tbuckley/cabot-search huggingface dataset:
Sunitinib treatment of pediatric metastatic GIST after failure of imatinib
Authors: K. A. Janeway, D. C. Matthews, J. E. Butrynski, G. Z. D’Amato, S. Agresta, C. Garrett, C. L. Corless, K. H. Albritton, G. D. Demetri
Journal: Journal of Clinical Oncology (2006)

9519 Background: The genotype of most GIST in pediatric patients (pts) is “wild type” (WT-GIST), with no detectable KIT or PDGFR-α mutations. Adults with metastatic WT-GIST often have suboptimal results and primary resistance to imatinib (IM) therapy. Treatment with sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activities, results in significant clinical benefit, such as improved survival, for adult pts with IM-resistant GIST, including WT-GIST. We report here the treatment of 3 pediatric pts with IM-resistant, metastatic GIST using sunitinib. Methods and Patients: Pt 1 presented at age 17 with numerous abdominal and hepatic GIST metastases. Following surgical debulking and 6 wks of IM treatment, objective progression was noted due to growth of omental masses and a new hepatic lesion. Pt 2 presented at age 8 with an isolated gastric GIST, fully resected, followed by adjuvant IM that continued until resection of a local recurrence 14 mos later. She had 2 more local recurrences and developed lung metastases. Pt 3 presented at age 13 with a large gastric GIST and a retroperitoneal metastasis, both fully resected and followed by adjuvant IM for 18 mos. Six mos after discontinuing IM, recurrent metastatic GIST was noted in the liver and retroperitoneum; IM therapy was resumed with stable disease for 1 yr when new hepatic lesions appeared with progression of the retroperitoneal mass. Pts 1 and 2 had WT-GIST, while genotyping of Pt 3 is pending. Sunitinib, obtained via an expanded-access protocol, was administered in 6-wk cycles, orally QD for 4 wks followed by 2 wks off dosing. Results: All pts have received 5 cycles of sunitinib. All GIST lesions have stabilized or decreased in size by CT imaging, with complete regression of 2 lung nodules in Pt 2. 18FDG-PET imaging obtained in 2 pts showed significant decreases in tumor-associated activity at all disease sites. Side effects with sunitinib have been manageable, including grade 2 GI and hematologic toxicities in pt 1, grade 3 fatigue in pt 2 and grade 3 hematologic toxicity in pt 3. Conclusions: Sunitinib shows important antitumor activity in pediatric pts with IM-resistant GIST. An expanded phase I/II trial of sunitinib in pediatric GIST is warranted. [Table: see text]
Abnormal response of growth hormone to thyrotropin releasing hormone injection in patients with gastric cancer
Authors: Y. Rino, Y. Takanashi, M. Shiopzawa, H. Cho, T. Yoshikawa, A. Tsuburaya, O. Kobayashi, M. Sairenji, T. Imada
Journal: Journal of Clinical Oncology (2005)

9676 Background: Patients with gastric cancer have been noted to have an abnormal response to thyrotropin releasing hormone (TRH) of growth hormone (GH). The abnormal response is called GH paradoxical response (PR). We estimated the correlation between endocrine abnormalities and prognosis of the patients with gastric cancer. Methods: Subjects were 101 patients with gastric cancer, 40 Stage I, 8 Stage II, 26 Stage III, 27 Stage IV. Stage I patients consisted of 29 males and 11 females. Stage II patients consisted of 5 males and 4 females. Stage III patients consisted of 23 males and 3 females. StageIV patients consisted of 17 males and 10 females. None of the patients had a history of endocrine diseases. Serum GH and serum TSH levels were measured by radioimmunoassay before and after a single shot of 500 micrograms of TRH. PR were evaluated all patients. Collu et al reported that PR is defined by an increase to at least twice the baseline levels and greater than 5ng/ml. Survival rates were compared between PR positive and negative groups. Results: PR was observed 10 out of 40 cases in Stage I, and 12 out of 27 cases in Stage IV. PR positive rate was not significantly higher in Stage IV than Stage I patients. Whereas there are two patterns of PR. One is a rapid response after TRH administration (rapid response type) and the other is a late response (late response type). Positive PR group had no significant poor prognosis. However, prognosis of gastric cancer patients was better in PR negative group and late response type of PR than rapid response type of PR positive group. There was significant difference that p-value was 0.0002. Conclusions: PR of GH may be a good prognostic indicator in gastric cancer patients. No significant financial relationships to disclose.
Fortnightly Review: Drug treatment of Parkinson's disease
Authors: N. Quinn
Journal: BMJ (1995)

