tbuckley/cabot-search huggingface dataset:
Loss of heterozygosity with acquisition of homozygous KIT-activating mutation promotes gastrointestinal stromal tumor progression
Authors: L. L. Chen, V. G. Prieto, M. Sabripour, E. F. Wu, A. K. Raymond, H. Sang, M. L. Frazier
Journal: Journal of Clinical Oncology (2006)

9530 Background: Gastrointestinal stromal tumors (GISTs) originate from interstitial cells of Cajal and represent the most common mesenchymal tumor of GI tract. The activating mutations of KIT and platelet-derived growth factor receptor α (PDGFRA) have been demonstrated in 88% and 6% of GISTs respectively. Multiple genetic events are involved in tumor initiation and progression. Activation of an oncogene can result from a single hit of gain-of-function mutation, but two hits leading to loss of heterozygosity (LOH) are necessary for inactivation of a tumor suppressor gene for the initiation of neoplasia. Little is known about the significance and mechanism of LOH of oncogenes in tumor progression. The LOH of activating-oncogenes is not infrequent, i.e. in more than 8% of GIST. These GIST clones with LOH prevail and dominate, strongly suggestive of proliferative and metastatic advantages. However, the significance and mechanisms of LOH acquiring homozygous activating-oncogene mutation remain unknown. Methods: Genomic DNA and cDNA sequencing analysis of KIT, single-nucleotide polymorphisms (SNPs), immunohistochemistry of GISTs clones, and 3D structural analysis of the mutated KIT. Results: Real-time genetic studies in GIST show initial development of overexpression of KIT without mutation, to coexistence of various heterozygous-activating mutations; eventually, one clone dominates. Comparisons within the same patient show that clonal evolution from heterozygous to LOH acquiring homozygous (diploid) KIT-activating mutation results in dominance of the latter, with augmented KIT signaling and doubling of mitotic figures. Using SNPs for allelotyping, we found that mitotic nondisjunction, rather than mitotic recombination, represents an important mechanism of the second hit. Conclusion: GIST clones with LOH acquiring homozygous KIT-activating mutation gain a selective advantage over the heterozygous counterpart. Mitotic nondisjunction, in addition to the commonly recognized mitotic recombination, is an important and perhaps the primary mechanism of LOH acquiring homozygous KIT-activating mutation during GIST progression. No significant financial relationships to disclose.
Association of VEGF feedback production in bevacizumab therapy with systemic response.
Authors: P. Starlinger, T. Maier, D. Schauer, C. Nemeth, L. Alidzanovic, B. Gruenberger, T. Gruenberger, C. Brostjan
Journal: Journal of Clinical Oncology (2010)

3056 Background: The monoclonal antibody bevacizumab (Beva) has proven a promising tool for anti-angiogenic cancer therapy by neutralizing vascular endothelial growth factor A (VEGF). However, in response to Beva administration an increased level of VEGF has been detected in patient blood. Although this feedback mechanism has been observed in several studies, it remains unclear if VEGF production is caused by the tumor itself or reflects a systemic host response. Furthermore, indirect effects of VEGF neutralization on other angiogenic mediators are of interest, as they may lead to compensation or therapy resistance. Under these aspects we have monitored levels of VEGF, circulating endothelial cells (CECs) and Tie-2 expressing monocytes (TEMs) in the context of a clinical trial. Methods: 18 patients with stage IV colorectal cancer and resection of liver metastases have been investigated to date. Blood samples were taken at the beginning and the end of their neoadjuvant as well as adjuvant treatment based on combined Beva and chemotherapy. VEGF was determined in platelet poor plasma by ELISA. TEMs and CECs were analyzed by flow cytometry in whole blood of a subset of 9 patients. Results: During neoadjuvant Beva therapy VEGF levels rose significantly (median pre 14 vs. post 68 pg/ml, p=0.001). A comparable increase was observed during adjuvant treatment (pre 18 vs. post 99 pg/ml, p=0.005). In contrast, a significant increase in TEMs (p=0.036) and CECs (p=0.025) was only observed for the neoadjuvant treatment period. Conclusions: VEGF feedback production in response to Beva therapy is entirely host derived and tumor independent, as VEGF blood levels increase to a comparable extent during neoadjuvant and adjuvant therapy when tumors have been largely excised. The selective regulation of angiogenesis associated cell populations (CECs and TEMs) during the neoadjuvant treatment period suggests a tumor-mediated effect with an interesting marker potential. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck, Roche Merck, Roche, sanofi-aventis Merck, Roche, sanofi-aventis
Prophylactic surgery and ovarian cancer treatment of women carriers of BRCA 1 gene mutation
Authors: I. Rzepka-Górska, A. Chudecka-Glaz, B. Górski
Journal: Journal of Clinical Oncology (2009)

