tbuckley/cabot-search huggingface dataset:
mTOR inhibition in MDR acute myeloid leukemia.
Authors: Aditi Karmakar, Sudeshna Gangopadhyay, Gouri Shankar Bhattacharyya, Ashis Mukhopadhyay
Journal: Journal of Clinical Oncology (2013)

7085 Background: Signaling through the PI3K/PTEN/AKT/mTOR pathway is aberrantly activated in several human cancers, including Acute Myeloid Leukemia (AML) patients where it contributes to leukemic cell proliferation, survival and drug resistance. In leukemia patients treated with drugs such as anthracyclines, vinca alkaloids, chemo-resistance one of the major problems contributing to therapeutic failure, where all this drugs are modulated in their intracellular retention by a 170 kDa Phospho-glycoprotein, an mdr-1 gene product. The role of mTOR in various processes such as proliferation, growth, has been comprehensively described in many reviews, following its inhibition by rapamycin. Thus inhibition of mtor signaling in AML blasts could account for enhancing their sensitivity to cytotoxic agents. This study is to embrace the effect of Rapamycin, an allosteric mTOR inhibitor on MDR AML patients. Methods: We selected samples of 25 MDR AML patients isolated from bone marrow or peripheral blood and cultured in vitro. The effects of Rapamycin on fresh AML samples were analyzed by treating the cells with intermediate drug concentrations (100 nM) for 24 h, 48 h, 72 h, 96 h respectively followed by cytotoxicity assay (MTT assay). The effects of the drug on proliferation of cells were analyzed also by cell counting. Results: A marked reduction in cell viability at 96 h was detected in 25 samples treated with rapamycin. Out of the 25 analyzed samples, 16 were sensitive to the drug where it was observed that the leukemic cell count came down to almost 2% whereas 9 samples displayed various degree of resistance to the drug. Overall, these findings demonstrated that rapamycin has a cytotoxic activity against primary cells from AML patients with up-regulated mTOR signaling. Conclusions: We have evaluated the in vitro effects of Rapamycin on AML patient samples where reduced cell viability primary cells from AML patients were observed. However, further studies of the additional effects of rapamycin will be of the supreme importance, as they could help in designing more efficient curative protocols, for the treatment of acute leukemia patients.
Therapeutic strategies for targeting telomerase in cancer
Authors: Xing Chen, Wen‐Jian Tang, Jing Bo Shi, Ming Ming Liu, Xin‐Hua Liu
Journal: Medicinal Research Reviews (2019)

Abstract Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere‐based therapies such as nucleoside analogs, non‐nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere‐based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.
Knowledge of cancer clinical trials in a population being screened for cancer
Authors: J. H. Walsh, D. Sahasrabudhe
Journal: Journal of Clinical Oncology (2006)

6095 Background: Only 2.5 percent of adult cancer patients enrolled in cooperative group clinical trials between 1998 and 1999. Increasing participation in clinical trials is important in efforts to improve cancer care. Methods: We administered an anonymous true/false questionnaire that assessed knowledge of clinical trials to 117 men seeking prostate cancer screening. Questions involved the rationale for conducting clinical trials, regulatory oversight of clinical trials, informed consent, randomization, blinding, use of placebos, and safeguards built into clinical trial design. We performed multi-way ANOVA and t-test analyses to compare the average proportion of correct responses by group. Results: On 71 percent of test questions, participants chose the correct answer 80 percent or more of the time. Descriptive general statements about the conduct of clinical trials were answered correctly 88 percent of the time. Questions in which participants scored less than 80 percent involved randomization, blinding, and the use of clinical trials to improve cancer treatments. 45 percent incorrectly answered a question about placebo use. Results of the univariate t-tests and multi-way ANOVA suggest that white men and employed men are significantly more knowledgeable about clinical trials. College educated men also appear somewhat more knowledgeable about clinical trials, although this effect does not attain statistical significance when other predictors are controlled. Marital status, age, health insurance status and income do not have a significant effect on men’s knowledge. Conclusions: Percent of participants answering correctly decreased for concepts such as randomization, placebo use, and blinding. A belief persists that placebos will be used in cancer clinical trials. This may play a role in low accrual, and may be an area in which educational interventions could improve accrual. This study identifies specific concepts, beliefs, and populations that have to be addressed to improve enrollment on cancer clinical trials. [Table: see text] No significant financial relationships to disclose.
Use of nano-immuno assay to generate rapid, quantitative nanoscale proteomic profiling of the hypoxia pathway in renal cell carcinoma clinical specimens.
Authors: Alice C. Fan, Prajna Banerjee, John Leppert, Lauren Christine Harshman, Chiara Sabatti, James D Brooks, Dean W. Felsher
Journal: Journal of Clinical Oncology (2012)

