tbuckley/cabot-search huggingface dataset:
Phase I study of sorafenib in children with refractory solid tumors: A Children's Oncology Group Phase I Consortium trial
Authors: B. C. Widemann, E. Fox, P. C. Adamson, S. Baruchel, A. Kim, A. M. Ingle, J. Glade Bender, D. Stempak, F. M. Balis, S. M. Blaney
Journal: Journal of Clinical Oncology (2009)

10012 Background: Sorafenib, an oral multitargeted kinase inhibitor, is indicated for treatment of adults with refractory renal cell or hepatocelluar carcinoma. We performed a phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of sorafenib in children with refractory solid tumors. Methods: Sorafenib was administered q12h for 28 consecutive day cycles. Cohorts of 3–12 patients were enrolled at 105, 130, 150, 200, and 250 mg/m 2 /dose dose levels. Results: 34 eligible pts [16M, median age 14.6 yrs, (range, 5–21)] with osteosarcoma (n = 8), rhabdomyosarcoma (n = 3), other sarcomas (n = 13), hepatoblastoma (n = 3), or other solid tumors (n = 7) received 1–22 cycles (median 2). Grade 3 dose-limiting toxicity (DLT) occurred in 4/6 pts at the starting dose (150 mg/m 2 ) and included hypertension (n = 1), rash/urticaria (n = 1), back pain (n = 1), thrombocytopenia (n = 1) and ALT/AST (n = 1). No DLTs were observed at 105 (n = 6) or 130 (n = 3) mg/m 2 , and the dose was re-escalated to 150 mg/m 2 with modified eligibility criteria (normal ALT) and revised guidelines for grading and management of hypertension. Gr 3 DLTs occurred in 1/6 pts (lipase) at 150 mg/m 2 and 2/2 pts (hyponatremia, hand-foot syndrome) at 250 mg/m 2 . At 200 mg/m 2 only 1/6 pts experienced DLT (gr 3 ALT). No objective responses were observed, but 2 pts had tumor shrinkage. Sorafenib AUC did not increase proportionally with dose - the mean AUC 0–24h was similar at 150 mg/m 2 (28±24 μg · h/mL, n = 9) and 200 mg/m 2 (28±17 μg · h/mL, n = 4). T max was prolonged and variable (10±11 h, n = 19). Plasma VEGFR (n = 13) decreased from 9.9±1.6 ng/mL at baseline to 8.3±1.7 ng/mL by d 28 (p &lt; 0.001). Conclusions: The MTD of sorafenib in children with solid tumors is 200 mg/m 2 , similar to the adult recommended dose (400 mg). No significant financial relationships to disclose.
Inhibition Of Telomerase Is a Novel and Effective Therapy In MLL-Rearranged Acute Myeloid Leukemia (AML)
Authors: Claudia Bruedigam, Frederik Otzen Bagger, Catherine Paine Kuhn, Therese Vu, Rebecca Austin, Florian H Heidel, Lars Bullinger, Geoff R Hill, Scott A. Armstrong, David A. Williams, Steven W Lane
Journal: Blood (2013)
Clinical stages I and II Hodgkin's disease: a specifically tailored therapy according to prognostic factors.
Authors: P Carde, J M Burgers, M Henry-Amar, M Hayat, W Sizoo, E Van der Schueren, M Monconduit, E M Noordijk, J Lustman-Marechal, A Tanguy
Journal: Journal of Clinical Oncology (1988)