e22139 Backgrounds. Tree BRCA 1 mutations commonly present in Polish population (5382 insC, C61G, 4153 delA) have been implicated in familial clustering of mammary-ovarian cancer. Prophylactic bilateral adnexectomy reduce the risk of ovarian cancer of more then 80% and the risk of brest cancer to 53%. Methods. It is retrospective study. We enrolled 193 women carriers of BRCA 1 mutation. 161 had prophylactic adnexectomy and 32 were treated because of diagnosed ovarian cancer. All were treated at our Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents between 1999–2008. We analysed the frequency of brest cancer in patients who were admitted to the hospital for prophylactic surgery and number of ovarian cancer diagnosed during prophylactic surgery. We analysed the response on standard treatment based on platinum analogs in carriers of BRCA 1 with ovarian cancer. It was also evaluated the incidence of primary peritoneal cancer in patients after prophylactic treatment. Results. The age of women at the time of prophylactic operation were between 41–60 y.o (mean 45 years old). We found, that 61 of patients had already diagnosed and were treated because of breast cancer (37.9%). During prophylactic surgery we diagnosed 10 cases of ovarian cancer, 2 cases of primary peritoneal cancer and 2 fallopian tubes cancer. These patients had no symptoms and were qualified to prophylactic adnexectomy. 32 women with ovarian cancer diagnosis had typical response to standard treatment, 70% were platinum sensitive and DFS was more then 12 months, 25 % had DFS between 6–12 months and 5% were platinum resistant. There were diagnosed only 2 cases of primary peritoneal cancer in patients after 31 and 61 months from prophylactic treatment. Conclusions. Separation the risk group - patients carriers BRCA 1 mutation let us to introduce effective prophylactic rules of conduct. No significant financial relationships to disclose.
Somatostatin analogue therapy and PROMIS health-related quality-of-life scores in patients with neuroendocrine tumors.
Authors: M. Dong, J. L. Beaumont, Z. Liu, A. T. Phan, S. Choi, D. Cella, J. C. Yao
Journal: Journal of Clinical Oncology (2010)

