tbuckley/cabot-search huggingface dataset:
Symptoms or signs due to different chemotherapeutics and their relationship with serum cytokines/VEGF levels in patients with cancer
Authors: A. Demirkazik, H. Yilmaz, H. Akbulut, B. Yalcin, F. Icli
Journal: Journal of Clinical Oncology (2007)

21176 Background: Several problems such as myalgia, arthralgia, fever, dyspnea, generalised edema and pleural effusion and rarely “systemic capillary leak syndrome” may appear following the chemotherapy in cancer patients. Although it is supposed that some cytokines are associated with the development of these problems, there is no clear evidence for the relation between the cause and the effect. In this study, the relation between some symptoms following the first chemotherapy in cancer patients and the serum levels of interleukin-2 (IL- 2), interleukin-11 (IL-11), tumor necrosis factor alpha (TNF-a) and vascular endothelial growth factor (VEGF) which are supposed to cause these symptoms was investigated. Methods: Forty-four (28 male and 18 female) patients with cancer who had no heart, lung or renal diseases were consecutively enrolled to this study. Twenty-nine patients (27 with lung cancer, 1 with locally advanced gastric and 1 with pancreatic carcinoma) had active tumors. Fifteen patients (11 with breast cancer, 2 with gastric carcinoma, 1 with colon carcinoma, 1 with ovarian cancer) had no tumor because they were just curatively operated. Patients’ symptoms and findings due to chemotherapy were noted just before the chemotherapy and 24 hours later following chemotherapy. Patients’ serum samples were taken for the measurement of VEGF, TNF, IL-2 and IL-11 levels. Results: Any relation between the chemotherapeutic drugs and the symptoms or findings such as edema, dyspnea, cough and flu-like syndrome in patients were not observed. Otherwise, there were no relation with response to the chemotherapy and serum levels of VEGF, TNF, IL-2 and IL-11. But, patients who were not treated with paclitaxel, docetaxel, gemcitabine and vinorelbine showed a significant decrease in their IL-11 levels (p: 0.006). Conclusions: There was no statistically important difference between chemotherapeutics in terms of cytokine related effects. Although, there was no relation with response to the chemotherapy and serum cytokine levels, serum IL-11 levels were stable in patients administered with paclitaxel, docetaxel, gemcitabine and vinorelbine when compared with other drugs. No significant financial relationships to disclose.
A retrospective review of anal squamous cell carcinoma in HIV positive and HIV negative patients
Authors: J. Grandhi, P. A. Philip, T. Washington, A. F. Shields, U. Vaishampayan, L. K. Heilburn, R. Venkatramanamoorthy, B. F. El-Rayes
Journal: Journal of Clinical Oncology (2006)

4153 Background: The incidence of invasive anal cancer is 120 times higher in the HIV infected patients than in the general population. The outcome of anal cancer in HIV infected patients has not been evaluated in prospective trials and the published literature is limited to small retrospective case series. The aim of this study is to describe the outcome, tolerability, event free survival, and overall survival in patients with squamous cell carcinoma of anal canal (SCCAC) with and without HIV infection treated at Karmanos Cancer Institute/Wayne State University from 1991 to 2005. Methods: We performed a retrospective chart review. Patients were identified using the SEER database. We collected data regarding HIV status, demographics (age, gender, race), stage at diagnosis, treatment, response to treatment, toxicity and survival. Results: Forty patients with SCCAC were identified, of which 13 were HIV positive and 27 were HIV negative. The HIV-positive and HIV-negative groups differed by mean age (44 vs. 55 years), male gender (100 vs. 37 percent), and African American race (92 vs. 59 percent). There were no differences in stage at diagnosis, type of chemotherapy received. HIV positive population received reduced chemotherapy (67 vs. 8 percent), and RT (22 vs. 7 percent) dosage. The major toxicities observed in HIV positive and negative patients were mucositis (23% vs. 29%), neutropenia (8% vs. 33%) and skin toxicity (46% vs. 55%) secondary to radiotherapy. Only 61 percent of HIV-positive patients were disease free vs. 60 percent of HIV-negative patients. Conclusions: We found that HIV positive patients received lower doses of chemo-radiotherapy. Patients with HIV tolerated the lower dose chemoradiotherapy and had a similar toxicity profile to the HIV negative patients. No major difference in the risk of recurrence between HIV positive and negative patients was observed. No significant financial relationships to disclose.
The role of EGF-induced EphA2 expression in EGFR mediated cancer cell proliferation and motility
Authors: Alice Larsen, Marie Stockhausen, Hans Poulsen
Journal: Cancer Research (2007)