10513 Background: Novel agents that inhibit kinases in the hypoxia pathway [VEGF, PDGF] can achieve response rates of 30-57% in renal cell carcinoma (RCC); however, threshold levels of targets and downstream signaling proteins in patient cells have not been identified as biomarkers to guide treatment. Rapid and quantitative measurements of overall levels and % phosphorylation of proteins in the hypoxia pathway from patient specimens might better enable the development of proteomic biomarkers. Methods: We have developed the use of an automated nanoscale immuno assay (NIA) to profile hypoxia proteins in solid tumors, and now present NIA assays to measure EGFR, VEGF-R, AKT2, GSK3β, CA-9, MEK1 and ERK1/2 proteins in RCC clinical specimens. Furthermore, to decrease the amount of tissue and the invasiveness of the procedure required to obtain specimens for analysis, we have optimized assays to profile RCC specimens acquired by fine needle aspiration (FNA). Results: Unique to NIA technology, we have analyzed percent phosphorylation for phosphorylated proteins and can distinguish differences in even a single phosphorylation in the FNA specimens, allowing us to group tumors based upon different patterns of phosphorylation. In addition, we compared 10-parameter hypoxia profiles in a panel of RCC paired with adjacent non-tumor tissue and will present the proteins that can distinguish tumor from non-tumor tissue. Importantly, we have determined that we can present protein profiles to the clinical team within 8 hours of receiving the specimen (1 hour preparation time, 6 hours of unattended automated instrument time, 1 hour of analysis). Conclusions: NIA is an extremely efficient, quantitative and high-throughput platform that has the potential to be used to rapidly generate proteomic profiles for clinical specimens for the development of novel diagnostic and predictive biomarkers.
Predictive and prognostic factors in locally advanced and metastatic sarcomas: A single institution experience.
Authors: Zineb Benbrahim El Mekkeoui, Samia Arifi, Lamiae Boudahna, Nawfel Mellas, Omar El Mesbahi
Journal: Journal of Clinical Oncology (2013)

