tbuckley/cabot-search huggingface dataset:
Role of ATP citrate lyase (ACL) in lung cancer progression
Authors: Toshiro Migita, Tadahito Narita, Kimie Nomura, Erika Miyagi, Yuichi Ishikawa
Journal: Cancer Research (2008)

2731   It was shown that tumor cells accelate glycolysis and derive almost all their fatty acids from de novo synthesis. However, how dysregulated tumor metabolism contributes to tumor progression remains elusive. ATP citrate lyase (ACL) is a key enzyme of de novo fatty acid synthesis to generate cytosolic acetyl-CoA and oxaloacetate from citrate. The purpose of this study is to demonstrate the role of ACL in lung cancer progression and its regulatory mechanism. We have performed real-time RT-PCR, Western blotting, and immunohistochemistry with frozen or formalin-fixed tissue of surgically resected non-small cell lung cancer. Using human non-small cell lung cancer cell lines, we investigated whether the phosphatidylinositol-3 kinase (PI3K)-Akt signaling pathway is involved in the regulation of ACL expression. First, phosphorylated ACL expression was evaluated by immunohistochemistry in tissue microarray and we found that ACL was overexpressed in lung cancer compared to normal tissue. Importantly, phosphorylated ACL expression correlates with pathological tumor grade (well, 56%; moderate, 74%; poor, 83%) and poor prognosis in 160 patients with lung adenocarcinoma. Secondly, the introduction of constitutively active Akt into lung cancer cells resulted in the hyperphosphorylation of ACL, whereas the dominant negative Akt abolished the phosphorylation of ACL. LY294002, a PI3K inhibitor, decreased cell viability concomitant with the decrease of the both of phosphorylated ACL and Akt in lung cancer cell lines. ACL knockdown also resulted in the decrease in cell viability of A549 cells. These data suggest that ACL activation is involved in lung cancer survival or progression and is regulated by PI3K signaling pathway. ACL may be a new therapeutic target in lung cancer.
PK and PD of recombinant human IL-18 (rhIL-18) administered IV in repeated cycles to patients with solid tumors
Authors: K. M. Koch, J. R. Roman, D. Jaworski, P. Godillot, M. J. Robertson, J. M. Kirkwood, S. Lucas, B. Bell, M. M. Dar
Journal: Journal of Clinical Oncology (2005)

2535 Background: rhIL-18, a potent immunomodulatory cytokine, has demonstrated anti-tumor activity in a variety of preclinical models. Clinical safety and biological activity were examined in a previous study of rhIL-18 administered in a single cycle at IV doses ranging from 3 - 1000 mcg/kg/day for 5 days. The current study examined the effects of administering repeated cycles, and the resulting PK exposure and PD biomarker response data, which are described below. Methods: Three cohorts of 3 patients each were enrolled (6 with melanoma and 3 with metastatic renal cell carcinoma), and received 100, 500, or 1000 mcg/kg doses of rhIL-18 (SB485232) administered as 2h infusions daily for 5 consecutive days every 28 days in repeated cycles (up to 6). Assessments included tolerability, immunogenicity, anti-tumor activity, PK, and biomarkers of immunomodulatory activity. PK and PD measurements were made on Days 1 and 5 of Cycles 1 and 2. Plasma drug concentrations were measured by ELISA. Cytokine/protein biomarkers were measured by ELISA and custom cytokine multiplex biochips. Cell activation biomarkers were measured by flow cytometry. Results: Plasma concentrations of rhIL-18 increased with increasing dose, were comparable between cycles, and exhibited 3-fold accumulation over 5 days with a half-life of 39h. Induction of IFN-gamma, GM-CSF, TNF-alpha, IP-10, MIG, MCP-1, and IL-18 Binding Protein (BP) was observed. These responses were attenuated in the second cycle. Cytokine and chemokine responses were also attenuated within each cycle (Day 5 vs Day 1). Lymphopenia and expression of CD69 on CD4, CD8, and NK cells were maximal 6h after the first infusion at all doses in each cycle, with no apparent attenuation of response. Conclusions: These data suggest that rhIL-18 induces inflammatory cytokine production and cell-mediated immunological activation. The apparent attenuation of cytokine responses with repeated exposure may be due in part to the regulatory effect of BP. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline
TCT-752 Endovascular Therapy Versus Medical Therapy for Management of Acute Ischemic Stroke: Systematic Review and Meta-Analysis of Prospective Randomized Controlled Trials
Authors: Pedro A. Villablanca Spinetto, Afiachukwu Onuegbu, David Briceno, Gaurav Rao, Olufisayo Otusanya, Jose D. Tafur, Mohsin Salih, Divyanshu Mohananey, Mohammed Makkiya, Christopher White
Journal: Journal of the American College of Cardiology (2015)
Age is not a prognostic factor in Korean women with breast cancer treated with breast conservative surgery and radiotherapy
Authors: D. Choi, E. Kim, Y. Kim, M. Lee, H. Park
Journal: Journal of Clinical Oncology (2006)