418   The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays an important role in the regulation of cell proliferation and motility. EGFR and its ligands is a well-characterized receptor-ligand system that is involved in the development and progression of tumors originating from the brain, lung, breast, colon, ovary, and head and neck.  We have identified the receptor tyrosine kinase EphA2 as an EGFR transcriptional target in cancer cells. EphA2 belongs to the Eph receptor family, which is the largest group of receptor tyrosine kinases in higher eukaryotes. The Eph receptor family is divided in two major classes (EphA and EphB) based on similarity of their extracellular domain sequences and their binding affinities for ephrin-A and ephrin-B ligands. The Eph family of receptors has mainly been associated with neuronal development. However, EphA2 is frequently overexpressed in advanced cancers, and evidence suggests that EphA2 contributes to multiple aspects of the malignant character including angiogenesis and metastasis. In contrast, recent studies have shown that EphA2 can function as a tumor suppressor in specific cancer. These results strengthen the importance of further investigating the role of EphA2 in tumourigenesis.  We are investigating the role of EGF-induced EphA2 expression in EGF-induced cell signaling, proliferation and motility. We have shown that the EGF-induced EphA2 expression in human cancer cells is dependent on activation of the MEK signaling pathway and on activation of the EphA2 promoter. Furthermore, we have shown that ligand activated EphA2 affects EGF-induced cancer cell motility by inhibiting cell migration and modulating the migration pattern. These results indicate that EphA2 could play a significant role in regulating EGF-induced migration of human cancer cells. Here, we show that ligand stimulation of EphA2 inhibits ERK1/2 activity and cancer cell proliferation. However, ligand activated EphA2 have no effect on neither EGF-induced ERK1/2 phosphorylation, nor on EGF-induced cell proliferation. These results indicate that ligand activated EphA2 could play an important role in regulating cancer cell proliferation in absence of EGFR activation. Ligand activated EphA2 could function by directly inhibiting cancer cell proliferation and motility, supporting a tumor suppressive role of EphA2. Alternatively, EphA2 could have ligand-independent effects cancer cell proliferation and motility, and that ligand stimulation of EphA2 leads to termination of ligand-independent effects. An update will be presented.
7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders
Authors: Chaoyang Liu, Chi Bun Chan, Keqiang Ye
Journal: Translational Neurodegeneration (2016)

Brain-derived neurotrophic factor (BDNF) regulates a variety of biological processes predominantly via binding to the transmembrane receptor tyrosine kinase TrkB. It is a potential therapeutic target in numerous neurological, mental and metabolic disorders. However, the lack of efficient means to deliver BDNF into the body imposes an insurmountable hurdle to its clinical application. To address this challenge, we initiated a cell-based drug screening to search for small molecules that act as the TrkB agonist. 7,8-Dihydroxyflavone (7,8-DHF) is our first reported small molecular TrkB agonist, which has now been extensively validated in various biochemical and cellular systems. Though binding to the extracellular domain of TrkB, 7,8-DHF triggers TrkB dimerization to induce the downstream signaling. Notably, 7,8-DHF is orally bioactive that can penetrate the brain blood barrier (BBB) to exert its neurotrophic activities in the central nervous system. Numerous reports suggest 7,8-DHF processes promising therapeutic efficacy in various animal disease models that are related to deficient BDNF signaling. In this review, we summarize our current knowledge on the binding activity and specificity, structure-activity relationship, pharmacokinetic and metabolism, and the pre-clinical efficacy of 7,8-DHF against some human diseases.
Deciphering the kinome in basal-like breast carcinoma for therapeutic usefulness
Authors: Berengere Marty, Fathia Djelti, Ingrid Lebigot, Anne Vincent-Salomon, Francisco Cruzalegui, Gordon Tucker, Xavier Sastre, Jean-Paul Thiery, John Hickman, Thierry Dubois
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2829 