The H5 program in clinical stage (CS) I to II supradiaphragmatic Hodgkin's disease (HD) was tailored to prognostic factors identified in former European Organization for the Research and Treatment of Cancer (EORTC) studies. Among the 494 adult patients included in the study, the 237 patients belonging to the favorable group (H5F) underwent a staging laparotomy (Sx) in order to select the patients who could be treated with limited radiotherapy (RT) only. Thus, 198 patients (84%) with negative laparotomy were treated with RT alone and randomized to either mantle irradiation (M) or extended field mantle plus para-aortic (M + PA) irradiation. Complete remission (CR) was achieved in 99% of the patients. There was no difference in the 6-year relapse-free survival (RFS) rate (74% and 72%, respectively) or survival rate (96% and 89%). Therefore, Sx helped to define those patients who could be treated with M alone in contrast to those who required more aggressive therapy. The 39 patients with positive laparotomy were treated as the unfavorable group (H5U) from onset and randomized to either total/subtotal nodal irradiation (TNI/STNI) or a sandwiched mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) X 3, M irradiation, MOPP X 3 protocol (3M). Although the RFS rate was higher in the 3M arm (100% v 53%; P = .002), the 6-year survival was not significantly different between the two arms (overall, 92%). In the 257 patients with initial unfavorable disease, the Sx was avoided. They were randomized to either TNI/STNI or 3M. In complete responders (96%), the 6-year RFS was 91% in the 3M arm and 77% in the TNI/STNI arm (P = .02). The pattern of failure differed in the two arms: the inverted Y and spleen irradiation controlled occult infradiaphragmatic disease better than MOPP; conversely, less patients begun on MOPP recurred in the involved mantle areas. The difference in 6-year actuarial total survival (TS) (89% and 82%; P = .05 in favor of the 3M arm) was not retrieved after exclusion of the unrelated deaths from the analysis. The two arms produced similar TS in patients under 40 years of age. TNI retains interest, especially in young men wishing to preserve fertility. The overall result shows that when treatment is tailored to initial prognostic factors, excellent results can be obtained in all patient subgroups at minimal morbidity and toxic cost.
Predicting early treatment response of advanced stage non-small cell lung cell to erlotinib by molecular imaging with <sup>11</sup>c-PD153035 PET/CT.
Authors: X. Meng, J. m. Yu, L. Ma, X. Sun, G. Yang, S. q. Zhao
Journal: Journal of Clinical Oncology (2010)

e13555 Background: To determine whether 11C-PD153035 PET/CT imaging was early predictive of the outcome of patients with advanced stage NSCLC who were treated with gefitinib or erlotinib. Methods: Nineteenpatients with pathologically proved advanced stage NSCLC were enrolled. A baseline 11C-PD153035 PET/CT was performed within 1 week before the initiation of treatment, and follow-up 11C-PD153035 PET/CT was performed at 4 weeks after start of treatment with assessment of maximum standardized uptake values (SUVmax) for correlation with response. Treatment response was also expressed as CT results on the basis of traditional response evaluation criteria in solid tumors (RECIST). Patients were followed for survival until death. Results: All patients were registered for this study between July 2007 and January 2009. All of them underwent baseline 11C-PD153035 PETCT scan and five patients did not complete the follow-up PET/CT. Receiver operating characteristic (ROC) curve analysis was performed to separated responders from those with PD. The area under the curve was 0.89 ± 0.07, with a sensitivity of 70.9% and a specificity of 85.7%. The baseline SUVmax was 2.8 that served as the optimal threshold for early treatment response. Tumor responders (PR+SD) had a higher baseline SUVmax than non-responders (PD) (p=0.004). However, there was no significant difference between baseline and follow-up SUVmax among 14 patients and 11C-PD153035 uptake changes between non-responder and responder groups (p=0.49, p=0.08, respectively). 12 patients had died and overall 6-month survival was 78.9%. Using the cutoff values, the baseline 11C- PD153035 uptake was significant predictors of patients' survival (p=0.016). Likewise, SUVmax at 4 weeks was weakly significant for overall survival (p=0.049). Conclusions: Our data indicated that 11C-PD153035 PET/CT before therapy may play a vital role for identification of patients that could be suitable for EGFR targeted therapies. Thus, it offers opportunities to individualize and optimize target therapy for NSCLC patients. No significant financial relationships to disclose.
Interim efficacy analysis of the French Intergroup R98 trial comparing 5FU-leucovorin alone or with irinotecan (CPT-11) in resected stages II-III rectal cancers
Authors: P. Piedbois, M. Ychou, A. Zawadi, J. Douillard, V. Guérin-Meyer, T. André, O. Dupuis, P. Rougier, R. Faroux, E. Quinaux
Journal: Journal of Clinical Oncology (2009)