e21513 Background: Ifosfamide is frequently applied in first line systemic therapy in sarcoma. Several, and sometimes, contradictory data have been reported in the literature regarding predictive factors of response and prognostic factors. The aim of this study was to assess predictive factors and factors associated with PFS and OS in patients with locally advanced and metastatic sarcoma treated with ifosfamide. Methods: We reviewed retrospectively 50 cases of sarcomas treated between January 2007 to June 2012 at the Medical Oncology Department at Hassan II University Hospital. Clinical, histopathologic and prognostic features were evaluated. Results: Median age was 30.9 ± 13 years. 56 % of patients were men. Synovialosarcoma was the predominant histologic type (23%). In 85% of cases, Ifosfamide was associated with Doxorubicine. The total dose of ifosfamide was 9g/m2 in 96% of cases. After A median duration of follow up of 15 months [3-26], the overall response rate was 57.7%. The median PFS was 6.1 months [3-13] and median OS was 10.04 months [3-23]. The Predictive factor of response was high grade (78% vs 41%; p=0.03). For PFS, the prognostic factor was high LDH level (5 vs 12 months p=0.01). For OS, prognostic factors were localization in upper extremity (8.5 vs 13 months ; p=0.03) presence of metastasis (7 vs 11 months; p=0.02) and high LDH level (7 vs 13 months; p=0.02). Conclusions: In patients with sarcoma treated with ifosfamide, the response rate is influenced by tumour grade. High LDH level was prognostic for both PFS and OS whereas upper extetermity site and presence of metastases were prognostic for OS only.
Correlation of ERCC1 expression on circulating tumor cells with progression-free survival in metastatic non-small cell lung cancer patients treated with platinum-based chemotherapy.
Authors: Jonathan Riess, Millie Snigdha Das, Paul Henry Frankel, Erich Schwartz, Robyn Bennis, H Ben Hsieh, Xiaohe Liu, Janey Ly, Lisa Ya Zhou, Jorge J. Nieva, Richard Bruce, Heather A. Wakelee
Journal: Journal of Clinical Oncology (2012)

10574 Background: Biomarkers predicting efficacy of chemotherapy are highly desirable. Fiber array scanning technology (FAST) is a novel method of detecting circulating tumor cells (CTCs) that does not employ an EpCam enrichment step. The purpose of this study was to use FAST to evaluate ERCC1 expression on CTCs to determine whether ERCC1 expression correlates with progression-free survival (PFS) in patients who received platinum-based chemotherapy for metastatic non-small-cell lung cancer (NSCLC). Methods: Peripheral blood from one hundred enrolled patients with metastatic NSCLC was collected by two institutions (Stanford Cancer Institute and Billings Clinic Cancer Center). FAST was used to identify individual CTCs on immunofluorescence by pancytokeratin antibodies. Nuclear localization of ERCC1 expression by immunofluorescence was quantified on individual CTCs. Total patient ERCC1 levels were determined from the average expression of all the CTCs in each patient sample. Fifty-seven of the one hundred patients enrolled received platinum chemotherapy. Seventeen of those fifty-seven patients (30%) had ≥ 2 evaluable intact CTCs and were analyzed retrospectively. Linear regression (F-test) was used to evaluate the correlation between ERCC1 expression and PFS. Kaplan-Meier survival analysis (log-rank test) was used to compare PFS in patients with CTCs with no detectable ERCC1 expression versus patients with CTCs that expressed any level of ERCC1. Results: PFS decreased with increasing ERCC1 expression (P&lt;0.04 F-test, linear regression). Lack of ERCC1 expression was associated with longer PFS (266 days vs. 172 days, log-rank test P&lt;0.02). The difference in survival was statistically significant with a hazard ratio of 4.20 (95% CI 1.25-14.1, p&lt;0.02, log-rank test). Conclusions: In this small study, using FAST to isolate CTCs, low expression of ERCC1 on evaluable CTCs correlated with increased PFS in patients with metastatic NSCLC who received platinum chemotherapy. A larger, prospective study to validate these retrospective results is warranted.
NHS pensions: thousands of doctors have cut their working hours to avoid tax charges, survey finds
Authors: Abi Rimmer
Journal: BMJ (2019)

Thousands of GPs and consultants in England, Wales, and Northern Ireland have reduced their working hours or are planning to do so because of pension tax laws, a BMA survey has found.