Our objective is to identify alterations in intracellular signaling pathways in order to reveal key kinases involved in the progression of basal-like breast cancers, the breast carcinoma sub-group having the more aggressive clinical behavior (with the Her2+ one) and no targeted therapy. We have chosen to set up a technology of reverse phase protein (RPP) microarray allowing high throughput screening with a limited amount of material. To validate the platform, lysates from an EGFR overexpressing cell line (A431 cells) were analyzed and data compared to Western-blot (WB) experiments. Quantification of experiments revealed that the degrees of activation of various proteins after EGF stimulation were very similar to those obtained with WB analysis. For example, stimulation with EGF led to a 6.0- fold difference in phospho-Erk1/2 by WB, and 6.9-fold by RPP. RPP microarray analysis of human biopsies discriminated Her2+ and Her2- breast carcinoma and measurement of the activities of several other kinases corresponded with those obtained with WB. Our validated RPP platform will be useful for comparing signaling pathways in basal-like human biopsies and cell lines where only 1-10ng of protein is necessary. In parallel, the signaling pathway profiles of basal-like human cell lines (BT20, HCC38, HCC1937) will be compared to that found in basal-like biopsies. Preliminary WB analysis showed high levels of Akt phosphorylation indicating that PI3K (mutated in 25% breast cancers) pathway is up-regulated in the 3 basal-like cell lines. BT20 is known to express an active PI3K mutant, and the activation of Akt in HCC38 and HCC1937 resulted from a low/lack PTEN expression. The Akt-dependent signaling pathway activated in these basal-like cell lines is under investigation. As the basal-like cell lines express high level of EGFR and/or Met, we aim to establish the pattern of changes in their phosphoproteome after stimulation with EGF/HGF. Our data revealed that EGFR is expressed at higher levels in BT20 compared to HCC38 and HCC1937. In contrast, Met is expressed at similar levels in the 3 basal-like cell lines and is not detectable in SKBr3 cells (overexpressing Her2). EGF or HGF stimulation induced the phosphorylation of EGFR and Met, respectively, as well as the activation of ERK, Akt and FAK. Characterization of EGFR/Met downstream events is under investigation. The results should suggest potential therapeutic targets (proteins) and strategies to target particular patients with sub-pathologies of breast cancers where changes in cell signaling pathways may render the tumor particularly sensitive to a targeted therapeutic strategy.
MO19390 (SAiL): Incidence of thromboembolic events and congestive heart failure with first-line bevacizumab (Bv)-based therapy in advanced non-small cell lung cancer (NSCLC)
Authors: N. Pavlakis, V. Hirsh, M. Reck, Y. Wu, E. Dansin
Journal: Journal of Clinical Oncology (2009)

e19003 Background: MO19390 (SAiL) is a single-arm, multicenter, international trial evaluating the safety and efficacy of first-line Bv with standard chemotherapy in over 2,000 patients (pts). Methods: Key eligibility criteria were untreated locally advanced, metastatic or recurrent non-squamous NSCLC, ECOG PS 0–2, tumor not abutting major blood vessels, no uncontrolled HTN (systolic &gt;150mmHg and/or diastolic &gt;100mmHg) or active cardiovascular disease at baseline. Pts received Bv (7.5 or 15mg/kg) with standard chemotherapy for up to six cycles. Non-progressors proceeded to receive Bv until disease progression. The primary endpoint was safety, including the incidence of serious adverse events (SAEs) related to Bv, and the incidence of AEs of special interest. Results: Safety analyses (data cut-off July 2008) were based on 2,008 pts. Pts (%) were: male 60.1; stage IIIB/IV 19.5/80.5 (no data for 3 pts); adenocarcinoma/large cell/other 85.8/7.1/7.1; ECOG PS 0/1/2 38.1/56.1/5.8. 4.2% of pts were receiving anticoagulants at baseline. A total of 1,008 pts (50.2%) experienced at least one adverse event of special interest (all grades). Of these, 172 pts (8.6%) experienced an arterial or venous thromboembolism, which included pulmonary embolism (49 pts; 2.4%), deep vein thrombosis (40 pts; 2.0%), thrombophlebitis (26 pts; 1.3%), myocardial infarction (12 pts; 0.6%), cerebral hemorrhage (2 pts; 0.1%), cerebral ischemia (4 pts; 0.2%) and cerebrovascular accident (6 pts; 0.3%). 59 pts (2.9%) experienced congestive heart failure (CHF). Conclusions: The incidence of thromboembolic events and CHF was low in Bv-treated pts enrolled in the SAiL trial. These results, taken together with the overall safety analysis from the SAiL trial, confirm that Bv-based therapy has a well-established and manageable safety profile. Updated results will be presented. [Table: see text]
Gonadal late effects, fertility and sexual functioning in long-term survivors after high-dose chemotherapy with autologous stem cell transplantation (HD-CT) for testicular cancer
Authors: C. Kollmannsberger, N. Schleucher, O. Rick, B. Metzner, K. Schaefer-Eckart, R. Naumann, R. Mayer-Steinacker, J. T. Hartmann, L. Kanz, C. Bokemeyer
Journal: Journal of Clinical Oncology (2004)

