tbuckley/cabot-search huggingface dataset:
Insulin-like growth factor (IGF)-II in gastrointestinal stromal tumors (GIST): expression, secretion, and clinical relevance
Authors: B. Rikhof, J. van Doorn, A. Suurmeijer, M. Rautenberg, P. Jager, J. Gietema, C. Meijer, S. de Jong, W. van der Graaf
Journal: Journal of Clinical Oncology (2007)

20504 Background: Non-islet cell tumor induced hypoglycemia (NICTH) has been reported anecdotically in patients with a GIST and is associated with increased plasma levels of ‘big’-IGF-II, a high molecular weight form of IGF-II. The role of IGF-II in GIST is unknown. In non- GIST cancer, it has been suggested to be an autocrine growth factor, mainly acting by its major growth promoting receptors IGF-1 receptor (IGF- 1R) and the isoform A of the insulin receptor (IR). We investigated the clinical and biological relevance of (‘big’-)IGF-II in GIST. Methods: Plasma levels of ‘big’-IGF-II, and their relationship with disease status and NICTH, were determined in 25 consecutive GIST patients treated with imatinib (n=24) or sunitinib (n=1). Plasma samples were collected prior to, 1 week, and median 5 months after start of treatment. The levels of ‘big’-IGF-II were measured by specific radioimmunoassay (RIA). Results were compared with those obtained from healthy subjects and expressed as standard deviation scores (SDS). Paraffin-embedded GISTs (n=69) were analyzed for IGF-II, IGF-1R and IR expression by RNA in situ hybridization and immunohistochemistry (IHC). IGF-II secretion by the GIST882 cell line was analyzed by ELISA and western blotting. Results: Before treatment and/or during follow-up, 4 of 25 patients (16%) showed increased (i.e. SDS &gt;2.0) plasma levels of ‘big’-IGF-II. Three of them developed NICTH. Patients with metastatic disease, high serum LDH, or total tumor size &gt;12 cm had the highest ‘big’-IGF-II levels (for all p&lt;0.05). 87% of GISTs expressed IGF-II mRNA, being excessive in tumors from patients with NICTH. These results were confirmed by IHC. GIST882 cells secreted mainly high molecular weight forms of IGF-II. The various GISTs and GIST882 cells did not express IGF-1R or IR. Conclusions: NICTH seems not to be a rare phenomenon in GIST patients. We showed for the first time that most GISTs express and secrete (‘big’-)IGF-II. Therefore, it is likely that many patients are at risk of developing NICTH, presumably especially in case of high tumor bulk. The exact role of (‘big’-)IGF-II in GIST is still not elucidated, as it does not seem to act as an autocrine growth factor since IGF-IR and IR isoform A are lacking. No significant financial relationships to disclose.
Four years trial in elderly people of appraisal and comparison by geriatric assessment instruments: Use of high potency opioids for cancer pain control and quality of life
Authors: G. Ferrero, F. Testore, S. Milanese, G. Porcile, C. Caroti, M. D’Amico, U. Folco, A. Gozza
Journal: Journal of Clinical Oncology (2006)