4015 Background: The R98 trial tests the hypothesis that irinotecan (CPT-11) combined with 5FU/LV is superior to 5FU/LV alone to prevent recurrence or death in resected stages II-III rectal cancers. Methods: 600 pts were planned to be randomized between 5FU/LV (control arm) or 5FU/LV + CPT-11. Recruitment was slow, with only 357 pts included in the study between 03/1999 and 12/2005 (178 in control arm and 179 in CPT-11) at which time the IDMC recommended closure of accrual. The primary endpoint was disease free survival (DFS), relevant events being death (whatever its cause), local or distant recurrence, and any new primary cancer. The trial was stratified by choice of control arm: either a Mayo-Clinic regimen (A: LV 20 mg/m 2 , 5FU 425 mg/m 2 bolus days 1–5, repeated at d29, d57, d92, d127 and d162) or a LV5FU2 regimen (A’: LV 200 mg/m 2 over 2-hour, 5FU 400 mg/m 2 bolus and 600 mg/m 2 22-hour infusion, d1–2, q2w for 12 cycles), depending on centre decision. The experimental arm (B) consisted of LV5FU2 + CPT-11 180 mg/m 2 d1 of every cycle. Results: Safety analysis was reported last year (P. Piedbois et al. Proc. ASCO 2008). We present here a first interim analysis of efficacy on half the numbers of events planned per protocol. Median follow-up is 55 months. Pretreatment characteristics were well balanced between the groups; median age 62 years, stage II in 32% of pts. 68% of pts received preoperative RT, and 80% had sphincter conservation. There was a trend in favor of 5FU/LV + CPT-11 in terms of DFS (77 vs 62 events in control and CPT-11 arms, hazard ratio=0.75, p=0.089) with similar effect in the Mayo-Clinic stratum (31 vs 25 events, hazard ratio=0.77) and in the LV5FU2 stratum (46 vs 37 events, hazard ratio=0.74). Conclusions: This interim efficacy analysis shows a trend in favor of 5FU/LV + CPT-11. If performed when at least 220 events are observed (projected in 2010), the next efficacy analysis would have a conditional power of about 60% to detect a true benefit of 5FU/LV + CPT-11 if the treatment effect remained the same as observed today. Study supported by Pfizer, France. [Table: see text]
Insulin-like growth factor-1 receptor/epidermal growth factor receptor (EGFR) heterodimerization and resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer
Authors: F. Morgillo, W. K. Hong, H. Lee
Journal: Journal of Clinical Oncology (2006)

13032 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used to treat lung cancers, but resistance to these agents has been observed. This study was designed to investigate whether the insulin-like growth factor (IGF)-mediated signaling pathway induces resistance to the EGFR TKIs in lung cancer. Methods: The antitumor activities and action mechanisms of EGFR inhibitors (erlotinib, gefinitib, cetuximab), single or in combination with IGF-IR inhibitors, were assessed in vitro in a subset of non-small-cell lung cancer (NSCLC) cell lines by the MTT assay, flow cytometry-based TUNEL assay, soft agar, confocal microscopy, metabolic labeling, coimmunoprecipitation, and northern and western blot analyses, and in vivo in animal models. Correlation of EGFR and IGF-1R expression was assessed using lung tissues from patients with NSCLC. Results: EGFR TKI inhibited the proliferation and anchorage-dependent and -independent colony-forming ability of NSCLC cells, which induced apoptosis, only when IGF-1R signaling was blocked. Treatment with EGFR TKIs, but not with the EGFR antibody, induced EGFR:IGF-1R heterodimerization on cell surface and activation of the IGF-1R, resulting in the stimulation of PI3K/Akt/ mTOR pathway, promoting the de novo protein biosynthesis of survivin and EGFR, resulting in the survival of NSCLC cells. When IGF-IR and mTOR were blocked, treatment of EGFR-TKIs induced apoptosis in NSCLC cells, resulting in suppression of the NSCLC tumor growth. When we tested the expression of IGF-R and EGFR in human lung tissue, 9/14 tumor samples exhibited increased expression of EGFR and 7/9 samples showed a correlative increases in IGF-IR protein levels compared to their paired normal counterparts. Conclusions: These findings suggest that simultaneous targeting of EGFR and IGF-1R signaling pathways might be an effective therapeutic strategy against NSCLC. No significant financial relationships to disclose.
Abstract 13202: IGF-1 Prevents High Glucose Induced Cell Cycle Arrest in Cardiomyocyte via Catenin Pathway
Authors: Xi-Yong Yu, Yong-Jian Geng, He-Ping Lei, Zhi-Xin Shan, Qiu-Xiong Lin, Jenny Song, Yangxin Li
Journal: Circulation (2012)