Recent changes to pension regulations have led to many senior doctors receiving big tax bills, which increase if they work additional hours.1

A BMA survey of its members of all …
Axillary recurrence after negative sentinel node biopsy in patients with breast cancer
Authors: G. E. Cassanello, F. Xynos, P. H. Capellino, A. Bacigaluppi, P. Betti
Journal: Journal of Clinical Oncology (2006)

10700 Background: To evaluate axillary recurrences (AR) in patients with negative sentinel node subjected to no further axillary local treatment. Methods: From June 1 st 2000 to April 30 th 2005, 219 patients with negative sentinel node (SN) were evaluated and axillary recurrences were assessed. The SN was identified using Isosulfan Blue only. The lymph nodes were evaluated intraoperatively with imprint cytology and with standard H&amp;E staining on permanent sections, sectioning lymph nodes every 3 mm. The false negative of imprint cytology was 6%. The mean age was 69.8 years (range 40–90), the average follow up was 17.6 months (range 1–48). Results: Three axillary recurrences (1.36%) and no distant metastasis were observed. The recurrences occurred 14,26 and 28 months after conservative treatment for ductal carcinoma with 1, 2 and 3 negative sentinel nodes respectively. At the time of recurrence axillary surgery revealed 1 of 11 positive axillary nodes with extra-capsular invasion, 6 of 19 positive axillary nodes with extracapsular invasion and 3 of 15 positive axillary nodes with extracapsular invasion Conclusions: In this short follow-up three axillary recurrence (1.36%) and no distant metastasis have been observed. In the case of axillary recurrences, extracapsular node invasion seems to be the rule. No significant financial relationships to disclose.
Optical/MRI dual-modality imaging of M1 macrophage polarization in atherosclerotic plaque with MARCO-targeted upconversion luminescence probe
Authors: Yabin Wang, Yan Zhang, Zhao Wang, Jibin Zhang, Rui Rui Qiao, Mengqi Xu, Ning Yang, Lei Gao, Hongyu Qiao, Mingyuan Gao, Feng Cao
Journal: Biomaterials (2019)
Are three drugs better than two and does docetaxel trump paclitaxel in induction therapy for locally advanced oral cavity cancers?
Authors: Vanita Noronha, Vijay Patil, Amit Joshi, S Juvekar, Bharatsinha Baburao Bhosale, Bhavesh Poladia, Sushmita Rath, Pankaj Chaturvedi, D. Chaukar, P. S. Pai, A. K. Dcruz, Kumar Prabhash
Journal: Journal of Clinical Oncology (2013)

6085 Background: A variety of regimens have been used for induction chemotherapy in locally advanced head &amp; neck cancers. Cisplatin &amp; 5 FU drug combination is inferior to the combination of taxane &amp; these 2 drugs. However, often in clinical practice at our center giving TPF is difficult in view of logistics &amp; tolerance issues. In such scenarios we prefer to use 2 drug combination of platinum &amp; taxane. However no study has addressed whether when the 2 drug combination includes taxane, is it still inferior to the 3 drug combination and which the taxane of choice is. Methods: This is a retrospective analysis of prospectively collected data of patients undergoing induction chemotherapy in oral cavity cancers from 2010-2012. We chose for analysis those patients who had a baseline scan and a follow-up scan done within 2 weeks of completion of the second cycle of induction chemotherapy. Response was scored in accordance with RECIST 1.1. Data was analyzed using SPSS, version 16. Chi- square analysis was done to compare response rates between regimens. Results: Two hundred &amp; forty five patients were indentified. The median age was 45 years (24-70 years), 208 (84.9%) were male patients &amp; in 154 patients (62.9%) had primary in buccal mucosa. The regimen received were TPF 22 (9%), TP (Docetaxel + cisplatin) 97 (39.6%), PP (paclitaxel+cisplatin) 89 (36.3%), TC (Docetaxel+ carboplatin) 16 (6.5%) &amp; PC (paclitaxel + carboplatin) 21 (8.6%).The overall response rates (RR) were CR, PR,SD &amp; PD in 4 (1.6%), 56 (22.9%), 145 (59.2%) &amp; 40 (16.3%). On comparison, 3 drug regimen (TPF) had 50% RR as against 22% RR with 2 drug regimen (p=0.004). On comparison for taxane, docetaxel containing regimens had 30.3% RR as against 17.2% RR with paclitaxel containing regimens (p=0.018). There was no statistically significant difference in RR between patients receiving carboplatin or cisplatin. Conclusions: TPF had better RR than a 2 drug taxane-containing regimen and docetaxel leads to a better RR than paclitaxel for induction chemotherapy in locally advanced oral cavity cancers.
Evidence to support or guide glucocorticoid tapering in rheumatoid arthritis is lacking
Authors: Beth I Wallace, David M Wallace, Akbar K Waljee, Daniel J Clauw
Journal: Annals of the Rheumatic Diseases (2019)

