tbuckley/cabot-search huggingface dataset:
A phase I study of sunitinib malate (S) and gemcitabine (G) in solid tumors.
Authors: S. S. Krishnamurthi, L. Rath, J. A. Bokar, A. Dowlati, P. Savvides, J. Gibbons, M. M. Cooney, N. J. Meropol, S. P. Ivy, J. M. Brell
Journal: Journal of Clinical Oncology (2010)

3046 Background: Continuous daily dosing (CDD) of S with G is a novel regimen that may have broad clinical activity. Methods: Eligible patients had no curative therapy options, adequate organ function, and no prior antiangiogenic treatments. A 3+3 dose escalation design was followed with expansion of the recommended phase II dose (RP2D) to 10 patients. G was administered as a standard 30-minute IV infusion. G was initiated at 800 mg/m2 days 1, 8, 15 of each 28-day cycle, with escalating once-daily oral doses of S. Treatment-related grade (gr) 4 toxicity, gr 3 cardiac or venous thrombosis, unresolved noncardiac gr 3 event, or uncontrolled hypertension in cycle 1 was defined as DLT. Results: 31 patients were treated (most common tumor type: pancreatic adenocarcinoma, n=9). DLTs are shown in the TableTable. Dose level 1 was expanded to 10 patients after the occurrence of 2 DLTs at dose level 2 and was found to be tolerable. Four patients at dose level 1 did not receive the three planned doses of G due to toxicity. The study was amended to evaluate day 1 and day 8 G every 21 days with continuous daily S. Excessive DLT occurred at dose levels -1a and -1. Of the 8 patients enrolled to dose level -2, all received the full dose of G and S for cycle 1. Four patients had a confirmed PR: 2 with pancreatic adenocarcinoma (dose level 1), 1 with pancreatic neuroendocrine cancer (dose level -2) and 1 with thymic carcinoma (dose level -2). 9 patients had stable disease (median 20 weeks, range 14-49 weeks). Conclusions: The MTD of weekly G + daily S is 800 mg/m2 G on days 1, 8, and 15 every 28 days with 25 mg daily S. The RP2D is 675 mg/m2 G on days 1 and 8 every 21 days with 25 mg daily S. This clinically active and well-tolerated regimen warrants further investigation. Supported by NIH/Cancer Therapy Evaluation Program U01 CA62502. Dose level S mg daily G mg/m2; days of G;days/cycle N # subjects with DLT/type of DLT 1 25 800; 1,8,15; 28 10 1/gr 4 ANC 2 37.5 800; 1,8,15; 28 5 2/gr 4 ANC and gr 4 platelet −1a 37.5 800; 1,8; 21 3 2/gr 4 platelet −1 25 800; 1,8; 21 5 2/gr 4 platelet and gr 3 cardiac LV systolic dysfunction −2 25 675; 1,8; 21 8 1/gr 3 hemorrhage Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, ImClone Systems, Merck, Pfizer, sanofi-aventis, Wyeth
Prophylactic cranial irradiation (PCI) in high-risk breast cancer patients: Preliminary data
Authors: T. Hashem, K. Kamal Eldin, H. Metwaly, E. Elkholy
Journal: Journal of Clinical Oncology (2008)

11501 Background: The rationale behind PCI is to control or eradicate undetectable micro-metastases without inducing severe adverse effects. In this study we assessed the effect of PCI in high-risk breast cancer patients. Methods: 62 consecutive patients, with high-risk breast cancer were enrolled in this trial and were randomized into 2 arms: Arm 1 included 31 patients who didn’t receive PCI. Arm 2 included 31 patients who received PCI. In arm 2, PCI was given after finishing the adjuvant treatment and before starting hormone therapy if indicated. The whole brain received 2.4 Gy per fraction, to a total dose of 24 Gy. MRI to the brain was part of the neurological assessment of the 62 patients included prior to adjuvant treatment, 6 months in the first year, and then annually. Neuro-cognitive Functions (NCF) were evaluated basically prior to and then 6 months and 1 year after PCI using Mini-Mental State Exam (MMSE). Functional Assessment of Cancer Therapy-Brain (FACT-Br) Questionnaire has been applied to assess health-related quality of life of the 62 patients included. Results: None of the patients in the PCI arm developed brain metastases in comparison to 6.4% in control arm. There is no statistical difference between control arm and PCI arm regarding the site of metastasis, P= 0.167. Alopecia was the most common side effect of PCI with G1 occurred in 48.4% of cases, and G2 occurred in 51.6% of cases and most of PCI arm cases showed hair re-growth within 11–15 weeks. PCI was well tolerated by most of patients. G1 and G2 headache occurred in 32.3% and 6.5% of patients, respectively. The initial levels of NCF in both arms were comparable, with no statistical difference through MMSE scores between both arms of the study, P=0.619. In PCI arm most of the MMSE scores were decreased at the 6 months assessment, but returned to the initial level at the one year assessment with no statistical difference among both groups. QOL was comparable in both groups prior to and at the end of treatment. The mean of DFS in control arm was 14.10 months (95% CI 10.18–18.02) and in PCI arm it was 18.42 months (95%CI 10.46–26–37), P=0.387. Conclusions: PCI was associated with tolerated toxicities and resulted in decreased incidence of CNS metastases. Whether this result may be translated into therapeutic gain warrants further evaluation. No significant financial relationships to disclose.
Induction chemotherapy (IC) and concomitant chemoradiotherapy (CCRT) for locally advanced head and neck cancer (LAHNC)
Authors: D. Ferrari, B. Jerekzec-Fossa, F. Chiesa, A. Rocca, M. Ansarin, S. Oldani, T. Tartaro, R. Bruschini, R. Orecchia, P. Foa
Journal: Journal of Clinical Oncology (2005)