18610 Background: Pain is probably under-recognized and under-treated in the Elderly with advanced cancer disease but the effect of a therapy with high potency opioids is not studied so much in geriatric age people. To evaluate efficacy and tollerability of escalating doses of Transdermal Fentanyl (TTS-F) or equipollent doses of oral morphine long acting with Immediate Release Oral Morphine (IROM) as rescue medication for treatment of moderate-severe cancer pain, we have started a Multicentric Observational Analysis in four cancer centres of north-western Italy. Studies of oncological palliation using valid measures of quality of life show that patients may be willing to accept some side effects of treatment as long as they gain relief from tumor-related symptoms Methods: -TIQ (Therapy Impact Questionnaire) -VAS (Visual Analogic Scale): 0 to 10 -Toxicity (WHO criteria) -Geriatric Assessment for pts aged &gt;70 yrs (only at time 0): CIRS (Comorbility Index) IADL/ADL (Instrumental Activities Daily Living/Activities Daily Living). Patients characteristics -159 pts -Total Median Age: 66 yrs (range 38–86) -Median ECOG PS: 1 (range 0–2) -Elderly (&gt;70 yrs): 75. Pain Starting situation -Median starting VAS: 5.5 (range 3–9) -TIQ: depression 70 pts, cachexia 55 pts, dispnoea 40 pts -CIRS (Comorbidity index): comorbidity were present among 66 pts. TTS-Fentanyl starting dose: 25 mcg/h every 72 h (range 25–50 mcg) or oral morphine long acting 60–90 mg plus IROM 10 mg every 4–6 hours for breakthrough pain present in 38 pts Results: -Quickly pain VAS downloading during first two weeks of treatment (median VAS 1) -Analgesic doses were not significantly increased after two months and not exceeded WHO grade 2 -IROM rescue was similar to that observed for the overall population -TIQ, ADL and IADL were not influenced by therapy. Conclusions: High potency opioids (TTS-F or long acting morphine equipollent doses, plus Rescue-IROM) offers durable long term maintenance pain relief wild acceptable toxicity also in elderly people, is particularly useful for cancer pts with compliance problems and may be considered as first-line treatment for moderate/severe cancer pain. No significant financial relationships to disclose.
Abstract 17629: Myocardial Scar by Standard and Dual Energy Late Enhancement Computed Tomography: Comparison to Pathology in a Chronic Infarct Porcine Model
Authors: Wai-ee Thai, Bryan Wai, Teresa Cheng, Jonathan Beaudoin, Ryan Caulfield, Kevin Cordaro, Conor D Barrett, Stephan Danik, Quynh A Truong
Journal: Circulation (2012)

Background: Myocardial scar is a substrate for ventricular tachycardia (VT) and sudden cardiac death. Using a chronic myocardial infarction (MI) porcine model, we aimed to (1) quantitatively compar...
Abstract 72: Inhibition of Dynamin Related Protein 1 Mediated Mitochondrial Fission During Cardiac Arrest Is Cardioprotective and Associated with Therapeutic Hypothermia
Authors: Willard W Sharp, Yong Hu Fang, Mei Han, John Ryan, Erik Morrow, Hannah Zhang, Peter Toth, David Beiser, Stephen L Archer
Journal: Circulation (2012)

Introduction: Mitochondrial fission increases cellular reactive oxygen species (ROS) and apoptosis but its role in cardiac arrest (CA) is unknown. Dynamin related protein 1 (DRP1) enhances fission by translocating to the mitochondria and is regulated by its phosphorylation at Serine 616 (activating) and Serine 637 (inhibiting). We hypothesized that inhibiting fission and DRP1 during CA would be cardioprotective. We also tested whether therapeutic hypothermia (TH) inhibited fission and DRP1. Methods: Cardiomyocytes isolated from 1-2 day old C57BL6/J mice were infected with a modified baculovirus containing mitochondrial targeted green fluorescent protein and then exposed to simulated ischemia/reperfusion (IR) at 37C or 30C (TH) to assess mitochondrial morphology. Hearts from Sprague Dawley rats were exposed to 30 min of global IR at 37C ± 5 uM mitochondrial inhibitor of division 1 (Mdivi-1) or 30C (TH) in a Langendorff perfusion system. ROS was measured using MitoSOX tissue staining. Left ventricular end diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), DRP1 gene/protein expression, and mitochondrial morphology (electron microscopy) were assessed. Heart samples were also collected from C57BL/6 mice after an 8-min cardiac arrest induced by KCl. Results: IR increased cell death, mitochondrial fragmentation, ROS, and LVEDP (62±1 mm Hg vs 9±1 mmHg, n=5, p&lt;0.05) while decreasing LVDP (26±11 vs 77±8 mm Hg, p&lt;0.05) compared to perfusion only controls. In IR, DRP1 Serine 637 decreased two-fold (n=4, p&lt;0.05) while total DRP1 in mitochondrial protein fractions increased two fold (n=4, p&lt;.0001). TH and Mdivi-1 maintained mitochondrial morphology, decreased ROS, inhibited DRP1 Serine 637 dephosphorylation and mitochondrial translocation. TH and Mdivi-1 also maintained LVEDP (12±1 and 14±2 mm Hg, n=5) and LVDP (84±6 and 84±2 mm Hg, n=5) at levels similar to perfusion-only controls. Conclusions: IR is associated with increased mitochondrial fission, DRP1 activation, ROS generation, and contractile dysfunction in cellular and organ models of IR and in vivo CA. Inhibition of fission and DRP1 with Mdivi-1 and TH are cardioprotective. DRP1 may be a therapeutic target for patients suffering CA or undergoing cardiopulmonary bypass.
Oncology research using electronic medical record data.
Authors: E. V. Bernstam, J. R. Herskovic, P. Reeder, F. Meric-Bernstam
Journal: Journal of Clinical Oncology (2010)

