tbuckley/cabot-search huggingface dataset:
Phase I/II study to evaluate the optimum dose of pegylated-interferon (PEG INTRON) in patients with platinum-resistant ovarian cancer
Authors: P. T. Soliman, J. B. Gano, C. F. Levenback, J. Kavanagh, D. M. Gershenson, J. K. Wolf
Journal: Journal of Clinical Oncology (2007)

16010 Background: Intraperitoneal interferon therapy has been shown to have response rates as high as 45% in patients with recurrent ovarian cancer. Continued exposure has also been associated with the effectiveness of interferon treatment. The purpose of this study was evaluate the optimum dose and toxicity profile of PEG INTRON given subcutaneously (SC) on a weekly schedule to women with platinum-resistant ovarian cancer. Methods: Women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer were eligible. Those whose tumors tested positive for IL-8, bFGF, or VEGF were randomized to three PEG INTRON treatment doses, 1.0, 1.25, or 1.5 micrograms/kg/wk SC for a total of 4 weekly injections per cycle. Re-evaluation for tumor response by imaging, physical exam and CA-125 was performed every 2 -3 cycles (8 - 12 weeks). Up to 12 cycles of treatment was allowed. Treatment was continued until progression of disease or unacceptable toxicity. Results: Thirty patients were enrolled, only 17 received treatment; 11 tested negative, 1 refused testing, 1 tested positive but refused treatment. Median age was 56 years (35–73). Of those treated, 94% (16/17) had a performance status of 0. All were heavily pretreated (3–8 prior chemo regimens). One patient received 9 cycles (1.25 micrograms/kg, total dose = 80 mcg) with stable disease. In the remaining 16 patients, 14 (75%) were taken off study due to disease progression; 3 after completing 2 treatment cycles and 11 after &lt;2 treatment cycles. Four patients (24%) discontinued treatment because of toxicity. Two episodes of grade 4 fatigue were reported. Other grade 3 toxicities included visual changes, pain, anemia, neutropenia, depression, myalgia, and nausea/vomiting. Conclusions: There were no clinical responses to weekly PEG INTRON in this patient population. In addition, the regimen was difficult to tolerate. Further investigation into the dose and delivery of PEG INTRON is needed to determine the safety and efficacy of interferon treatment in patients with reuccurent ovarian cancer. No significant financial relationships to disclose.
Expression profiling of microdissected papillary serous ovarian epithelial cancers identifies genes describing the unique phenotypes of borderline and malignant tumors
Authors: H. Donninger, T. Bonome, J.-Y. Li, D.-C. Park, M. Radonovich, C. Pise-Masison, J. Brady, J. C. Barrett, S. C. Mok, M. J. Birrer
Journal: Journal of Clinical Oncology (2005)

5029 Background: To delineate the genotypic relationships among borderline and malignant epithelial ovarian tumors of varying grade and stage, and describe the differentially expressed genes that define these associations. Methods: A set of microdissected papillary serous ovarian epithelial cancers comprising 20 borderline, 34 late stage (31 high grade & 3 low grade), and 14 early stage (11 high grade & 3 low grade) tumors with confirmed RNA integrity were selected for two-round amplification and analyzed on Affymetrix U133 Plus 2.0 microarrays (47K transcripts). Ten normal ovarian epithelial brushings were also assessed to identify differentially expressed genes associated with each tumor type. Results: Unsupervised clustering analysis of 14,200 probe sets displaying the greatest variance revealed a clear separation between clusters containing borderline, late stage high grade, and normal ovarian brushings. Early stage high grade tumors associated most closely with late stage high grade cancers. For borderline tumors, a single cluster was observed. The majority of low grade tumors regardless of stage clustered with the borderline cancers. Comparing normal ovarian brushings to borderline and late stage high grade expression profiles revealed that 30% of the differentially expressed genes (p ≤ .001) in borderline tumors were unique. Only 14% of the differentially expressed genes (p ≤ .001) in early stage high grade specimens were not found in late stage high grade cancers, when compared to normal ovarian brushings. Conclusions: Borderline and late stage high grade tumors grouped seperately agreeing with the phenotype attributed to each cancer. Low grade malignant tumors grouped with borderline cancers implying that low grade tumors commence with gene expression patterns similar to borderline cancers and proceed to high grade lesions. The association of early stage and late stage high grade tumors suggests that early stage tumors possess a phenotype that approximates late stage cancers. Genes implicated in adhesion, cell cycle, and motility account for the phenotypic differences between borderline and high grade malignant cancers. No significant financial relationships to disclose.
Goserelin versus CMF as adjuvant therapy for node-negative, hormone receptor-positive breast cancer in premenopausal patients. The GABG IV-A-93 trial
Authors: G. Von Minckwitz, E. Graf, M. Geberth, W. Eiermann, W. Jonat, B. Conrad, K. Brunnert, B. Gerber, H. H. Zippel, M. Kaufmann
Journal: Journal of Clinical Oncology (2004)