4110 Background: Somatostatin analogues (SSAs) are used in patients with neuroendocrine tumors (NETs) for the management of carcinoid syndrome and/or delay of disease progression. The objective of this study was to evaluate the impact of SSA use on health-related quality of life (HRQL) in patients with NETs. Methods: Patients with NETs were invited via e-mail to participate in an online anonymous survey. The survey consisted of demographics, disease-related questions, and standardized measures of HRQL (RAND-36 and PROMIS- 29). PROMIS-29 scores were compared between patients who reported treatment with a SSA in the past month versus those who did not using two-sample t-tests. Score differences of 2.5 - 5.0 points are generally regarded as clinically meaningful. Lower scores on the physical function and social role scales of the PROMIS-29 indicate worse HRQL. Higher scores on other scales indicate worse HRQL. Results: 663 patients participated in the survey. Among the 422 patients with carcinoid syndrome, 332 (78.7%) reported treatment with a SSA in the past month. In these patients with carcinoid syndrome, those on a SSA reported better HRQL scores compared to those not on an SSA for all PROMIS domains (Table). Statistically significant differences were observed on pain, sleep disturbance, anxiety, and depression (Table). Among the 228 patients without carcinoid syndrome, those on a SSA reported better HRQL scores with significantly less sleep disturbance compared to those not on an SSA (p=0.003). Conclusions: In this cross-sectional study, use of somatostatin analogue was associated with overall better health-related quality of life among patients with carcinoid syndrome and less sleep disturbance among patients without carcinoid syndrome. HRQL comparison in patients with carcinoid syndrome No somatostatin past month (n = 90) Somatostatin past month (n = 332) p value PROMIS T-score Mean (SD) Mean (SD) Physical function 42.2 (9.0) 43.1 (9.1) 0.435 Anxiety 57.6 (8.6) 54.9 (9.1) 0.015 Depression 54.9 (10.1) 52.6 (8.9) 0.043 Fatigue 58.7 (10.4) 56.7 (9.8) 0.090 Pain impact 56.8 (9.5) 53.7 (9.4) 0.008 Sleep disturbance 56.5 (8.9) 53.6 (9.1) 0.010 Social role 43.6 (10.2) 44.5 (10.2) 0.467 No significant financial relationships to disclose.
A phase III adjuvant vinorelbine plus cisplatin (NP) versus NP plus endostar (NPE) in patients (pts) with completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): An interim preliminary result.
Authors: H. Jie, Z. Xiangru, B. Han, Y. Liu, Q. Wang, S. Xu, Y. Sheng, Q. Li, S. Wu, C. Chen
Journal: Journal of Clinical Oncology (2010)

7019 Background: Adjuvant chemotherapy demonstrated a 5-15% benefit in 5-yr survival in early-stage NSCLC and the results are far from perfect. Endostar is a recombinant human Endostatin, could inhibit tumor angiogenesis. In a phase III trial, the addition of Endostar to NP regimen resulted in higher clinical benefit rate compared with NP alone in advanced NSCLC pts. Because of these promising results, we investigated adjuvant NP regimen with or without Endostar in early-stage NSCLC, and the preliminary results of the first enrolled 545 pts were reported. Methods: Completely resected pts (stage IB to IIIA) were randomized to receive adjuvant NP plus Endostar (arm A, N 25mg/m2 on d1 and d8 plus P 80 mg/m2 split 3 days, and iv plus Endostar 7.5mg/m2 per day iv for consecutive 14 days. Every 21 days as one cycle for 4 cycles) or NP regimen alone (arm B). Study design: open, multicenter, randomized (1:1), stratified by gender, stage and histology. Main endpoint: overall survival. Results: 545 pts (arm A 274; B 271) from 39 centers in China were included between 9/2007 and 04/2009. Two arms were well-balanced with regard to age, gender, histology, staging, and resection type. The follow-up time is 22 months. The cumulative death in arm A was 18 cases and in arm B 19 cases. Median survival was 19.4 months in arm A and 20.5 months in arm B (p=0.8965). The cumulative relapse disease in arm A was 73 cases and in arm B 64 cases. The median relapse-free survival time was 21.9 months in arm A and 18 months in arm B (p=0.3257). 78.6% of pts in arm A finished 4 cycles of treatment and 76.3% of pts in arm B received 4 cycles of chemotherapy. There was no significant difference in cardiac toxicities in two arms. Conclusions: This preliminary result showed no significant OS advantage for adding Endostar to adjuvant NP currently. Pts in arm A experienced a longer median relapse-free survival time (21.9 months vs. 18 months) than in arm B, although there was no statistical difference now. Over two third of pts have finished 4 cycles of chemotherapy in each arm. The toxicity profiles for both treatment arms were tolerable in this study. The pts enrollment and follow up are ongoing. No significant financial relationships to disclose.
A phase II multi-institutional trial of chemoradiation (CR) using weekly docetaxel (Doc) and erythropoetin (Epo) for high-risk postoperative head and neck cancer (HRHNC) patients
Authors: B. A. Murphy, B. Shakhtour, D. Raben, W. Reid, E. Weng, B. Burkey, B. Kish, J. Netterville, W. Yarbrough, A. J. Cmelak
Journal: Journal of Clinical Oncology (2005)