<h3>Summary points</h3> A wide variety of drugs is available for treating Parkinson9s disease, including anticholinergics, amantadine levodopa, dopamine agonists, and selegeline In younger patients (&lt;50) levodopa is usually delayed provided that adequate relief of symptoms can be achieved with other drugs. In older patients (&gt;70) levodopa should be started as soon as symptom relief is required. Between these ages there is no consensus, but at present most such patients should probably be given controlled release levodopa before a dopamine agonist is added Fluctuations can often be alleviated by giving controlled release preparations of levodopa, by giving small doses at frequent intervals, by adding selegiline or a long acting oral agonist, or by subcutaneous apomorphine Dyskinesia can be peak dose, diphasic, or "off period." The diphasic form is hardest to alleviate Psychiatric side effects should initially be managed by changing the antiparkinsonian treatment before resorting to antipsychotic drugs
Kupffer cells in high fat diet-induced insulin resistance
Authors: Isabelle Leclercq
Journal: Hepatology (2011)

Kupffer cells are re-emerging as a critical mediator of liver injury. While the role of Kupffer cells in alcoholic liver disease has been well studied, there is a growing appreciation that Kupffer cells are also critical to the development of hepatic insulin resistance, as well nonalcoholic fatty liver disease (NAFLD) in obesity and metabolic syndrome. NAFLD is a spectrum of disorders that include steatosis, steatosis with inflammation, nonalcoholic steatohepatitis (NASH) and NASH with fibrosis. Advanced NAFLD, particularly NASH with fibrosis, is a considerable risk for progression into cirrhosis and hepatocellular cancer. Because of its high prevalence, NAFLD may surpass chronic hepatitis C as the leading indication for liver transplant by 2020. Kupffer cells are the resident macrophages in the liver. Kupffer cells exhibit a tremendous plasticity: depending on the local metabolic and immune environment, Kupffer cells can exhibit a range of polarized phenotypes, ranging from a pro-inflammatory M1 phenotype to an alternative/M2 phenotype. Multiple M2 phenotypes can be distinguished, each involved in the resolution of inflammation and wound healing. The goal of this symposium is to provide an update from basic research on developing perspectives for contribution of Kupffer cells to NAFLD/NASH and new insights into the potential for therapeutic manipulation of Kupffer cells to promote the resolution of inflammation and enhance wound healing in liver disease. Course objectives and goals • Appreciate the phenotypic plasticity of tissue resident macrophages • Understand the interactions between Kupffer cells and metabolic activity in hepatocytes • Describe the role of Kuppfer cells in animal models of NAFLD • Discuss potential therapeutic implications of Kupffer cell plasticity
Use of KBMA Listeria monocytogenes as an antigen loading platform for dendritic cell-mediated induction of antitumor immunity
Authors: M. Skoberne, A. Yewdall, K. S. Bahjat, E. Lemmens, W. Liu, P. Lauer, W. Luckett, T. W. Dubensky, D. G. Brockstedt, N. Bhardwaj
Journal: Journal of Clinical Oncology (2008)

