 3 -RAs and MCP in the delayed phase of MEC demonstrating no apparent difference in efficacy. MCP is a less expensive alternative to setrons in this setting. However, the results of this meta-analysis have to be interpreted with cautious due to the potential carry over effect from the acute phase and heterogeneity of the included studies. Despite these limitations, it should be discussed to recommend MCP again for the propyhlaxis of delayed emesis for MEC when preparing the new antiemetic guidelines. No significant financial relationships to disclose.
Prevention of acid aspiration during surgery for cancer using I.V rabeprazole
Authors: D. R. Mehta, A. Maseeh
Journal: Journal of Clinical Oncology (2005)

8275 Background Acid aspiration syndrome at the induction of anesthesia is still a potentially life-threatening complication. Its severity is affected by both pH and volume of the gastric juice that is aspirated. Rabeprazole is a new (PPI) with antisecretory properties and it has 2–10 fold greater antisecretory activity than Omeprazole. Evidence has shown that Rabeprazole may have two major differences from its predecessors. Primarily, it is a partially reversible PPI, thus there is a shorter duration of acid inhibition, Secondly, it has gastric effects other than its antisecretory properties. It caused production of gastric mucin. The increased intracellular mucin content suggests a beneficial gastric effect. Methods We compared the effects of Rabeprazole (a new proton pump inhibitor), on gastric fluid properties in a open labeled study on 8 adult patients undergoing cancer surgery. We have compared the effects of Rabeprazole on gastric secretion. one hours before operation, the patients were put on I.V Rabeprazole (20mg in 100 ml of Normal Saline infusion over 15 minutes). Gastric volume and pH were measured immediately after induction of anaesthesia. Results I.V Rabeprazole produced a significant increase in gastric pH and a significant decrease in gastric volume. Median Acidity Index was 140.5 +/[font“Times New (W1)”]−[/font“Times New (W1)”] 33.36. Conclusions: We conclude that I.V Rabeprazole to be given 2–3 h before surgery provide adequate prophylaxis for the acid aspiration syndrome during cancer surgery. No significant financial relationships to disclose.
Abstract #4706: High-sensitivity detection of BCR-ABL kinase domain mutation (M351T) in patients with chronic myeloid leukemia who develop imatinib (STI571) resistance
Authors: AB Rashid Mir, Sudha Sazawal, Alpana Saxena, Renu Saxena
Journal: Cancer Research (2009)

Objectivies: (1) To evaluate the Incidence and prevalence of M351T mutation in CML patients treated with Imatinib. (2) To study the clinical significance of imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a M351T BCR-ABL mutation. Methods: One hundred consecutive patients who presented with a diagnosis of CML had blood examined by RT-PCR for BCR-ABL transcripts. Early screening for the M351T mutation was performed by allele specific-oligonucleotide-PCR (ASO-PCR). The primer sets designed were similar to those used by Catherine Roche-Lestienne et al for M351T . Results: One hundred CML patients were studied among whom 85 were in CP-CML, 10 in BC-CML and 5 in AP-CML. Patients with CP-CML received an initial dose of 400mg imatinib daily, and patients with accelerated phase or blastcrisis received 600 mg daily. After the 6-12 months of initiation of therapy, all patients were screened for M351T mutations by ASO-PCR .Overall the mutation was detected 40 of 100 (40%) .The mutation was observed in 25/85 CP-CML , 3 of 5 AP-CML and 7 of 10 BC-CML .Overall the mutation was seen in 40 of 100 (40%) CML patients .Primary resistance was to imatinib was observed in 20 of 40 patients who also showed positivity for M351T mutation. Of these, 15 patients had hematologic resistance and 5 had molecular resistance besides being positive for M351T mutation. All 20 imatinib resistant CML patients were subjected to dose escalation. Patients of CP-CML (10/ 20) received imatinib 600mg daily and consequently 8/10 AP/BC CML patients received imatinib 800 mg daily. All twenty CML patients were screened for M351T mutation by ASO-PCR after three to six months of dose escalation, 8/10 CP-CML and 6/10 AP/BC CML patients became negative for M351T mutation but six resistant patients retained the M351T mutation consequently developed another more fatal mutation called T315I mutation which is reported in literature to be resistant to imatinib/dasatinib and Nilotinib. Three of five died and 3 remained in advanced disease which is now treated with dasatinib. Harboring of M351T and T315I mutations are significantly associated with a greater likelihood of resistance and disease progression (P  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4706.
A phase I/II study of preoperative oxaliplatin (O), 5-fluorouracil (5-FU), and external beam radiation therapy (XRT) in locally advanced rectal cancer: CALGB 89901
Authors: D. P. Ryan, D. Niedzwiecki, D. Hollis, B. E. Miedema, S. Wadler, J. E. Tepper, R. J. Mayer
Journal: Journal of Clinical Oncology (2004)