10740 Background: The median age of the breast cancer at diagnosis in Korean women is 45 years and a quarter of the patients are at age 40 or younger. The purpose of this study was to analyze the prognostic factors including age for patients treated with breast conserving surgery and radiotherapy. Methods: Two hundred and eleven breast cancer patients were treated with breast conserving therapy at Soonchunhyang University Hospital, Seoul, Korea, between May 1991 and May 2003. The radiation dose to the whole breast was 50.4 Gy over 5 weeks and boost doses of 10–14 Gy administered to the tumor bed in the majority of the patients (180/211). Nodal radiotherapy was delivered in patients with 4 or more node metastasis. Adjuvant chemotherapy was performed in most of the patients with node metastasis or tumors larger than 1cm, or younger patients. One hundred and thirty four patients received CMF regimen, 14 patients treated with CEF regimen. The median and minimum follow-up periods were 58 and 30 months respectively. Results: The average age at the time of operation was 41.9 years (median 42 years, range 23–67 years), and the mean tumor size was 2.03 cm (median 1.80 cm). One hundred and forty seven patients (69.7%) had pathologically node negative disease and fifteen patients had 4 or more lymph node metastasis. Local, regional relapse and distant metastasis occurred in 7, 3 and 10 patients respectively. The 5 year disease free, loco-regional relapse free and overall survival rate were 89.5%, 93.4%, 95.6%, respectively. Three patients among the 31 patients who received 50.4Gy or incomplete radiotherapy to the breast experienced loco-regional relapse. Age (40 years or less versus more than 40 years old) was not a prognostic factor in univariate analysis. T stage (p = 0.027), lymph node metastasis (p &lt; 0.01) were significant factors for recurrences. By multivariate analysis, only lymph node status was a significant prognostic factor for treatment related failure. Conclusions: A breast conserving procedure is effective for patients with early stage breast cancer regardless of age in Korean women. Axillary lymph node status was the most important independent predictor for a recurrence, and more efficient treatment is required for these patients with lymph node metastasis. No significant financial relationships to disclose.
A phase II study of temsirolimus/sorafenib in patients with radioactive iodine (RAI)-refractory thyroid carcinoma.
Authors: Eric Jeffrey Sherman, Alan Loh Ho, Matthew G. Fury, Shrujal S. Baxi, Sofia Haque, Susan H. Korte, Stephanie Smith-Marrone, Han Xiao, Ronald A. Ghossein, James A. Fagin, David G. Pfister
Journal: Journal of Clinical Oncology (2012)

5514 Background: Sorafenib is an oral tyrosine kinase inhibitor of multiple targets, including RAF, VEGFR1, and VEGFR2. Published response rates with sorafenib in RAI refractory thyroid cancer have ranged from 11-23%. Temsirolimus is an intravenous inhibitor of mTOR; mutations in the PI3K/mTOR/AKT pathway occur late in thyroid cancer and may be associated with aggressive disease. Methods: The study was a single institution, phase II design. Primary objective was response rate. Eligible patients (pts) had progressive, RAI-refractory/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-medullary, thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Sorafenib was given at 200 mg orally twice a day and temsirolimus at 25 mg intravenously weekly. 38 patients were enrolled; 37 were eligible and 36 patients started treatment between 12/18/09 – 10/20/11. Data cutoff date is 1/19/12. Fourteen pts are still actively on study. Results: Of the 37 eligible pts, demographics: female-46%; median age-64 years (30-81); histology-papillary (23)/follicular (1)/Hürthle (5)/poorly differentiated (6)/anaplastic (2); prior systemic treatment (21); prior sorafenib (6). Grade 4-5 adverse events at least possibly related to drug: grade 5 – sudden death, NOS (1 pt): grade 4 – colonic perforation (1 pt). Evaluation of best response: partial (PR) (8, including 3 with anaplastic/poorly differentiated); stable disease (SD) (21); progression (1); inevaluable (7). The partial response rate was 38% in the cohort that previously did not receive any systemic treatment. There was no correlation of response to either BRAF (10) or RAS (5) mutational status. Median time on treatment is 203 days (range 14-638 days) at the cutoff date. For the 21 pts with SD, the maximum percentage shrinkage by RECIST criteria ranged from -2% to -35% (one patient with unconfirmed PR) with a median time on treatment of 203 days (range 39-503 days). Conclusions: The combination of sorafenib and temsirolimus shows promising results in a heavily pretreated population. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Pfizer, Inc.
Impact of T status and its concerns on NK cell counts in operable breast cancer patients before primary treatment: A cross sectional study
Authors: K. S. Gopinath, R. M. Raghavendra, M. Acree, R. Nalini, S. B. Srinath, B. S. Ajaikumar, S. Chandrashekara
Journal: Journal of Clinical Oncology (2008)