3044 Background: Melanoma is one of the most rapidly growing cancers worldwide yet there is no satisfactory treatment. Dendritic cells (DC) are attractive cellular adjuvants which can increase host resistance to tumor. To optimally prime naïve T cells, DCs must not only present high levels of MHC-peptide complexes, but must also undergo activation and maturation. Methods: The highly attenuated killed but metabolically active (KBMA) Listeria monocytogenes (Lm) were engineered to express the HLA-A*0201 CD8+ T cell epitopes of melanoma-associated antigen (MAA) MelanA/Mart-1 and of control influenza matrix protein, both encoded within the OVA scaffold protein. These bacteria served as a DC antigen-loading platform. Monocyte-derived DC were generated from PBMCs of healthy donors, infected with recombinant attenuated KBMA Lm (rLm) and evaluated for maturation and presentation of the tumor-specific epitope. These DC were also used to generate tumor-specific CD8+ T cell lines, which were tested for effector potential through lysis of HLA matched patient-derived tumor cell lines. Efficacy of the KBMA rLm-infected DCs was confirmed in a B16-OVA mouse tumor model. Survival and tumor burden was compared between the vaccinated and control group. Tumor survival results were analyzed by one-way ANOVA and two-tailed Student's t test for statistical significance. Results: Highly attenuated KBMA Lm expressing the MelanA/Mart-1 epitope induced up-regulation of costimulatory molecules and lymph node homing molecule CCR7 on human DC, secretion of proinflammatory cytokines, including IL-12p70 and IFNα. In vitro co-culture with naive T cells from healthy donors significantly induced MelanA/Mart-1 specific CD8+ T cells, which in turn were able to lyse melanoma cells expressing the antigen but not a control tumor cell line. In mice, vaccination with rLm-infected DCs resulted in reduced tumor burden and enhanced survival. Conclusions: Our studies demonstrate that KBMA Lm is a novel and effective ex vivo DC antigen loading platform combining a potent DC-maturation stimulus with the cytosolic delivery of recombinant antigen for presentation. The platform results in priming of tumor antigen-specific and protective CD8+ T cells. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Anza Therapeutics Anza Therapeutics Anza Therapeutics Anza Therapeutics
Levetiracetam for the treatment of hot flashes: A pilot study
Authors: S. L. Thompson, A. Bardia, A. Tan, D. Barton, L. Kottschade, J. Sloan, B. Christensen, D. Smith, C. Loprinzi
Journal: Journal of Clinical Oncology (2007)

9116 Background: Hot flashes affect 75 % to 90 % of women transitioning to menopause and are a major cause of morbidity among breast cancer survivors. Levetiracetam, a popular anticonvulsant, is a centrally active agent that anecdotally appeared to reduce hot flashes in clinical practice. This phase II trial sought to evaluate the efficacy of levetiracetam in reducing hot flashes among women with a history of breast cancer or women who did not wish to take estrogen therapy for fear of an increased risk of breast cancer. Methods: Women who were experiencing bothersome hot flashes (≥ 14 times per week, for ≥ 1 month) were eligible. A single arm pilot study design based on previous work was used with a planned sample size of 30 patients. The patients did not receive any study medication during the first week (baseline week). At the beginning of the second week, patients were started on levetiracetam (500 mg), and were to increase the dose by 500 mg each week to a goal of 1,000 mg twice daily. Hot flash diaries were completed daily. The primary endpoint was hot flash score (frequency times average severity). The change from week 1 (baseline) to week 5, the last treatment week, was analyzed by paired t-test and related Wilcoxon procedures. Results: A total of 30 women were enrolled onto this study in eight months. All patients were eligible. 19 women completed all 4 weeks of the study treatment and provided complete data. After treatment with levetiracetam for 4 weeks, mean hot flash scores were reduced by 57% (95% CI 39%-75%), while mean hot flash frequencies were reduced by 53% (95% CI 38%-68%), reductions being greater than what would be expected with a placebo. There were significant improvements, compared to baseline week data, in sweating, hot flash distress, and satisfaction with hot flash control. Eight subjects stopped the study drug due to treatment related adverse events (grade I/II), with the most frequently reported being somnolence, fatigue and dizziness. Conclusions: While levetiracetam appears to be a promising therapy for the treatment of hot flashes, further study is needed to better substantiate the toxicity and efficacy of this drug before it can be more definitively recommended for use in clinical practice. No significant financial relationships to disclose.
Promoter hypermethylation of TMS1 and DAPK were correlated to low chemosensitivity and poor prognosis in patients with recurrent gastric cancer
Authors: H. Uetake, K. Kato, S. Morita, S. Iida, K. Sugihara
Journal: Journal of Clinical Oncology (2005)