3560 Background: 5FU and XRT administered preoperatively is a standard regimen for patients with T3/T4 rectal cancer. Preclinical data demonstrate radiation sensitization for O and 5FU. The aims were to determine the MTD of weekly O with 5FU and XRT and to determine the pathological response at the MTD. Methods: Eligibility criteria included adenocarcinoma of the rectum within 12 cm of the anal verge; T3/T4 disease as demonstrated by endorectal USG or MRI; no metastatic disease; adequate bone marrow, liver, and kidney function. 5FU 200 mg/m2 was administered over 24 hours daily. XRT was delivered at 1.8 Gy per day, 5 days/week (28 fractions total). O was administered over 1 hour on day 1 of each week. Surgical resection was recommended 4–6 weeks after chemoradiation. DLTs included grade 4 neutropenia, grade 3/4 thrombocytopenia or grade 3/4 nonhematologic toxicity requiring > 7 days interruption in therapy. A traditional phase I accrual design was followed. The MTD is the dose level below the level where 2 of 6 patients experience DLT or a maximum dose of O of 60 mg/m2. Results: 18 patients (7 women, 15 caucasian, median age 56.5) were enrolled to 4 dose levels of O (30, 40, 50, 60mg/m2). No DLTs were observed in the first 3 dose levels. 2 patients were replaced in dose level 2 (1 hypersensitivity reaction, 1 colonic obstruction). The third patient enrolled at dose level 4 experienced a DLT (diarrhea week 4) and a patient at this level was replaced due to disease related bowel perforation. Three additional patients were enrolled at dose level 4 without any DLTs. Two patients experienced grade 3 neutropenia. No patient experienced grade 3 thrombocytopenia or neuropathy. Grade 3 diarrhea occurred in one patient each at the 30 and 50 mg/m2 dose levels during weeks 4 and 1, respectively, and 3 patients at 60 mg/m2 during weeks 2, 3, and 4, respectively. An additional 19 patients have been accrued at dose level 4. Conclusions: The recommended phase II dose of weekly O when administered with 5FU and XRT is 60mg/m2. Updated toxicity and pathological response rate for 25 patients treated at the MTD will be available in Spring 2004. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi Sanofi
Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy
Authors: Frida Dalin, Grazyna Adamus, Sufang Yang, Eva Landgren, Josefine Palle, Åsa Hallgren, Britt-Marie Frost, Therése Hugosson, Nils Landegren, Daniel Eriksson, Sten Andréasson, Khalid F. Tabbara, Olle Kämpe, Mohammad Alimohammadi
Journal: Ophthalmology (2016)
Effects of Cyclosporin A and α-Difluoromethylornithine on the Growth of Hamster Pancreatic Cancer In Vitro&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: R Saydjari, C M Townsend, S C Barranco, E James, J C Thompson
Journal: JNCI Journal of the National Cancer Institute (1986)