5600 Background: In LAHNC, CCRT has been shown to improve locoregional control and overall survival; the efficacy of IC before radiation therapy is controversial, but results from meta-analyses show a possible advantage with regimens containing cisplatin (C) and fluorouracil (FU). The value of adding IC and CCRT remains debatable. We designed a phase II study in order to evaluate the feasibility and activity of this approach. Methods: Patients (pts) with stage III-IVA squamous cell carcinoma of the head and neck or with nasopharyngeal (NP) undifferentiated carcinoma were eligible. Main endpoint was complete response to IC + CCRT. In order to differentiate between an unacceptable response rate (RR) of 70% and one acceptable of 90%, 28 pts should be enrolled (optimal design, α=.1, β=.1). Treatment consisted of 2–3 cycles of C 100 mg/m2 i.v. on day 1 and FU 1000 mg/m2/day on days 1 to 5 as i.v. continuous infusion, followed by external beam radiotherapy (RT) using a shrinking-field technique (66 to 70 Gy) with concomitant either C 100 mg/m2 on days 1–22-43 (11 pts with NP cancer) or Carboplatin AUC 1,5 every week for 7 cycles (11 pts, other tumor sites). All pts received prophylactic treatment for mucositis with benzhydamine from the first day of RT. Results: Twenty-two pts (median age 53 years, range 28–71; nasopharynx: 11, oropharynx: 8, larynx: 3) have been enrolled. During IC grade 1–2 hematologic and gastrointestinal toxicity was observed in 7 pts. Toxicity due to subsequent CCRT was: grade 3–4 mucositis in 10 pts (45,4%) with oral candidiasis in 2 pts; grade 3–4 hematologic toxicity in 5 pts; grade 3 emesis in 2 pts; grade 2 dermatitis in 10 pts; grade 2 neuropathy in 2 pts. Anemia was not observed in our series. One patient died of pneumonitis and sepsis following grade 3 neutropenia during CCRT. Dose intensity CT was 93% of planned dose. Four patients stopped RT but were able to complete the programmed dose resuming RT a few days later. Twenty-one pts were evaluable for response: 4 pts (18,2%) had progressive disease, 5 pts (22,7%) had partial response and 12 pts (54,5%) had complete clinical response (overall RR 77,3%). Conclusions: These preliminary findings suggest that IC followed by CCRT is feasible and active in LAHNC. No significant financial relationships to disclose.
Risk of Recurrent Pancreatitis and Progression to Chronic Pancreatitis After a First Episode of Acute Pancreatitis
Authors: Usama Ahmed Ali, Yama Issa, Julia C. Hagenaars, Olaf J. Bakker, Harry van Goor, Vincent B. Nieuwenhuijs, Thomas L. Bollen, Bert van Ramshorst, Ben J. Witteman, Menno A. Brink, Alexander F. Schaapherder, Cornelis H. Dejong, B.W. Marcel Spanier, Joos Heisterkamp, Erwin van der Harst, Casper H. van Eijck, Marc G. Besselink, Hein G. Gooszen, Hjalmar C. van Santvoort, Marja A. Boermeester
Journal: Clinical Gastroenterology and Hepatology (2016)
Antibody-secreting cells to deliver antibody against brain metastases
Authors: L. A. Lampson, C. A. Tripp
Journal: Journal of Clinical Oncology (2007)