Background: High glucose(HG)-induced cell cycle arrest of cardiomyocytes is considered to be the main cause of the development of cardiomyopathy in patients with diabetes. Insulin-like growth facto...
Haploinsufficiency of CDK4 prevents hepatocarcinogenesis in mice deficient in ELF, a mediator of TGF-beta signaling
Authors: M. J. Pishvaian, T. M. Blake, K. Kitisin, S. S. Kim, A. Kang, A. Rashid, Y. Tang, B. Mishra, E. P. Reddy, L. Mishra
Journal: Journal of Clinical Oncology (2007)

10608 Background: The transforming growth factor-β (TGF-β) has a dual role in cancer, but in the prevention of tumorigenesis, TGF-β signaling inhibits cell cycle progression through an increase in cell cycle inhibitors and decrease in cell cycle activators. The adaptor protein embryonic liver fodrin (ELF) is crucial for normal TGF-β signaling. ELF facilitates the association and nuclear translocation of the TGF-β signaling proteins, Smad3 and Smad4. We have demonstrated that elf± mice develop hepatocellular cancers (HCC) spontaneously within 12 months. We have also shown that most human HCCs demonstrate a decreased expression of ELF. Our goal was to assess the interaction between ELF and cyclin dependent kinase 4 (CDK4), which is overexpressed in most human cancers. Methods: We compared the expression of CDK4 and ELF by immunohistochemistry and analyzed the interaction between CDK4 and ELF, in vitro by immunoprecitpitation and western blot. Finally, we assessed the development of HCC in intercrossed elf± and CDK4+/neo mice. Results: CDK4 and ELF expression are inversely correlated in HCCs from elf± mice. Furthermore, ELF interacts with CDK4 by forming a complex that includes Smad3 in COS-7 and HepG2 cells. ELF is phosphorylated upon overexpression of CDK4, revealing a possible mechanism by which CDK4 may inhibit ELF-dependent TGF-β signaling. To further assess whether the development of HCC in elf± mice is dependent upon CDK4 expression, we have intercrossed elf± and CDK4+/neo mice. At 12 months, only 17% of the elf±/CDK4+/neo mice developed HCC, compared to 40% of our historical control elf± mice. This initial data strongly suggests that haploinsufficiency of CDK4 can prevent the HCCs seen in elf± mice, and provides the genetic foundation for further exploring the benefits of specific inhibitors of CDK4 in the treatment of HCC. Conclusions: These results demonstrate the molecular interactions between ELF and CDK4, and suggest a mechanism by which CDK4 may render cells unresponsive to the growth inhibitory effects of TGF-β signaling. Furthermore, haploinsufficiency of CDK4 prevents the formation of HCC, and thus targeted-inhibition of CDK4 activity may be a logical treatment for HCC in humans. No significant financial relationships to disclose.
Gemcitabine and paclitaxel chemotherapy effective for good risk advanced urothelial malignancies
Authors: S. Srinivas, A. E. Guardino
Journal: Journal of Clinical Oncology (2004)