The growth and survival of hamster H2T pancreatic ductal adenocarcinoma in vitro are known to be significantly reduced by inhibitors of polyamine biosynthesis. alpha-Difluoromethylornithine (alpha-DFMO) is a specific and irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in polyamine biosynthesis. alpha-DFMO treatment inhibits the growth of H2T pancreatic cancer cells and decreases H2T cell survival in vitro and in vivo. In the present study, the effects of cyclosporin A (CsA) were examined on growth, survival, and polyamine levels in H2T pancreatic ductal adenocarcinoma in vitro. CsA had inhibitory effects on H2T pancreatic cancer growth similar to those of alpha-DFMO; these effects were blocked by the addition of the polyamine putrescine. Polyamine levels were found to be significantly altered in cells treated with CsA and/or alpha-DFMO. The combination of CsA (8.3 X 10(-4) mM) and alpha-DFMO (0.5 mM or 1.0 mM) inhibited H2T cell survival to a greater extent than either agent alone. These results suggest that CsA in combination with other agents that inhibit polyamine synthesis may be useful for the treatment of pancreatic cancer.
Abstract 17953: GrBeta Gammar Independent Recruitment Of G-protein Coupled Receptor Kinase 2 Drives TNF Alpha-induced Cardiac Beta-adrenergic Receptor Dysfunction
Authors: Neelakantan T Vasudevan, Maradumane L Mohan, Manveen K Gupta, Elizabeth E Martelli, Afshan K Hussain, Yilu Qin, Unni M Chandrasekharan, David Young, Arthur M Feldman, Subha Sen, Gerald W Dorn, Paul E DiCorleto, Sathyamangla V Naga Prasad
Journal: Circulation (2012)

Inflammatory cytokine tumor necrosis factor α (TNFα) induces β-adrenergic receptor (βAR) desensitization, but mechanisms proximal to the receptor in contributing to cardiac dysfunction are unknown....
Temozolomide as a vaccine adjuvant in GBM
Authors: J. H. Sampson, K. D. Aldape, M. R. Gilbert, S. J. Hassenbusch, R. Sawaya, B. Schmittling, G. E. Archer, D. Mitchell, D. D. Bigner, D. A. Reardon, A. B. Heimberger
Journal: Journal of Clinical Oncology (2007)

2020 Background: Cytotoxic chemotherapy that induces lymphopenia is predicted to ablate the benefits of active antitumor immunization. Temozolomide (TMZ) is an effective chemotherapeutic for patients with glioblastoma multiforme (GBM), but it induces significant lymphopenia. Methods: In a Phase II trial, patients with newly-diagnosed, completely resected GBM are vaccinated with an EGFRvIII-specific peptide q2 weeks X 3 after radiation (XRT)(∼60Gy) and TMZ (75mg/m 2 /d) and then monthly with 5 day TMZ cycles (200mg/m2/d). Results: TMZ induces transient, Grade 3 lymphopenia (&lt; 500 cells/uL) in 70% of patients after the first TMZ cycle with nadirs occurring 14–21 days after treatment (n=10). Regulatory T cell (T Reg ) (CD4 + CD25 ++ CD45RO + FOXP3 + ) levels increased from 5.2+1.5% (3.3 - 7.5) to 11.8+2.6% (6.9 - 13.8)(P=0.0004; paired t-test) with TMZ and XRT and averaged 12.2+4.0% (6.4 - 18.1) after the second TMZ cycle (P=0.007) (n=6). Despite these findings, in patients assayed, both humoral and cellular EGFRvIII-specific immune responses appear to be enhanced with TMZ. Median survival and TTP after vaccination is 26.2 weeks with no patients progressing (n=8). Conclusions: Despite conventional dogma, we demonstrated that both chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. TMZ-induced lymphopenia may prove to be synergistic with a peptide vaccine. No significant financial relationships to disclose.
New GP contract will replace targets with seven day working
Authors: Zosia Kmietowicz
Journal: BMJ (2015)

GPs in the United Kingdom will be offered a new contract, with scaled-back targets in exchange for seven day services, the government has announced.