3047 Background: Antibody (AB) therapy has been successful against breast cancer, but brain mets are not well controlled. One likely factor is that AB molecules are too large to cross the blood-brain barrier (BBB). One approach is to truncate the AB, but this can affect its function. We propose an alternative. Unlike inert proteins, cells can cross the BBB. Indeed, antibody-secreting cells (ASC) are found in the brain in many neurologic disorders. Our hypothesis is that ASC, lodged within the brain, can be a source of AB to attack both pre-existing and new brain mets. We describe a new rat model to test this, and initial findings. Methods: Rat mammary carcinoma 13762 was made to constitutively express surrogate tumor antigens, either b-galactosidase (b-gal) or alkaline phosphatase (ap). Tumor cells were injected into the left common carotid artery of syngeneic CDF rats, to favor delivery to the brain. Tumor is identified by staining for keratin or the surrogate antigen. In a new assay, ASC are identified by a histochemical stain for their cognate antigen. As a positive control for ASC staining, spleens of immunized rats are used. Results: 1) The new histochemical assay does identify ASC correctly in positive and negative control spleens. 2) In the brains of rats that had been pre-immunized to b-gal, ASC specific for b-gal were seen at sites of b-gal+ tumor. 3) Some ASC were also seen away from tumor. Conclusions: Although ASC are known to enter the brain in many neurologic disorders, little work has stressed brain metastases. This new model allows study of ASC traffic to the brain in a tumor context. Favored sites of ASC entry and retention can be defined in both tumor-free brains (as appropriate for prophylaxis) and brains with pre-existing metastases. No significant financial relationships to disclose.
Abstract 15843: Mapping of the G-Protein Coupling Domains of the Human Platelet Thromboxane A2 Receptor
Authors: Olivia A Lin, Enma V Espinosa, John P Murad, Fadi T Khasawneh
Journal: Circulation (2012)

While the molecular signaling pathways for the thromboxane A2 receptor (TPR) have been elucidated from multiple organ systems, much less research efforts have focused on the TPR- G-protein (GP) cou...
T-Cell Recruitment From the Thymus to the Spleen in Tumor-Bearing Mice. II. Functional Characteristics of Recruited T-Cells
Authors: Kazuo Tanaka, Yasuhiro Koga, Kazuto Taniguchi, Kazufumi Kamikaseda, Yuhji Nihashi, Kikuo Nomoto
Journal: JNCI Journal of the National Cancer Institute (1986)

The effect of prostaglandin E2 (PGE2) on characteristics of splenic T-cells in tumor-bearing mice (TBM) was studied from the viewpoint of PGE2-mediated cell-recruitment system from the thymus to the spleen. The splenic T-cells of TBM enhanced tumor growth. In the TBM, the total number of thymocytes decreased, and the number of splenic T-cells concurrently increased. In adult thymectomized tumor bearers, these tumor growth-enhancing T-cells were absent in the spleen, and the number of splenic T-cells remained unchanged. Such suppressor T-cells in the spleens of TBM may relate to recruitment of immature T-cells from the thymus. The levels of PGE2 in the plasma were depressed in the TBM. Replenishment by exogenous PGE2 prevented both an increase in splenic T-cell population and an augmented generation of T-cells that had an enhancing effect on tumor growth. Our findings show that a low level of PGE2 induced the T-cell recruitment from the thymus to the spleen and that such recruited cells led to an acceleration of tumor growth.
The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury
Authors: Olga Ruiz-Andres, Beatriz Suarez-Alvarez, Cristina Sánchez-Ramos, Maria Monsalve, Maria D. Sanchez-Niño, Marta Ruiz-Ortega, Jesús Egido, Alberto Ortiz, Ana B. Sanz
Journal: Kidney International (2015)
Combining anti-CTLA4 with RG7787, an immunotoxin targeting mesothelin, promotes tumor eradication
Authors: Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Jay A Berzofsky, Birgit Bossenmaier, Gerhard Niederfellner, Ira Pastan
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Antibodies to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) potentiate an immune response against cancer. Response rates in melanoma patients are range from 10 to 19%[[1][1]]. To increase the efficacy and variety of cancer types treated by anti CTLA4, a combination therapy
Randomized pharmacokinetic evaluation of subcutaneous versus intravenous administration of granisetron in cancer patients treated with platinum-based chemotherapy
Authors: J. Perez-Gracia, B. Sadaba, J. Lopez-Picazo, J. Azanza Perea, J. Cabello, M. Campanero Martinez, S. Martin Algarra, I. Gil-Aldea, J. Garcia-Foncillas, A. Gurpide
Journal: Journal of Clinical Oncology (2006)