5591 Background: Postoperative radiation with concurrent cisplatin is the current standard of care for patients with HRHNC (≥2 involved nodes (N), extra-capsular disease (EC), +margins (+M)). This phase II trial in HRHNC evaluates the efficacy and toxicities of postop CR using weekly docetaxel instead. Methods: HRHNC patients were enrolled 2–8 weeks after surgery with PS 0–1, no distant mets, and no prior regional radiation or chemotherapy Treatment: 60Gy/6 weeks (3D=15, IMRT=3) with weekly Doc 25mg/m2 and Epo 40,000U (if Hgb≤12 gm/dl). Primary endpoints include locoregional control, DFS, and patterns of failure. Secondary endpoints: toxicity and QOL. Results: 18 HRHNC (14 male, 4 female) ages 24–70 (med 55) were enrolled. Characteristics include: OP=7, OC=8, Hypo=1, Larynx=2; Pathologic AJCC stage III=3 pts, IV=15 pts. HRHNC eligibility included: N=6, EC=2, +M=2, 2 risk factors=6, 3 factors=2. Doc was held for Gr4 mucositis (muc), Gr4 dermatitis, allergy, or PS≤2. Doc was reduced to 20mg/m2/wk after 5 pts had prolonged Gr≥3 muc. At 20mg/m2, the number of doses tolerated/prescribed were: 3/6=2, 4/6=1, 5/6=3, 6/6=6 pts, and were held for acute Gr3/4 muc in 4 pts, allergy in 1, FUO in 1. Median FU is 20 months (2–52): 14 (78%) remain NED. Patterns of failure: 3 local recurrence (2 with distant mets also), and 1 distant mets only. Actuarial median survival is 3 years, and median DFS is not yet been reached. No late Gr≥3 toxicities have been observed, although prolonged muc and taste loss (∼3 months) has been observed in a few patients, particularly at doc 25mg/m2/week. No pts are PEG dependent after 3 months, and no thromboembolic events have occurred. Conclusions: Postoperative RT with weekly doc 20mg/m2 (+/- Epo) for HRHNC is feasible but with high mucosal toxicity, especially with doc at 25mg/m2/week. Actuarial 3-yr locoregional control rate is 83%, which does not appear significantly better than concurrent cisplatin and radiation. Distant metastases remain a major pattern of failure. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ortho-Biotech
Chemotherapy for advanced or metastatic biliary tract cancer (ABC): Results of a single-center experience for 78 patients over three years.
Authors: M. Pracht, E. Boucher, C. Le Roux, G. Le Roux, K. Boudjema, P. Porée, H. Mesbah, P. Kerbrat, J. Raoul
Journal: Journal of Clinical Oncology (2010)