4675 Background: The prognosis for patients with progressive or recurrent invasive bladder cancer is generally poor. Best responses are seen when patients are treated with a cisplatin based combination chemotherapy. Unfortunately, poor renal function and performance status precludes use of cisplatin in all patients. Identifying those patients who may benefit from a non-platinum combination is important. Poor Performance status and presence of visceral metastases identifies patients who are at a higher risk of relapse and lower survival.Methods: Patients with histological proven metastatic bladder cancer, who have normal organ function and be able to give informed consent, were eligible. Patients received chemotherapy in the outpatient clinic with paclitaxel at110 mg/m2, q weekly day 1 and day 15 and gemcitabine 1000mg/m2 on day 1, and 15 of a 28-day cycle. Patients were evaluated after 2 cycles of therapy with CT scans and bone scans. Response and survival were evaluated in the low risk and intermediate/high risk group.Results: Eleven patients (65%) had an objective response rate. Complete responses were seen in 17% of patients. The median duration of response was 5 months and the toxicity was mild. The median survival was 7.5 months. Grade 3/4 hematological toxicities included fever and neutropenia (9%) and anemia requiring blood transfusions (18%). The most common nonhematologic toxicity was fatigue (36%), anorexia (27%), rash, paraesthesia and myalgias (18%. All patients with low risk disease had a response compared to 27% in intermediate/high risk group (P=0.001) Conclusions:The combination of paclitaxel and gemcitabine given in a q 2 week regimen is very well tolerated and has significant activity in good risk patients with metastatic transitional cell carcinoma of the bladder and disease. Cisplatin based chemotherapy is essential for patients with visceral metastases or impaired performance status. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly
Endoscopic response evaluation of gastric primary lesion for chemotherapy compared to CT in advanced gastric cancer.
Authors: Keisho Chin, Yorimasa Yamamoto, Junko Fujisaki, Mariko Ogura, Eiji Shinozaki, Mitsukuni Suenaga, Nobuyuki Mizunuma
Journal: Journal of Clinical Oncology (2015)

50 Background: Significance of evaluation of gastric primary lesion with endoscopy remains unclear in chemotherapy (CTx) for advanced gastric cancer (AGC). Endoscopic evaluation is not necessary in RECIST. Methods: We compare the response of chemotherapy using RECIST by CT with or without upper GI endoscopy in AGC cases retrospectively. Among 175 cases of unresectable AGC treated by CTx in our institution between 2004 and 2008, we reviewed 141 evaluations in 74 cases which were examined by both endoscopy and CT within 2 weeks before and after CTx. Results: Patient backgrounds: Gender; M47/F27, Age; median 59(24-75), PS; 0or1=71/2=3, histological type; intestinal28/diffuse46, metastatic site; LN47/liver26/peritoneum29, CT per case; median number 4.5/ median interval 64.5days, endoscopy per case; median number 2/ median interval 91.3days. Response evaluation for gastric primary lesion between CT and endoscopy was compared in 141 examinations. Identical response 123(87.2%); both non-CR/non-PD 101/ both PD 22, not identical response 10(7.1%); endoscopy PD /CT non-CR/non-PD 10, not detected by CT; 8(5.7%). All of the cases of not identical response between CT and endoscopy were PD in endoscopy whereas non-CR/non-PD in CT. The overall response evaluation with or without endoscopy was concord in 133 evaluations (94.3%). Conclusions: It is almost appropriate that response evaluation of chemotherapy in AGC is mainly performed by CT without endoscopy to primary gastric lesion.
Favorable genetic polymorphisms predictive of clinical outcome of chemoradiotherapy for stage II/III esophageal squamous cell carcinoma in Japanese
Authors: T. Okuno, T. Tamura, M. Yamamori, N. Chayahara, I. Miki, D. Shirasaka, T. Nakamura, M. Kasuga, T. Azuma, T. Sakaeda
Journal: Journal of Clinical Oncology (2007)