8557 Background: 5-HT3 antagonists are one of the mainstays of antiemetic treatment and they can be used either intravenously or orally. Nevertheless sometimes neither intravenous (IV) nor oral administration is possible, such as in patients unable to admit oral intake managed in an outpatient setting. Our objective was to assess if pharmacokinetics of subcutaneous (SC) granisetron were comparable to IV delivery, using Area Under the Curve between 0 and 12 hours (AUC 0–12 h) as our main endpoint. Methods: Patients receiving platinum-based chemotherapy were randomized to receive granisetron 3 mg by either SC or IV administration during the first cycle and by the other route during the second one. Blood samples were drawn at 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8 and 12 hours after granisetron. Drug levels were determined by HPLC with fluorescence detection after liquid-liquid extraction of the samples, with a quantitation limit of 1 ng/ml. Clinical assessment of emesis in both cycles was performed. Results were analyzed using Student’s t-test and Wilcoxon test for paired samples. Assuming a 20% difference in AUC 0–12 h between both routes, 25 patients were required to obtain statistical significance (α=0.05, β=0.10). The protocol was approved by the Ethics Committee and all patients signed informed consent. Results: From May to November 2005, 30 patients were included and 25 of them were evaluable. SC granisetron resulted in a 27% increase in AUC 0–12 h (95% CI: 7–74) and higher levels at 12 hours (see table). Cmax was higher and was reached faster by IV route. Emetic symptoms were equivalent with both alternatives. Conclusion: SC administration of granisetron achieves higher AUC 0–12 h than IV administration, resulting in increased exposition to the drug. This is the first study that shows that SC granisetron is a valid alternative to IV or oral use. This new route of administration might be specially relevant for outpatient management of emesis in cancer patients. [Table: see text] No significant financial relationships to disclose.
Compassionate use of fulvestrant: Experience from the Institut Bergonié
Authors: L. Mauriac, M. Debled, A. Jourand, J. Donamaria-Joseph
Journal: Journal of Clinical Oncology (2005)

746 Background: Fulvestrant (‘Faslodex’) is a new type of estrogen receptor antagonist with no known agonist effects. The fulvestrant Compassionate Use Program (CUP) enables its use in patients after progression on previous endocrine treatments and chemotherapies for advanced breast cancer (ABC). Method: As part of the CUP, we treated 41 women and one man with fulvestrant between August 2001 and September 2004. In accordance with rules imposed by the French Drug Agency (AFSSAPS), fulvestrant could only be used after most other endocrine treatments had been prescribed. Permission was given for the use of fulvestrant in each case. Results: Our patients had a median age of 65 years (range 41–86). All patients had advanced disease, including 19 patients with visceral metastases (liver and lung) and 25 with bone metastases. Adjuvant endocrine treatment (tamoxifen) followed primary surgery in 16 cases, and 3 patients received adjuvant chemotherapy. Fulvestrant was given after a median of 3 (range: 1–5) prior endocrine treatments and a median of 1 prior (range: 0–5) chemotherapy for ABC. Twelve patients achieved a partial response (PR) on fulvestrant therapy, and 10 experienced stable disease ≥6 months (SD), giving a clinical benefit (CB) rate of 52%. Fulvestrant was used as 2nd-line ABC therapy in 6 patients, with a CB rate of 83% (2 PR, 3 SD). The remaining 36 patients received fulvestrant as 3rd to 9th-line treatment for ABC (CB rate = 47%; 10 PR, 7 SD). In patients with visceral metastases the CB rate was 58% (6 PR, 5 SD). Across all patients, median duration of treatment was 5 months (range: 1–38). Currently, 19 patients are deceased, 2 are receiving further endocrine therapy (progestins) and 21 are receiving palliative chemotherapy. Fulvestrant was well tolerated; 6 patients (14%) reported adverse events as a result of treatment. Conclusion: In our institution, fulvestrant demonstrated good efficacy when given after other endocrine treatments and chemotherapies. The CB rate appeared to be higher when fulvestrant (which is approved for 2nd-line use), was given early in the therapy sequence; however, efficacy was retained in more heavily pre-treated patients. Patients with visceral metastases also gained clinical benefit from fulvestrant. No significant financial relationships to disclose.
17DMAG inhibits NFkB activity in tumors in mice monitored by bioluminescence imaging
Authors: Tsuyoshi Suzuki, Junichi Ohya, Hideo Nakamura
Journal: Cancer Research (2007)