The prime minster, David Cameron, said on the BBC’s current affairs Andrew Marr Show on 4 October that the government would be publishing a new GP contract “to get rid of the box ticking and the form filling and to focus on making sure people in our country can get access to a GP on a seven day a week basis, 8 am to 8 pm.”

The BMA condemned the government for announcing the new GP contract with no prior discussion with the association and no regard to the problems facing primary care.

The new contract, which will be voluntary, will …
Cancer immunotherapy with a chimeric anti-CD40 monoclonal antibody: Evidence of preclinical efficacy
Authors: T. R. Geldart, M. Harvey, N. Carr, M. Glennie, P. Johnson
Journal: Journal of Clinical Oncology (2004)

2577 Background: CD40, a member of the tumour necrosis factor receptor super-family is expressed primarily on antigen presenting cells (APCs) but has also been described on a number of malignancies. Interaction of CD40 on APCs with its natural ligand CD154 (on activated CD4+ T helper cells) is central to the generation of T cell dependent, humoral responses and cytotoxic T cell responses. Methods: Following the development of a chimeric anti-CD40 mAb Chi Lob7/4, preclinical efficacy was assessed against CD40+ human malignant epithelial (EJ138, Caski) and non-Hodgkin's lymphoma (NHL) (RL, Daudi) cell lines, using standard assays of growth inhibition ([3H methyl] thymidine incorporation), complement dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC), (chromium51 release). Tissue expression patterns of CD40 in human tissues were evaluated using standard immunohistochemical techniques performed on paraffin embedded specimens following pronase antigen retrieval. Potential toxicities of anti-CD40 (mAb) therapy were assessed in a comparative mouse model using a rat anti-mouse CD40 mAb (3/23). Results: Chi Lob7/4 caused significant growth inhibition in all cell lines tested and effectively mediated CDC and ADCC in NHL cell lines. CD40 expression in normal tissues was predominantly confined to APCs; tumour CD40 expression was observed on a variety of tumour specimens including NHL, malignant melanoma, lung and breast carcinoma. In toxicity studies, treatment related mortality was not seen in single dose studies of up to 10mg 3/23 and therefore the LD50 was not reached. 3/23 caused a dose dependent but reversible lympho-granulomatous hepatitis. Reversible splenomegaly and mild, tubulo-interstitial lymphocytic nephritis were also noted. Conclusions: Chi Lob7/4 shows significant efficacy in-vitro. Immunohistochemistry confirmed CD40 expression in a variety of human tumour types. In-vivo, treatment with anti-CD40 mAbs is feasible but may be associated with reversible hepatic toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cancer Research UK
Preventive Tamoxifen After Ductal Carcinoma in Situ (Dcis) Diagnosis According to Age and Ethnicity
Authors: A. Toss, A. Berger, F. Guiles, J.A. Sendecki, N. Simone, P.R. Anne, T. Avery, R. Jaslow, J. Palazzo, M. Lazar, T. Tsangaris, M. Cristofanilli
Journal: Annals of Oncology (2014)
Effect of Thymectomy on Development of Lucké Renal Adenocarcinomas in Virus-Infected Leopard Frog Tadpoles&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: L A Rollins-Smith, N Cohen
Journal: JNCI Journal of the National Cancer Institute (1982)

Thymectomy of very young leopard frog (Rana pipiens) larvae dramatically reduced in vitro lymphocyte responses to the mitogen phytohemagglutinin-P and prolonged survival of Lucké tumor alloimplants. However, tumor incidence in premetamorphic or metamorphosing frogs that had received injections as embryos of Lucké tumor herpesvirus (LTHV) was the same in thymectomized and normal immunocompetent animals. This result suggests that T-cell-mediated cytotoxicity does not prevent development of Lucké tumors in immunocompetent larvae and that if tumor-specific transplantation antigens appear, they may induce tolerance rather than destructive immunity in normal LTHV-infected larvae.