4280 Background: Promoter hypermethylation plays an important role in the inactivation of tumor suppressor genes during tumorigenesis. Gene silencing associated with aberrant methylation of promoter region CpG islands is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor and other genes in human cancers. Target of methylation-induced silencing (TMS1) is a novel CpG island-associated gene and induces apoptosis through activation of caspase-9 and inhibited the survival of human breast cancer cells. Methylation of the apoptosis-associated gene death-associated protein kinase (DAPK) has been recently described in stage I lung cancer, in which it portends a poor prognosis. In the present study, promoter hypermethylation of TMS1 and DAPK were investigated and in gastric cancer specimen and compared to chemosensitivity and patient’s prognosis. Methods: Methylation status of forty-one gastric cancer specimens, all of which were formalin-fixed and paraffin embedded, were studied by methylation specific PCR. All the patients were administered 5-FU based chemotherapy for the treatment of recurrent lesion. Results: Hypermethylation of TMS1 and DAPK was observed 36.7% and 37.1% of the specimen, respectively. In TMS1 (DAPK) unmethylated group, 42.3 (45.5) % of the patients responded to the chemotherapy, while 20.0 (23.1)% responded in TMS1 (DAPK) methylated group. Patients with both TMS1 and DAPK methylated cancer showed significant poor survival than the others (p=0.0452, Log-rank test). Conclusions: Promoter hypermethylation of TMS1 and DAPK were supposed to be negative predictive and prognostic factors in patients with recurrent gastric cancer, probably through preventing apoptosis. No significant financial relationships to disclose.
Decision-making in incurable cancers : A retrospective analysis of 150 patients entered into the CTRL algorithm of Cochin
Authors: J. P. Durand, P. Vinant-Binam, J. Alexandre, L. Zivkovic, M. Y. Guillard, S. Dispa, S. Chauffour, F. Goldwasser
Journal: Journal of Clinical Oncology (2004)

8226 Background A specific pluridisciplinary approach is beneficial beyond evidence-based medicine to protect patients from either medical futility or too early anti-tumoral treatment withdrawal. Methods Between May 2002 and November 2003, a team including nurses, psychologists, social workers and physicians (medical oncologists and palliative care specialists) prospectively tailored a decision-making process and aimed to answer to 3 questions : What is the \(\underline{\mathrm{life\ expectancy}}\) of the patient ? What is the \(\underline{\mathrm{best\ medical\ plan}}\) (continuation of anti-tumor treatments or entering in a phase I trial or exclusive palliative care) ? and \(\underline{\mathrm{Where}}\) (at home, in a palliative care unit or at the University hospital) ? A tool was built including the severity of the Cancer disease, the effects and potentialities of anti-tumor Treatments, the Relationship between the patient, his family, and the caregivers (patient's understanding about prognosis, patient's treatment preferences, ability to talk about death), his social and affective Life (life plan, affective bonds). Endpoints were : date of death and satisfaction of the family and the caregivers concerning the circumstances of death. Results 150 consecutive patients with progressive, incurable cancer were discussed and the results were retrospectively analysed. Correlations (p<0.05) were found between : -poor survival and >2 tumor-related symptoms, PS>2, cachexia, recent episode of thrombo-embolism, benefit of last antitumoral treatment <3 months. -feasability of palliative care at home and asthenia as predominant symptom, cachexia, massive liver involvement, ability to talk about death, family understanding. Conclusions The CTRL algorithm may help to define the most reasonable treatment in incurable cancer patients. A prospective validation of the CTRL tool in a larger population and a graphic modelling are ongoing. No significant financial relationships to disclose.
Deletion of NFKBIA in malignant gliomas.
Authors: M. Bredel, A. Yadav, J. Renfrow, D. Scholtens, C. Bredel, J. Chandler, A. Scheck, K. D. Aldape, A. Chakravarti, G. Harsh
Journal: Journal of Clinical Oncology (2010)