Low-dose glucocorticoids (GCs) improve symptoms and physical function and reduce joint damage in rheumatoid arthritis (RA).1 Over a third of patients with RA are managed with long-term oral GC, defined as daily use for ≥3 months.2 Current RA management guidelines recommend tapering GCs to the lowest effective dose as quickly as possible3 4 to minimise risk of GC-associated side effects, such as infections, cardiovascular events and bone fractures. However, there is little evidence to guide clinicians attempting to taper GCs,5 6 leading to widely variable practice patterns. This is of particular importance for patients with established RA who are maintained on long-term GCs. Such patients have higher cumulative GC exposure and increased rates of cardiovascular disease, osteoporosis and insulin resistance relative to early patients with RA, …
New Target for Pancreatic Cancer Treatment Shows Potential
Authors: Tracy Hampton
Journal: JAMA (2019)

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The sequential use of abiraterone and enzalutamide (MDV3100) in castrate resistant prostate cancer patients: Experience from Birmingham, United Kingdom.
Authors: Robert Stevenson, Daniel Ford, Anjali M Zarkar, John Glaholm, Emilio Porfiri, Alice Tew, Ahmed El-Modir, Nicholas David James
Journal: Journal of Clinical Oncology (2013)

e16048 Background: Phase III studies have demonstrated survival benefits from abiraterone 1 (Abi), and Enzalutamide 2 (MDV3100; Enz) following disease progression in metastatic castrate resistant prostate cancer (mCRPC). Abi is available for treatment of mCRPC in the UK in patients previously treated with docetaxel. Enzalutamide (Enz) is available, via early access scheme, for progressive disease post docetaxel, regardless of prior Abi exposure. There has been no randomised trial on sequential usage of Enz post Abi. We therefore report our experience. Methods: We searched our pharmacy database for patients who have received Enz and identified 51 patients who started treatment between the 2 nd August 2012 and 10 th January 2013. A detailed notes review was carried out of these patients. Results: Median age was 76 (range 55-87) years. All patients had received androgen deprivation therapy and Docetaxel. 46 patients had received previous Abi, 38 of patients’ receiving Abi as the last treatment prior to Enz. At the time of submission 10 patients had stopped Enz due to PSA progression with a mean TTP of 15 weeks (range 7-22) and 6 patients had died; 2 from disease progression (mean TTP 3.5 weeks). For the 30 patients still on Enz, the mean duration of treatment was 16.47 weeks (range 4-27). 33 patients didn't report any significant side effects associated with Enz treatment. The most common side effect was fatigue (23.6%); 3 patients (6%) experiencing G3 fatigue. Other reported side effects included diarrhoea (4%), nausea (6%), confusion (6%), anxiety (6%), depression (6%), hallucinations (2%) and insomnia (2%). 3 patients (6%) had Enz stopped due to G3 fatigue. Conclusions: The AFFIRM study demonstrated TTP of 8.3 months (36 weeks) in patients post-docetaxel 2 . In this audit the TTP of patients receiving Enz post-Abi was 15 weeks, suggesting possible reduced efficacy in patients receiving Enz post-Abi and docetaxel. However, longer follow-up of the 30 patients currently taking Enz is required. The number of patients experiencing G3 fatigue was the same as reported in AFFIRM, but there were a surprising number of patients experiencing psychiatric side-effects.