e16501 Background: Clinical data stored in electronic medical records may be useful for oncology research. The first step for such research is to identify patients who have been diagnosed with malignancies within large clinical cohorts. Structured data (labels) are often collected for billing purposes. Thus, it is tempting to leverage billing data for research purposes. In contrast, clinical information is generally expressed as unstructured text (e.g., dictations). We determined the accuracy of using billing data and machine-learning based classifiers in identifying patients diagnosed with endometrial and breast malignancies. Methods: We manually created a gold standard of persons who have (cases) and have not (controls) been diagnosed with breast/endometrial malignancies. We then determined the recall (R, aka sensitivity) and precision (P, aka positive predictive value) of billing data and sequential minimal optimization support vector machine-based classifiers with polynomial kernels (SMO-SVM, a type of machine learning) and manual feature reduction at identifying cases within a dataset of approximately 230,000 persons. Results: The endometrial cancer gold standard contained 298 randomly selected records enriched for cases using text word searches (22 cases, 276 controls). ICD-9-CM (billing) diagnosis search yielded R=22.7% and P=88.3%. An SVO-SVM classifier identified endometrial neoplasia cases with R=59.1% and P=92.9%. The breast cancer gold standard contained 111 records selected using keyword search (for “breast cancer”). Of 111 records, there were 44 breast cancer cases and 67 controls (keyword search P=39.6%). Searching the gold standard for the ICD-9-CM code for breast cancer (174.*) yielded R=52.2% and P=92.0%. An SMO-SVM classifier performed better (R=88.6%, P=88.6%). Conclusions: To reuse clinical data for oncology research, we cannot rely on billing data or simple text-word searches of clinical cohorts. Machine learning natural language processing techniques are more accurate than either billing data or text-word searches at identifying patients with malignancies within large data sets. Endometrial Breast Recall Precision Recall Precision Billing data 22.7% 88.3% 52.2% 92.0% SMO-SVM classifier 59.1% 92.9% 88.6% 88.6% No significant financial relationships to disclose.
Discordance in estrogen (ER) and progestin receptor (PR) status between primary metastatic breast cancer: a meta-analysis
Authors: A. Franco, N. Col, R. T. Chlebowski
Journal: Journal of Clinical Oncology (2004)

539 Background: Hormone therapy for metastatic breast cancer is commonly based on ER and PR status of the primary invasive breast cancer but studies comparing receptor status of primary and metastatic disease in the same patient are limited. Methods: A systematic literature review identified all reports comparing primary to metastatic ER and PR status (lymph nodes were not considered metastases). The relative risks (RR) of discordant values (as reported by criterion used in each publication) for ER and PR were calculated and combined using random-effects models. Results: Eight observational studies (with 17 to 200 cases) included ER and PR analyses in both primary and metastatic disease in 658 patients with (ER) and 418 patients with PR results.Reports were based on both dextran charcoal certrifugation and immunohistochemical assays. Conclusions: The meta-analysis identified a significant discordance in both ER and PR status between primary and metastatic breast cancer. Prospective studies to confirm these observations and determine their significance regarding hormone therapy response prediction are warranted. No significant financial relationships to disclose.
Clinical and molecular factors predictive of outcome with first-line sorafenib-based therapy in advanced renal carcinoma (RCC): An analysis of SWOG 0412
Authors: B. H. Goldman, P. N. Lara Jr., T. M. Beer, P. C. Mack, H. A. Drabkin, W. S. Holland, E. Crawford, C. W. Ryan
Journal: Journal of Clinical Oncology (2007)