22218 Background: Both stress of a cancer diagnosis and cancer per se are known to affect immune responses (NK cell counts) prior to surgery. Breast cancer patients in India often relate the size of their tumor (T status) to an advanced disease. This cross- sectional study examined the association of tumor size and patients concerns regarding them with self reported anxiety and depression, and NK cell counts in Sixty -Nine stage II and III breast cancer patients prior to their primary treatment. Methods: Breast cancer patients were assessed for self report anxiety and depression using state scale of Spielberger's Inventory and Beck's depression inventory prior to their primary treatment. Morning fasting blood samples taken from each patient was used for enumeration of T lymphocyte subsets (NK cell counts), by flow cytometry. We used regression analysis, path analysis and tested mediation using Sobel's test. Results: The path coefficient from Tumor size to NK cell counts (−0.20) alone was strong. There were strong path coefficients from concerns regarding tumor size to NK cell counts (−0.55), anxiety state (0.42) and depression (0.38). There was a strong path coefficient from depression to NK cell counts (−0.33) and not from anxiety to NK cell counts (−0.12). There was a significant partial mediation effect of depression between concerns regarding tumor size and NK cell counts with the direct effect coefficient being −0.48 and indirect effect being 0.47 (Sobels z = −3.2, p = 0.001). Conclusions: Concerns regarding T status can exert its influence on immune outcomes through psycho-immune mechanisms mediated by depression in Indian breast cancer patients. Further studies should explore the racial and ethnic differences in concerns and their relationship to magnitude of psychologic distress and immune responses in breast cancer patients. No significant financial relationships to disclose.
Use of SUVmax to predict response to neoadjuvant chemoradiotherapy in patients with adenocarcinoma of the distal esophagus and GE Junction
Authors: N. P. Rizk, M. S. Bains, B. J. Park, R. M. Flores, R. J. Downey, K. Goodman, D. H. Ilson, V. W. Rusch
Journal: Journal of Clinical Oncology (2008)

4565 Background: Previously, we have shown that patients with surgically treated adenocarcinoma of the esophagus and GE- junction with an SUV-max of <4.3 on PET imaging experience a favorable overall survival. In this study, using the same SUV-max cutoff, we analyze the predictive value of SUVmax of the primary site of disease in patients with locally advanced disease (clinical stages IIa-IVa) treated with neoadjuvant chemoradiotherapy followed by surgery. Methods: We performed a retrospective analysis of a prospectively maintained database, selecting patients with adenocarcinoma of the esophagus and GE-junction (Siewert 1 & 2) who were imaged by PET scan prior to receiving neoadjuvant chemoradiotherapy and surgery. Data recorded included patient demographics, PET SUVmax, treatment details (chemotherapy, radiation), pathologic details (N status, pathologic complete response-PCR, estimated treatment response), and survival data. Comparison of categorical variables was done by chi square analysis, continuous variables by t-test, survival analysis by the Kaplan- Meier method, and comparisons of survival using the log rank test. The censoring date was 2/1/07. Results: 197 patients underwent treatment between 1/96 and 9/06. 28 had an SUVmax <4.3 (low SUV), and 169 had an SUVmax >4.3 (high SUV). The two groups were similar with regards to age, sex, radiation dosing, and chemotherapy type (p>0.05). Patients in the low SUV group showed evidence of reduced pathologic response to therapy, with a higher likelihood of being node positive, and a lower likelihood of a PCR, and a lower estimated treatment response (p<0.05). Survival of the low and high SUV groups was similar, however (p=0.59). Conclusions: Treatment with neoadjuvant chemoradiotherapy for locally advanced adenocarcinomas of the distal esophagus and GE-junction appears to benefit patients with a high SUVmax more than patients with a low SUVmax, suggesting a difference in tumor biology between these two groups. No significant financial relationships to disclose.
Palliative response measurement in a phase III study of patients with prostate cancer and painful bone metastases: Secondary analysis of NCIC-CTG PR6
Authors: S. K. Taylor, K. Ding, S. D. Ernst, C. Elliott, W. R. Parulekar
Journal: Journal of Clinical Oncology (2008)