4537 Background: Dose-intensive chemotherapy is currently used in patients (pts) with “poor prognosis” or relapsed germ cell cancer. No studies have thus far investigated endocrinological disturbances, infertility, parenthood, and subjective patient impairment with respect to sexual functioning in long-term survivors after HD-CT. Patients and methods: 53 pts treated within prospective trials of the German Testicular Cancer Study Group and a minimum follow-up of 6 months after completion of HD-CT agreed to complete a standardized and validated questionnaire regarding the subjective impact of HD-CT on fertility and sexual functioning. Testosteron, FSH, and LH levels were investigated in 33 of these pts. All pts were recruited during routine follow-up visits in 2002–2003. Results: Median age at initial diagnosis was 31 years [17–60]. 55% of pts were followed for 1–2 years after therapy and 45% for 2.1–8 years after therapy. 30% of pts had received HD-CT as second-line and 70% as first-line therapy. Testosterone levels were normal in 32/33 pts (97%) with a median of 4.7 ng/ml [range: 1.15–9.97 ng/ml]. LH and FSH levels were elevated in 45% and 91% of pts, respectively. Median levels of LH and FSH were 8.9 U/l [range: 2.8–25 U/l] and 21.4 U/l [range: 0.3–54 U/l], respectively. 4 healthy children had naturally been conceived by 2 men with all of them being healthy. 70% of pts stated to have had a “very satisfactory sex life” prior to therapy, but only 48% were “very satisfied” after therapy (p=0.05). 27% of pts had a “poor sex life” after therapy in contrast to none prior to therapy (p=0.05). 57% of pts had reported “frequent sexual intercourse” prior to therapy but only 42% after treatment (p=0.05). The frequency of “lack of libido” raised from 11% prior to 34% after therapy (p=0.05). Conclusions: Pts receiving HD-CT for testicular cancer should be advised about possible effects on sexual functioning and counselling should be offered after therapy. Sperm banking should be recommended to all pts undergoing HD-CT, despite the fact that single pts may still retain full fertility. No significant financial relationships to disclose.
Painful Right Inguinal Swelling
Authors: Florian Fanget, Eddy Cotte, Kayvan Mohkam
Journal: JAMA Surgery (2016)

A 69-year-old man presented to the emergency department with a 5-day history of painful irreducible right inguinal swelling, a normal white blood cell count, and a hypodense mass on computed tomographic imaging. What is your diagnosis?
Clinical trial of Serratia marcescens extract and radiation therapy in patients with malignant astrocytoma.
Authors: K L Black, J D Ciacci, M Ammirati, M T Selch, D P Becker
Journal: Journal of Clinical Oncology (1993)

PURPOSE A clinical trial was undertaken to determine the safety and efficacy of combining a biologic response modifier derived from the bacterium Serratia marcescens (ImuVert) and radiation therapy (RT) in patients with newly diagnosed anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM). PATIENTS AND METHODS Fifteen patients who had undergone either a gross total resection, a partial resection, or a biopsy were treated concurrently with ImuVert and RT. Safety and tolerance were examined by assessment of symptomatic reactions recorded at each ImuVert treatment. Efficacy of treatment was examined in terms of time to progression of tumor and survival. RESULTS All patients experienced local reactions at the injection sites that consisted of erythema and induration. The majority of patients experienced flu-like symptoms. Hypotension was responsible for the most significant morbidity (which required fluid resuscitation and extended observation) and dose deescalation. No patients were removed from the study because of toxicity. There were no on-study deaths related to ImuVert treatment. Median time to progression was 33.4 weeks, and median survival was 78 weeks. CONCLUSION These results compare favorably with those of recent studies in patients with malignant astrocytomas who received multimodality therapy.
Expression of estrogen-regulated genes in ER positive primary and metastatic breast cancer patients: possible applications for personalized treatment
Authors: M. Tamburo de Bella, P. Forouhi, S. Shousha, N. Livni, D. A. Stephens, D. Peston, C. R. Coombes, M. J. Slade
Journal: Journal of Clinical Oncology (2005)