5108 Background: SWOG 0412 was a phase II study of sorafenib and interferon-a2b (IFN) as first-line therapy for RCC. Response rate was 19%, median PFS was 7 months, and estimated median OS was 17 months (Ryan ASCO 2006). We investigated several potential risk factors among participants in SWOG 0412. Methods: Hemoglobin (hgb), LDH, number of metastatic sites, grade, gender, time from diagnosis to treatment, and MSKCC risk category were analyzed in 62 patients. Von Hipel-Lindau (VHL) gene status was determined by direct sequencing of DNA amplified by PCR methods from archival tumor. Immunohistochemistry for p-MAPK, p-p38, and p- AKT was performed to assess for enhanced signaling through the RAS-RAF and related pathways. Survival differences between subgroups were assessed by the logrank test. Results: Clinical factors associated with improved PFS and OS: favorable MSKCC risk category, time from diagnosis to treatment = 1 year, normal hgb. Fewer metastatic sites was also associated with improved OS but not PFS. No association was found with gender, grade, or LDH. VHL mutations were detected in 4 of 18 (22%) archival tumor specimens. P-p38 was overexpressed in all tumor specimens and p-MAPK was absent in all but one specimen. p-AKT was overexpressed (&gt;20% staining) in 18 (82%) of patients. In this limited subset analysis, none of these tumor markers was found to be significantly predictive of survival. Conclusions: Time from diagnosis, hgb, and MSKCC risk grouping were predictive of PFS and OS in patients receiving sorafenib + IFN. The median PFS of 18 months for favorable MSKCC risk patients is higher than the 8 months expected for first-line patients treated with IFN-based therapy, while the median PFS of 4 months for intermediate and poor risk patients is similar to the expected 5 months (Motzer JCO 2002). This observation is consistent with a hypothesis that the benefit of first-line sorafenib-based therapy may be most profound in or limited to favorable MSKCC risk patients. [Table: see text] [Table: see text]
Overexpression of chemokine receptor CXCR4 in cancer specimens following neoadjuvant chemotherapy predicts outcome in patients with locally advanced breast cancer (LABC)
Authors: N. T. Holm, K. Byrnes, M. MacDonald, F. Abreo, F. Ampil, M. Sanders, G. V. Burton, B. Li, Q. Chu
Journal: Journal of Clinical Oncology (2007)

10578 Background: Despite significant advances made in the treatment of locally advanced breast cancer (LABC) with neoadjuvant chemotherapy, a significant number of patients continue to die. A molecular predictor to identify those who are at an increased risk for relapse is sorely needed. CXCR4 is a chemokine receptor that has been linked to breast cancer invasion and metastasis. We postulate that CXCR4 overexpression levels in cancer specimens following neoadjuvant chemotherapy predict cancer outcome in patients with LABC. Methods: 54 patients with LABC were prospectively accrued and analyzed. All had neoadjuvant chemotherapy, followed by definitive surgical and adjuvant chemo-radiation therapy. Study homogeneity was maintained by standardized treatment, surveillance, and compliance protocols. A 1 cm 3 cancer from the surgical specimens of each patient was retrieved for analysis. CXCR4 levels were detected using Western blots and results were quantified against 1 μg of HeLa cells (positive controls). CXCR4 expression was defined as low (&lt;6.6 fold) or high (= 6.6 fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model. Results: With a median follow-up of 30 months, patients whose tumors had high CXCR4 overexpression (= 6.6 fold) had a statistically significantly higher incidence of recurrence (p= 0.0009) and cancer-related death (p= 0.0168) than those in the low CXCR4 group (&lt; 6.6 fold). After adjusting for tumor size, nodal status, ER, PR and HER-2 status, the relative risk for recurrence and death in the high CXCR4 group was 27.3-fold (p=0.001; 95% CI: 6.2 to 120.8) and 4.8-fold (p=0.0076; 95% CI: 1.5 to 15.0) higher than those in the low CXCR4 group, respectively. Conclusion: High CXCR4 overexpression in cancer specimens following neoadjuvant chemotherapy was highly predictive of cancer recurrence and cancer death in patients with LABC. No significant financial relationships to disclose.
Mortality trends in colorectal cancer (CRC) and influencing factors
Authors: V. Arrazubi, M. Majem, M. Navarro, L. Pareja, S. Biondo, J. Ribes, M. Cambray, M. Martínez-Villacampa, G. Soler, J. Germà
Journal: Journal of Clinical Oncology (2006)