15088 Background: A 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT) was proposed for esophageal cancer patients. Currently, there is an urgent need to establish a methodology to decide which is preferable for a patient, i.e., surgical treatment or CRT, especially for Stage II to III tumors defined as resectable. This study was performed to find the genetic factors predictive of clinical outcome to a 5-FU/ CDDP-based CRT in Japanese patients with locally advanced esophageal squamous cell carcinoma (ESCC). Methods: Thirty-one patients with Stage I-IVa ESCC (I/II/III/IVa = 7/7/14/3) were enrolled in this study. One course of treatment consisted of protracted venous infusions of 5-FU (400 mg/m 2 /24 h for day 1–5 and 8–12), CDDP (40 mg/m 2 /3 h on day 1 and 8) and radiation (2 Gy/day on day 1–5, 8–12 and 15–19), and a 2 nd course was successively repeated after a 2-week interval. A total of 8 measurements of the plasma concentration of 5-FU were made using high performance liquid chromatography. Genetic polymorphisms examined herein included those in the genes coding thymidylate synthase (TS), glutathione S-transferase P1 (GSTP1) and multi-drug resistant transporter MDR1/P-glycoprotein. Results: The complete response rate depended on Stage (p = 0.001), but the analysis was not sufficiently powered to reach a level of statistical significance for the 2-year survival rate (p = 0.061). For Stage II/III patients, to have 2 or 3 polymorphisms of 3R/3R of 5’-TSER, a 6bp of 3’-TSUTR, and GSTP1-Leu105Val resulted in an extensively longer survival (p =0.0197), although no difference was found between 2 groups, with respect to the plasma concentrations of 5-FU and clinical or pathological characteristics. Conclusions: The genetic prognostic index may allow predictions of the clinical outcome of a 5- FU/CDDP-based CRT in Stage II/III ESCC patients. Now, we are analyzing the contribution of genetic polymorphisms of cytokines, including tumor necrosis factor a. No significant financial relationships to disclose.
Hepatic intra-arterial chemotherapy in patients with metastatic breast cancer
Authors: N. Fazio, M. Medici, M. Colleoni, A. Rocca, R. Torrisi, F. Orsi, P. Della Vigna, G. Bonomo, L. Monfardini, A. Goldhirsch
Journal: Journal of Clinical Oncology (2006)

10581 Background: Hepatic intra-arterial chemotherapy has been reported to produce higher response rate than systemic in patients (pts) with metastatic colorectal cancer. In breast cancer the liver is involved in up to 60% of cases and often conditions the prognosis. Nevertheless, only rare hepatic arterial infusion studies were published. Therefore, based on our previous experience in hepatic metastatic colorectal malignancies, we evaluated efficacy and toxicity of hepatic intra-arterial chemotherapy in pts with metastatic breast cancer. Methods: A three-day continuous arterial infusion (CAI) of fluorouracil 1000 mg/m 2 q 24 hrs, with cisplatin 10 mg/m 2 twice daily, and mitomycin-c 1 mg/m 2 twice daily, was performed through a percutaneous radiological temporary trans-subclavicular catheter. Pts with responsive disease received up to four cycles every six weeks. Pts still responding could carry on with cisplatin and fluorouracil, without mitomycin-c. Pts were hospitalized and the catheter was removed upon end of infusion. Results: From 9.2000 to 6.2005, 25 pts with progressive liver metastases from breast cancer were treated. Nine had more than 50% of liver involvement. Fifteen had also extra-hepatic metastases. All had received antracyclines and 22/25 taxanes. Pts had a median of five previous chemotherapy lines. Median time from diagnosis of liver metastases to first CAI was 33 months (range: 7–110). Sixty-four total courses were administered, with a median of 2 (range: 1–7) per pts. Epigastric pain was the main clinical toxicity (54%) and iatrogenic gastro-duodenal ulcer, the main complication (28%). No relevant catheter-related complications occurred. Fifteen partial responses (60%) and eight stable diseases (32%) were observed. Response duration was 5.4 months (range: 2 - 27), time to progression 5.1 months (range: 2.5–29+), and median overall survival 13 months (range: 3.5+–32+). Conclusions: Hepatic arterial infusion of chemotherapy in heavily pre-treated pts with metastatic breast cancer is feasible and effective. A specific evaluation of quality of life should be performed to verify a real clinical benefit. An earlier timing during course of liver disease, and a shift to radiological implanted arterial port (allowing out-patient treatment), will be investigated. No significant financial relationships to disclose.