9696 Background: Breast cancer is characterized by an important histo-clinical heterogeneity. New prognostic and predictive factors are needed to allow an individualization of therapy for patients with ER positive breast cancer since approximately 50% respond to endocrine therapy. Methods: We have carried out a data mining exercise and identified genes up-regulated by estrogen (> two fold) and developed Real-Time quantitative RT-PCR using LightCycler to identify a panel of 26 genes that would enable us to determine individual profiles and tailor therapy on this basis. Results: Of the 26 genes analyzed, 9 (ERα, PR, EEIG-1, PS2, GREB 1a, 1b and 1c, GATA-3 and EP-3) were shown to be expressed preferentially in a panel of ERα positive breast cancer cell lines and responsive to estradiol stimulation. The fold increases were: ERα 1–3 (after 24h), PR 2–6 (after 48h), PS2 2.5–18 (after 48h), EEIG-1 1–8 (after 8h), GATA-3 1–20 (after 48h) and EP-3 3–10 (after 24h). The expression pattern of GREB 1a, 1b and 1c, was also examined but not quantitated. The expression of the 9 genes was analyzed using purified breast cancer cells from 22 primary tumors, 3 involved lymph nodes and 7 metastatic effusions. ERα and PR expression was confirmed in all the ERα/PR positive tumors. The primary patients were categorized on the basis of immunohistochemistry into three groups ER+/PR+, ER+/PR- and ER-/PR-. The greatest difference in expression was seen between the ER/PR+ and the ER/PR- patients for ER (p <0.0005), PS2 (p =0.0005), EEIG-1 (p <0.0005) and GATA-3 (p<0.0005). 3/7 of the metastatic patients did not express ERα or any of the ER target genes. This evidence is of particular interest and could explain the presence of acquired resistance to anti-endocrine therapy in those particularly patients and may be a useful tool in guiding treatment choice. Conclusions: Limited gene profiling in individual breast cancer patients may enable us to predict those patients who will benefit from targeted therapy. This individualized classification of primary tumors based on ex vivo analysis, may lead to more effective therapeutic decisions. No significant financial relationships to disclose.
Cost-effectiveness of darbepoetin alfa (DA) 500 mcg every three weeks (Q3W) with IV iron compared to DA Q3W alone in cancer patients (pts) with chemotherapy-induced anaemia (CIA)
Authors: N. Demarteau, L. Annemans, T. Mossman, A. Bracco
Journal: Journal of Clinical Oncology (2007)

19531 Background: IV iron supplementation during erythropoiesis-stimulating agent treatment in anaemic cancer pts may help to optimize anaemia management. We assessed the cost-effectiveness of DA Q3W with IV iron (net 200 mg Q3W; DA+IV iron) to DA Q3W without IV iron (standard practice [SP]= oral iron allowed; DA+SP) from a French societal perspective. Methods: A prospective 16-week, randomized, open-label, multicenter study in 396 pts with non-myeloid malignancy and CIA (hemoglobin [Hb] &lt; 11g/dL) was conducted to evaluate the safety and efficacy of DA+IV iron vs. DA+SP. Data collected include: cumulative doses (IV iron, oral iron, and DA), number of transfusions, and Hb values. Quality adjusted life years (QALY) weights were obtained using the EQ-5D at baseline and at end of treatment. The medical resources used for one DA administration and one transfusion, including pts’ time, were determined by a panel of 20 French clinical experts. Costs were applied to both time (valued at the gross hourly wage) and medical resources (extracted from official sources: AMELI; INSEE). Effectiveness was expressed in average Hb values over the treatment period and the change from baseline in QALY weights. A 5,000- replication probabilistic sensitivity analysis was performed with RISK ® after applying distributions to medical resources used and effectiveness parameters. Results: Compared to DA+SP, DA+IV iron showed higher average Hb values (+0.2 g/dL [95% CI: -0.0, 0.4]; 10.9g/dL [10.8, 11.1] vs. 11.1g/dL [11.0, 11.3] respectively), higher QALY weights (+0.017 [-0.028, 0.064]; 0.016 [-0.019, 0.050] vs. 0.033 [0.002, 0.064]) and lower cost (-647.5€ [-938.0, -352.4]; 4,788.3€ [4,561.2, 5,018.2] vs. 4,140.8€ [3,955.4, 4,319.8]). Probabilistic sensitivity analysis revealed that DA+IV iron had a 94% chance of a higher average Hb value and lower costs and 73% chance of a higher QALY level and lower costs. Conclusions: DA Q3W with IV iron is a cost effective alternative to Q3W without IV iron. Further studies in this patient population are needed to determine whether systematic administration of IV iron with DA Q3W will demonstrate cost savings, higher average Hb values, and more QALYs. No significant financial relationships to disclose.
Molecular Mechanisms Of Adipocyte-Leukemia Interactions Revealed By The Quantitative Proteomics Technology: Pro-Survival Function Of Adipocyte-Derived Free Fatty Acids On Acute Monoblastic Leukemia Mitochondrial Biogenesis
Authors: Yoko Tabe, Linhua Jin, Saiko Kazuno, Tsutomu Fujimura, Hiromichi Matsushita, Takashi Ueno, Takashi Miida, Michael Andreeff, Marina Konopleva
Journal: Blood (2013)