13527 Background: A decline in overall cancer death rate was observed in the early 1990s after more than six decades of increase in cancer mortality. Effective prevention, screening and early detection as well as improved treatment strategies may be influencing factors. The aim of this study is to compare the overall survival of patients (pts) with CRC in two different years using our prospective regularly updated register database. Methods: Patients diagnosed of CRC during 1996 and 2000 were included in the study. To analyse the relation between variables the exact Fisher test was used. Survival curves were constructed according to the Kaplan-Meier method and compared by log rank analysis. Analyses were performed using the SPSS package. Results: 289 pts in 1996 and 380 in 2000 were included. Demographic data and tumour characteristics were similar in both groups. 42% of pts in 1996 and 56% in 2000 had received chemotherapy (ChT) (p&lt;0.05). In adjuvant setting, 41.8% of patients with stage II-III colon cancer received ChT in 1996 and 57.5% in 2000 (p=0.019). ChT schedules for advanced CRC included Oxaliplatin and Irinotecan in 23% of ChT in 1996 and in 68% in 2000 (p&lt;0.005). The number of palliative ChT lines was significantly higher in 2000 (p&lt;0.05). Radiotherapy was administered as part of rectal cancer therapy to 48% of pts 1996 and to 60% in 2000 (p=0.05). From those, preoperative radiotherapy was administered to 21% of pts in 1996 and to 66% in 2000 (p&lt;0.05). 4.1% of all pts were lost of follow up. With a median follow up of 104.5 months (m) for 1996 and 56.3 m for 2000, the 5-year overall survival (OS) was 45% and 61.6% respectively (p&lt;0.001). The 5-year disease free survival (DFS) of pts with radical surgery was 73% and 81% respectively (p=0.09). The median survival of pts with radical surgery that relapse during follow up was 13.4 m in 1996 and 17.6 m in 2000 (p&lt;0.04). There were statistical significant differences in OS between 1996 and 2000 in tumour site, stage II-III cancer and males, not in females. DFS for stages II-III was better in 2000, but no significant differences were observed. Conclusions: A positive CRC mortality trend was observed. The influencing factors were related with the use of ChT as an adjuvant treatment and the addition of new drugs in colon cancer therapies as well as preoperative radiotherapy for rectal cancer. No significant financial relationships to disclose.
Adverse effects and associated costs with second- and third-line therapies for non-small cell lung cancer
Authors: X. Ye, T. Darkow, C. Reyes
Journal: Journal of Clinical Oncology (2009)

e19009 Background: Chemotherapies used in the treatment of non-small cell lung cancer (NSCLC) are associated with a number of adverse effects (AEs), which may increase health care use and costs as patients receive treatment for these AEs.The objectives of this study were to compare occurrence of selected AEs and associated costs among patients receiving docetaxel (D), erlotinib (E), or pemetrexed (P) monotherapy as 2nd- or 3rd-line treatment of NSCLC in a retrospective claims database. Methods: Commercial enrollees with evidence of lung cancer were identified using ICD-9-CM diagnosis codes between 6/2004 and 12/2006. Pharmacy and medical claims were used to identify patients who received D, E, or P monotherapy as 2nd- or 3rd-line treatment. AEs were identified based upon diagnosis, procedure and prescription codes. Costs were compared between cohorts on a per month basis due to variable follow-up time. Results: Of 679 patients receiving 2nd-line treatment, 110 received D, 145 received E, and 116 received P. The most frequent AE was nausea/vomiting (N/V), which occurred in 90% of study subjects. Anemia (64%), neutropenia (35%), dyspnea (34%), and other respiratory AEs (35%) were also common. Compared with D, E was associated with significantly lower rates of neutropenia (3% vs. 46%; p &lt; 0.0001), N/V (60% vs. 100%; p &lt; 0.0001), and dehydration (10% vs. 20%; p = 0.03). P was also associated with higher rates of neutropenia and N/V than E (22% and 97%, respectively; p &lt; 0.0001), as well as having a higher occurrence of anemia (74% vs. 49%; p &lt; 0.0001). Costs to manage these AEs were also lower for E, with total costs related to AEs of $1494 for E, compared with $4386 for D (p = 0.004) and $6317 for P (p &lt; 0.0001). Of 335 patients receiving 3rd-line treatment, 33 received D, 79 received E, and 80 received P. At least one AE was experienced by all patients in the D and P cohorts, while 73 (92%) E patients experienced at least one AE (p = 0.10 vs. D; p = 0.01 vs. P). Costs to manage AEs in the 3rd-line setting were lower for E ($2765) than for P ($4718; p = 0.02), while costs for E and D ($3680) were not significantly different (p = 0.28). Conclusions: Overall, occurrence of AEs commonly associated with 2nd- and 3rd-line agents for NSCLC was less frequent and less costly among E users. [Table: see text]