e14628 Background: Last year at the ASCO Annual Meeting JW Valle et al. demonstrated the superiority of the association of gemcitabine (G) plus cisplatinum (P) over gemcitabine alone for the treatment of ABC. Overall survival 11.7 vs. 8.3 months and progression-free survival 8.4 vs. 6.5 months. This combination was already widely used in France for several years due to the results of phase II trials combining gemcitabine and oxaliplatin (Gemox). Methods: From 2007 to 2009, 78 patients received chemotherapy for the treatment of ABC, we analysed retrospectively our results. Results: We treated 25 women and 53 men, aged 60.8± 11.4 years. 57 had an intrahepatic tumor. Treatment protocols were Gemox (n=62), G (n=7) or the association of 5FU plus P (n=9). Twenty-eight patients experienced a partial response (PR-34%) and 21 had a stable disease (SD-27%). In December 2009, 64 patients were dead. Median survival was 11 motnhs (CI 95% 7-13) and median progression-free survival was 7 months (CI 95% 6-8). Our results are in accordance with other published results, for response rate, survival rate, and progression-free survival. In mutivariate analysis, tumor location was not a prognostic factor (p=0.07). 42% of intrahepatic cholangiocarcinoma occurred on a cirrhotic liver (all liver primary tumor had an histologic diagnosis in our center), but the prognosis was similar than noncirrhotic patients. Conclusions: The Gemox protocol stay our standard first-line treatment for ABC, trial combining a biotherapy are ongoing. We recommend systematic biopsy of liver cancer; the rate of biliary tumor occurring on cirrhotic liver seems to be high. Localization Intrahepatic n = 57 Extrahepatic n = 21 Cirrhosis/normal liver 25/32 5/16 Treatment protocol Gemox/G/5FU+P 43/5/9 19/2/0 Nb of treatment (median) 8 (1-31) 11 (3-89) Second line (n=) 22 3 Adverse event grade 3-4 13/15 3/11 Hemato/other (n=) Response (PR/SD) 17 (30%)/13 11 (52%)/7 Progression-free survival 7 m (CI 95% 6-8) 8 m (CI 95% 5-15) Survival 10 m (CI 95% 7-12) 12 m (CI 95% 7-35) Surgery (n=) 4 4 (1 OLT) No significant financial relationships to disclose.
A novel intermediate endpoint for predicting overall survival in men with metastatic castration-recurrent prostate cancer (CRPC)
Authors: S. Halabi, S. Ou, N. J. Vogelzang, H. Scher, E. J. Small
Journal: Journal of Clinical Oncology (2007)

5113 Background: In this proposed study, we developed and validated a novel composite clinical benefit endpoint constructed from symptoms that have intrinsic clinical importance in 800 men with CRPC who were treated with front-line chemotherapy. Methods: Data from nine multimember trials (five phase II and four randomized phase III studies) conducted by the Cancer and Leukemia Group B (CALGB) from 1992–2004 were combined. Eligible patients had progressive adenocarcinoma of the prostate during androgen ablation (despite castrate testosterone levels), an ECOG performance status of 0–2, adequate hematologic, renal and hepatic functions. The tripartite composite clinical benefit endpoint (TCCBE) had three components: one based on disease progression (whether it be PSA, bone, or soft tissue progression), and the second based on weight loss (defined as at least 10% decline from baseline) or on performance status (PS) decline (by at least one level) to capture clinical deterioration. The third component was based on pain control and opioid analgesic use (no or yes). For a person to fall in the TCCBE “yes” category, at least two of the three components had to be recorded as no. For instance, if a patient at 3 months had no progression, no change in weight and did not use opioid analgesic, then he will be classified in the “yes” group and for the purpose of this analysis was considered as someone who achieved “clinical benefit”. The sample was randomly split into 526 (67%) and 274 (33%) men in the training and testing datasets, respectively. Results: From the training dataset, the median survival times in men who had and did not have clinical benefit were 20.9 months (95% confidence interval (CI) = 18.5–22.8) and 11.1 months (95% = 8.79–12.6, p- value&lt;0.001). In the testing dataset, the median survival times in men with and without clinical benefit were 21.7 months (95% CI= 19.1–26.1) and 8.8 months (95% CI= 7.8–11.6) and in men. The hazard ratio (HR) for men with a clinical benefit compared to men without was 0.52 (95% CI= 0.43–0.62, P&lt;0.001). Conclusions: The TCCBE is a statistically significant intermediate endpoint for predicting overall survival. Prospective validation of this endpoint is needed. No significant financial relationships to disclose.
Abstract 16417: Carotid Plaque Component Reproducibility at 3.0 Tesla Mri in Patients with Overt Atherosclerosis
Authors: Diederik F van Wijk, Aart C Strang, Raphael Duivenvoorden, Rob van der geest, eric de Groot, Erik S Stroes, aart J Nederveen
Journal: Circulation (2012)