9636 Background: In hormone-refractory prostate cancer (HRPC), clinical benefit can be measured using a composite palliative endpoint including pain intensity and analgesic use. This analysis examines the relationship between different measures of analgesic use and their correlation with palliative response and pain intensity. Methods: A secondary analysis was performed of a double-blind, placebo controlled, phase III trial examining the palliative response to mitoxantrone and prednisone with or without IV clodronate (Ernst DS, Tannock IF, Winquist EW, et al: J Clin Oncol 21:3335–3342, 2003). Using a daily analgesic diary and a 6 point pain intensity scale, 209 patients with HRPC and pain due to bone metastases recorded pain and analgesic scores (AS) at baseline and at each treatment visit. Palliative response was defined as a reduction from baseline in the PPI to 0 or by 2 points, or a reduction by 50% in the average daily AS over 2 visits, without an increase in either measure. In this analysis we measured: correlation between average daily AS and AS in the 24 hours prior to systemic therapy (24 hour AS); relationship between AS and PPI per cycle, correlation between palliative response based on average daily AS versus the 24 hour AS. Results: There was a strong correlation between the average AS and the 24-hour AS (correlation coefficient 0.77, p < 0.0001). Patients with high PPI scores had a higher AS (p < 0.0001).The association persisted when adjusted for baseline factors correlated to PPI (p < 0.0001). The correlation between palliative response based on average daily AS and 24-hour AS showed very close agreement (Kappa 0.89, 95% CI 0.83 - 0.96). Conclusions: AS over a 24 hour period prior to treatment appeared to correlate with daily average AS in HRPC patients and appears to be useful as a measure to determine the palliative response to systemic cancer therapy. No significant financial relationships to disclose.
Multiple subsequent neoplasms in the Childhood Cancer Survivor Study (CCSS) cohort.
Authors: G. T. Armstrong, W. Liu, S. Hammond, S. Bhatia, J. P. Neglia, M. Stovall, W. Leisenring, Y. Yasui, D. Srivatava, L. L. Robison
Journal: Journal of Clinical Oncology (2010)

9519 Background: Childhood cancer survivors demonstrate an increased incidence of subsequent neoplasms (SNs). Those surviving the first SN remain at risk to develop multiple SNs. As SNs are a common cause of late-morbidity and mortality, characterization of risk for multiple SNs is needed. Methods: Analysis included 14,358 ≥5 yr survivors of childhood cancer diagnosed 1970-86 (median age at follow-up 30.9 yrs, range 5.6-56.3; median follow-up 18.0 yrs, range 0-32.6). Among survivors with a subsequent neoplasm (SN1), the 15-yr cumulative incidence of second subsequent neoplasm (SN2) or subsequent malignant neoplasm (SMN) other than non-melanoma skin cancer (NMSC) was calculated with death as a competing risk. Hazard ratios (HR) were calculated from multivariable regression models that included age at diagnosis, age at SN1, treatment era, radiation therapy (RT) exposure, and family history of cancer. Results: 1383 (9.6%) survivors developed SN1, of whom 384 (27.8%) developed an SN2. Of those with SN2, 153 (39.8%) developed >2 SNs. Cumulative incidence of SN2 was 38.8% (95% CI 35.1-42.5) 15 yrs after SN1. Cumulative incidence of SN2 was highest in those with a primary diagnosis of Hodgkin lymphoma (50.3%, 44.1- 56.6), CNS malignancy (44.5%, 33.3-55.6), and osteosarcoma (40.9%, 21.5-60.4). Among those experiencing an SN1, multivariable analysis identified older age at SN1 (HR 2.21, p<0.0001) and RT for the initial cancer (HR 1.83, p=0.003) as independent risk factors for SN2. Cumulative incidence of SN2 among RT-exposed survivors was 41.3% (95% CI 37.2-45.4). For those RT-exposed with an SN1 of NMSC, the cumulative incidence of SMN (excluding NMSC) was 19.4% (95% CI 12.1-26.5). In SN1 survivors not exposed to RT for their initial cancer, the 15-yr cumulative incidence of SMN (excluding NMSC) was 18.6% (95% CI 10.6-26.5). Conclusions: Multiple SNs are common among aging survivors of childhood cancer who experience and survive an SN1. Exposure to RT and increased age at SN1 place survivors at significantly higher risk. SN1 of NMSC identifies a population at high risk for invasive SMN. Multiple SNs among non-RT exposed patients reflect a population of interest for genetic susceptibility to neoplasia. No significant financial relationships to disclose.
No treatment related mortality in patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) in Dutch Childhood Oncology Group protocols ALL-7 and ALL-8
Authors: D. M. Te Loo, S. S. de Graaf, W. A. Kamps, W. J. Tissing
Journal: Journal of Clinical Oncology (2008)