5729  The transcription factor NFkB is a key regulator of cellular activation, proliferation and apoptosis and recognized as an important target for inflammation and cancer therapies.  Recently bioluminescence imaging has greatly facilitated the development of animal models of cancer, allowing sensitive detection of luciferase-expressing cancer cells in living mice.  Here we have developed a method for detecting and quantifying changes in NFkB activity in vivo non-invasively by inoculating cancer cells, stable transfectant of firefly luciferase under the control of NFkB with IVIS 100 imaging system (Xenogen).  There are several reports demonstrating geldanamycin inhibits TNF-induced NFkB activation in cultured cells. And its possible mechanism is explained by both the consequence of hsp90-inhibition and direct inhibition of NFkB-DNA binding.  Since there are no reports demonstrating in vivo inhibition of NFkB by geldanamycin or its analogs, we investigated the effect of 17DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) on NFkB activity in tumors in mice by using our animal model of molecular imaging.  To monitor NFkB activity in vivo, tumor xenografts are formed by injecting EBC-1/NFkB/Luc human lung cancer cells subcutaneously near the right hindlimb of nude mice. This luciferase was induced by extrinsic stimulation such as TNF-alpha or LPS. To neglect the non-specific anti-luciferase activity of test compounds, EBC-1/Luc cells, in which luciferase was consitutively expressed are also injected subcutaneously near the left hindlimb as a control.  Once tumor mass has established, basal luciferase activity in the tumor was measured prior to 17DMAG administration on the day of its treatment. One hour after the drug treatment, mice were treated with TNF-alpha (0.12mg/kg, ip), then post-TNF imaging was monitored at 4h later.  We found that TNF-alpha induced NFkB luciferase average 6 fold from basal level. After treatment with 17DMAG (30mg/kg, po), NFkB induction by measuring the specific luciferase activity was significantly decreased. Meanwhile, basal luciferase in the contralateral tumor was not impaired after 17DMAG treatment.Thus, We have developed a new animal model, which enables evaluation of pharmacodynamics of NFkB inhibitors and demonstrated that a geldanamycin derivative, 17DMAG has an inhibitory activity of NFkB in vivo.
Improving the targeting of bevacizumab therapy for colorectal carcinoma
Authors: Alex Varey, Emma Rennel, Steven Harper, David Bates
Journal: Cancer Research (2007)

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

4083 

Introduction

Vascular Endothelial Growth Factor (VEGF-A) is a key contributor to growth of colorectal carcinoma (CRC). Consequently, several anti-VEGF-A drugs have been developed to target this pathway, the most notable of which is bevacizumab, licensed for treatment of metastatic CRC. The phase III clinical trial demonstrating its efficacy achieved an overall 30% increase in median survival, but to date there have been no markers identified that can predict the subgroup of responders (~20%).

We have previously shown that CRC tumours produce variable ratios of both pro-angiogenic VEGF-A165 and anti-angiogenic VEGF-A165b and that the latter can inhibit tumour growth in vivo (Varey et al., 2006b). We have also shown that bevacizumab has a similar affinity for both VEGF-A165 and VEGF-A165b (Varey et al., 2006a). Therefore we sought to evaluate whether CRC tumours producing principally anti-angiogenic VEGF-A (VEGF-A165b) would respond differently to bevacizumab therapy compared to those producing predominantly VEGF-A165.

Methods

The human colon carcinoma cell line LS174t (expresses 5.7±0.3% VEGF165b) was transfected to over-express VEGF-A165b (expresses 109±16% VEGF165b). We then subcutaneously injected 2x106 cells/ nude mouse of either the parent cell line (n=12) or the VEGF-A165b derivative (n=14). The following day treatment with twice weekly intra-peritoneal injections of either 50µg bevacizumab or saline commenced in each cell line group and tumour growth monitored.

Results

The parent cell line, expressing principally VEGF-A165 grew much faster than VEGF-A165b over-expressing cells, with or without treatment with bevacizumab. However, whereas the VEGF-A165 cells grew much slower when treated with bevacizumab compared to saline (p=0.0026), there was no difference in the growth of the VEGF-A165b tumours when treated with bevacizumab or saline (p=0.79).

Conclusions

We have previously shown that a significant minority of patients with CRC have a predominance of VEGF-A165b expression in their tumours. The results here demonstrate that inhibition by bevacizumab of VEGF-A works effectively in those tumours that express a predominance of pro-angiogenic VEGF-A165, but not those producing predominantly anti-angiogenic VEGF-A165b. We therefore suggest that measuring the ratio of VEGF-A165b to VEGF-A165 in tumours from CRC patients may enable more accurate selection of patients most likely to benefit from Avastin treatment.

Varey, A. H. R., et al. (2006a). Microcirculation 13, 511-34.

Varey, A. H. R., et al. (2006b). Colorectal Dis 8, 99-102.