2025 Background: Aberrant activation of the epidermal growth factor receptor (EGFR) oncoprotein is a molecular hallmark of glioblastomas. Two-thirds of tumors with excessive EGFR activation show alteration of the EGFR gene. The mechanism of deregulation of EGFR in the other third remains poorly understood. Nuclear factor of κB inhibitor α (NFKBIA) is a potential tumor suppressor. Methods: Multidimensional molecular profiles for NFKBIA and EGFR and clinical profiles of 728 malignant glioma patients from multiple academic institutions, The Cancer Genome Atlas Pilot Project, the Repository of Molecular Brain Neoplasia Data, and a randomized phase III trial of temozolomide. NFKBIA mutational and functional analyses in a glioblastoma cell model. Results: We found that about 25% of glioblastomas harbor heterozygous NFKBIA gene deletions at chromosome 14q13. NFKBIA functions as a haploinsufficient tumor suppressor in glioblastomas by terminating EGFR signaling. Tumors with NFKBIA deletion lacked EGFR amplifications, indicating functional redundancy of both genetic events in glioblastoma pathogenesis. Loss of NFKBIA gene dosage was significantly associated with briefer patient survival. Patients with low NFKBIA expression had a significantly worse outcome than patients with intact NFKBIA expression. NFKBIA expression was also significantly associated with patient survival in subsets of tumors with unmethylated promoter of the O6-methylguanine DNA methyltransferase (MGMT) gene. A combined outcome predictor model of NFKBIA and MGMT proved highly predictive of duration of survival. Conclusions: Deletion of NFKBIA is an alternative mechanism for tumorigenic increase in EGFR signaling in glioblastomas. NFKBIA inactivation is associated with shorter survival of patients with malignant gliomas. No significant financial relationships to disclose.
What are the supportive care service needs of recently diagnosed cancer patients? Results of a population based study
Authors: J. Sussman, T. Whelan, E. Grunfeld, A. Willan, S. Sellick, M. A. O’Brien, S. Schiff, A. Edwardson
Journal: Journal of Clinical Oncology (2005)

8096 Background: Previous studies have suggested that a substantial proportion of recently diagnosed cancer patients may have unmet supportive care needs. As part of a cancer supportive care initiative in the province of Ontario Canada, we evaluated patients’ need, use and access to supportive care services. Methods: A prospective cross-sectional population based survey of patients with breast, colorectal and prostate cancers randomly selected from a provincial registry who were within 12 months of diagnosis was performed in 3 representative regions of the province of Ontario, Canada between June 2001 and April 2003. A validated, self- completed supportive care questionnaire that reviewed 46 unique core supportive care services was mailed to patients. Respondents indicated whether a particular service type was needed and used during the previous 12 months. Need and use scores were tabulated by adding the number of services chosen (score range 0–46). Access was measured by the gap between need and use of services. Demographic variables were collected to study predictive factors for need and use. Results: Responses were obtained from 2733 patients representing an adjusted response rate of 76%. Mean respondent age was 65.9 years with 51% of respondents being female. 83.5% attended a cancer centre in the previous 12 months. Mean need score from all respondents was 10.8 (SD 6.9). Need scores appeared highest for Information, Psychological and Physical Services. On multivariate regression, a higher need was predicted by: lower age, gender (female), non-attendance at a cancer centre, lower socioeconomic status, and disease type (breast) (all P<.001). Mean use score for all respondents was 8.7 (SD 5.1). In fewer than 10% of respondents a gap between need and use was recorded. Conclusions: Cancer patients reported need and use of few specific supportive care services in this population based survey. In contrast to previous studies, access did not appear to be a significant problem based on a small gap between need and use of services. Patient reported needs varied by a number of demographic factors. These findings are important for the planning of supportive care services in cancer centres and communities. No significant financial relationships to disclose.