Background: Carotid MRI has recently shown to provide compositional information about carotid atherosclerosis. Currently available reproducibility data is performed using an in-plane resolution of ...
Combined effects of creatinine clearance and peak oxygen consumption in risk stratification of patients with chronic systolic heart failure
Authors: Carl J. Lavie, Elise L. Milani, Hector O. Ventura
Journal: Circulation (2006)

Background: Peak oxygen consumption (PkVO2) remains a potent independent discriminator of survival in patients with chronic systolic heart failure (HF). Our laboratory has shown that the predictive...
Long-term disease modifying effect by glucosamine sulfate in knee osteoarthritis : relationship between structure and symptom changes
Authors: Jean-Yves Reginster, Rita Deroisy, RL Lee, LC Rovati, E Lejeune, G Giacovelli, Yves Henrotin, J Dacre, Christiane Gosset
Journal: Annals of the Rheumatic Diseases (2000)
Deforolimus trial 106- A Phase I trial evaluating 7 regimens of oral Deforolimus (AP23573, MK-8669)
Authors: M. M. Mita, C. D. Britten, E. Poplin, W. D. Tap, A. Carmona, L. Yonemoto, D. S. Wages, C. L. Bedrosian, E. H. Rubin, A. W. Tolcher
Journal: Journal of Clinical Oncology (2008)

3509
Increases in Neutral, Mg2+-Dependent and Acidic, Mg2+-Independent Sphingomyelinase Activities Precede Commitment to Apoptosis and Are Not a Consequence of Caspase 3–Like Activity in Molt-4 Cells in Response to Thymidylate Synthase Inhibition by GW1843
Authors: Ronald M. Laethem, Yusuf A. Hannun, Supriya Jayadev, Connie J. Sexton, Jay C. Strum, Rebecca Sundseth, Gary K. Smith
Journal: Blood (1998)
Survey of arm activity after breast cancer
Authors: T. S. Lee, S. L. Kilbreath, G. Sullivan, K. M. Refshauge, J. M. Beith
Journal: Journal of Clinical Oncology (2007)

9054 Background: Post-operative education of women with breast cancer is inconsistent as guidelines provide conflicting advice regarding how vigorously women can use their arm. Current post-operative advice about lymphoedema focuses on the avoidance of strenuous arm activity and exercise, but common physiotherapy practice advocate this to address possible impairments after surgery such as loss of shoulder range and weakness. Methods: A 30-minute survey based on the Protection Motivation Theory was developed to explore the relationship between patients’ perception of what they can do with their affected arm following breast cancer treatment and their intention to use their affected arm. In addition, patients’ cancer and treatment characteristics, demographics, arm and chest symptoms, and arm function were assessed by the survey. The survey was pre-tested, and then distributed to 175 consecutive breast cancer survivors at 6–15 months after breast cancer treatment. Results: Of the women surveyed, 91(52%) had sentinel node biopsies, 67 (38%) had axillary dissection, 14 (8%) had no surgery to the lymph nodes, and 3 (2%) were unknown. There was a high incidence of shoulder restriction and upper limb pain in both women who had sentinel node biopsies and women who had axillary dissections ( Table 1 ). The majority of women who had sentinel node biopsies (51%) and axillary dissections (61%) perceived it was necessary for them to avoid strenuous arm activity. Overall, women who intended to avoid strenuous arm activity were found to have a greater likelihood of reporting upper limb swelling (LR=17.6, p=0.000) and weakness (LR=10.9, p=0.001). Conclusion: Women who had sentinel node biopsies intended to avoid strenuous arm activities even though they have a negligible risk of lymphoedema, placing them at risk of developing secondary musculoskeletal problems. [Table: see text] No significant financial relationships to disclose.