10004 Background: Children with DS have an approximately 12-fold increased risk of developing ALL compared to the general pediatric population. Outcome in patients with DS and ALL is inferior compared to non-DS patients. This may be due to an increased treatment related toxicity and mortality. The purpose of this study was to evaluate our experience with treatment related toxicity in DS children with ALL. Methods: We retrospectively analyzed the medical records of children with ALL who were enrolled on the virtually identical Dutch ALL-7 or ALL-8 protocols between 1988 and 1996. The same protocols were used for DS and non-DS patients, without a priori treatment modifications for DS patients. Results: Among 685 children with de novo ALL, 16 (2.3%) patients had DS. Three of these patients were not treated according to protocol because of physicians or parents’ choice and were excluded from this analysis. Mean age at diagnosis was 6.5 years (range 2.6 to 15.8 yrs). One patient died during induction treatment as a consequence of an acute cardiac event, which did not appear to be chemotherapy related. Serious toxicity, requiring treatment modification according to protocol guidelines, occurred in 8 of the remaining 12 patients (66.7%). None of the patients died as consequence of treatment related toxicity. Four patients had a relapse, in one case 18 yrs after the initial diagnosis. Event free survival (EFS) after 10 yrs was 69% in DS patients compared to 72.6 % in non-DS patients. Relapse rather than toxic mortality was the first event in patients with DS treated according to Dutch ALL-7 and ALL- 8 protocols. Conclusions: These data do not support an a priori reduction of ALL treatment in children with DS. Dose modification according to traditional guidelines appears adequate. The balance between efficacy and toxicity may be different when more intensive treatment regimens are used in children with DS. No significant financial relationships to disclose.
Adjuvant CAF versus AC followed by paclitaxel for operable breast cancer with 4 or more involved axillary lymph nodes: Retrospective analysis
Authors: J. Ahn, S. Kim, B. Son, S. Ahn, W. Kim
Journal: Journal of Clinical Oncology (2006)

10610 Background: Recently, adjuvant AC followed by paclitaxel has improved disease-free survival (DFS) or overall survival (OS) of node-positive breast cancer. Although adjuvant TAC, as compared with FAC, significantly improves DFS and OS rate in node-positive breast cancer, AC → T has not been yet compared with FAC. Since 2001, we discussed the options of adjuvant CAF versus AC → T with patients who had 4 or more positive axillary nodes. We evaluated the efficacies of adjuvant CAF and AC→T, retrospectively. Methods: Between September 2001 and July 2004, a total of 1,394 patients underwent surgery and received adjuvant chemotherapy. Among them, 253 (18.1%) patients had 4 or more than axillary nodes and received either six cycles of CAF (n = 116) or 4 cycles of AC → T) (n = 137). The medical records and pathologic data of these patients were reviewed, retrospectively. Results: Median age of all patients was 46 years (range, 22∼76 years). The two groups were well balanced in terms of demographic and tumor characteristics. With a median follow-up period of 24 months (range, 6∼90 months), 49 (19.4%) patients had disease recurrence including 27 (23.3%) in CAF group and 22 (16.1%) in AC→ T group (p = 0.155). The 3 year-DFS rate was 68.3% in CAF group and 71.1% in AC → T group (p = 0.9366), and the estimated 3-year OS rate was 90.3% and 92.3%, respectively (p = 0.8237). There was no significant difference in 3-year DFS rate according to hormone-receptor status. Febrile neutropenia occurred in 11 (9.6%) patients in CAF group and 7 (5.1%) patients in AC → T group (p = 0.222). Conclusion: Our data suggest that there is no significant difference in DFS or OS rates between six cycles of CAF and 4 cycles of AC followed by 4 cycles of paclitaxel as adjuvant chemotherapy in patients with 4 or more than involved axillary nodes. However, long-term follow-up period and prospective studies are needed to define better regimen. No significant financial relationships to disclose.