534 Background: Increasing evidence supports the use of GnRH analogues as adjuvant treatment in hormone sensitive, premenopausal breast cancer. However, only limited information is available in patients with node-negative disease. Methods: We randomised 771 patients to either goserelin (3.6 mg every 28 days for 2 years; n=393) or 3 cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy (500 mg/m2, 40 mg/m2 and 600 mg/m2, days 1,8 q 29; n=378). Patients' characteristics were well balanced with 26% of the patients being 40 years or younger, 64% having a tumor size below 21mm, 79% having grade 1 or 2 tumors, and 72% receiving breast conserving surgery. 123 events were observed during a median follow up of 4.9 years. Results: The first event of failure (goserelin vs CMF) was an isolated locoregional recurrence (20 vs 18), a distant failure (35 vs 46), and death without recurrence (2 vs 2). Five-year event-free survival rates were 84.4% (95% confidence interval (CI): 80.4% to 88.5%) and 81.0% (95% CI: 76.3% to 85.7%) in the goserelin and in the CMF group, respectively. The estimated hazard ratio (intention-to-treat analysis) of goserelin vs CMF was 0.81 (95% CI: 0.56 to 1.17, P=0.24). Conclusions: Although the results of the trial are still based on relatively few observed events, they add important information to the current attempts of defining the role of medical ovarian ablation with goserelin in premenopausal patients with node-negative, hormonsensitive breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca Germany
Radical retropubic prostatectomy in patients with high risk prostate cancer
Authors: E. Özgür, C. Ohlmann, D. Pfister, U. Engelmann, A. Heidenreich
Journal: Journal of Clinical Oncology (2007)

15549 Background: Patients with high risk prostate cancer (Gleason score 8 to 10, cT3 disease or PSA &gt; 20 ng/ml) are at high for cancer recurrence after local therapy such as radical retropubic prostatectomy (RPE) or radiation therapy. We examined the long-term oncological and functional outcome of patients with high risk prostate cancer (PCA) on biopsy. We further investigated prognostic risk factors associated with good prognosis. Methods: We retrospectively analysed the outcome of 304 patients with high risk PCA. All patients received a questionnaire to obtain information with regard to continence, potency, PSA recurrence, PSA mortality and quality of life (EORTC QLQ-30). 237 (78%) patients returned the questionnaires. Results: The mean follow-up is 94 (15–146) months, mean age of all patients is 62.6 (32–78) years. 231 (76%) patients had PSA serum levels of 20–50ng/ml, 62 (23.4%) and 39 (12.8%) had PSA serum levels of 50–100 ng/ml and &gt; 100 ng/ml, resp., a pT3 PCA was identified in 192 (63.1%) patients, pTxpN1 disease was found in 84 (27.6%) patients. Overall survival rate is 81.9%, 86.2% and 85.3% in patients with PSA &gt; 20ng/ml, pT3 or pTxpN1 PCA, resp.; cancer specific survival was 85%, 89.5% and 88.7% in PSA &gt; 20ng/ml, pT3 and pTxpN1 PCA, resp. PSA recurrence rate is 28%; the most significant parameters associated with survival are biopsy Gleason score (p = 0.02), pN1 status (p = 0.001), perineural invasion (p = 0.001), seminal vesicle invasion (p &lt; 0.0005). There was no significant difference with regard to pre- and postoperative quality of life. Continence was good with no pads in 85%, 1- 2 pads/day and = 3 pads/day in 10.6% and 4.4%, resp. Conclusions: RPE can be safely performed in patients with high risk PCA resulting in a high cancer specific survival rate. Most suitable candidates are patients with biopsy Gleason score &lt; 8, pN0 and = pT3a; even in cT3 PCA RPE is a valuable therapeutic option with long-term PCA-free survival and might be considered in men with a long life expectancy. No significant financial relationships to disclose.
DETECTION AND FOLLOW-UP OF LIVER FIBROSIS IN CYSTIC FIBROSIS: A ROLE FOR DIAGNOSTIC LIVER BIOPSY AND SERUM MARKERS IN THE EVALUATION OF AND FOLLOW UP OF CYSTIC FIBROSIS LIVER DISEASE
Authors: MJ Walsh, PJ Lewindon, RW Shepherd, RM Greer, S Bell, GA Ramm
Journal: Hepatology (2009)
Targeting Src- Family Kinase Activation and Downstream Molecular Events To Overcome MM Cell Growth, Survival, and Drug- Resistance.
Authors: Klaus Podar, Yu-Tzu Tai, Dean Abtahi, Marc S. Raab, Hiroshi Yasui, Kenji Ishitsuka, Norihiko Shiraishi, Laurence P. Catley, Martin Sattler, Noopur Raje, Teru Hideshima, Dharminder Chauhan
Journal: Blood (2005)
Evaluation of platinum-based chemotherapy, glutathione metabolic genes, and survival in advanced non small cell lung cancer: A NCCTG 97–24–51 based study
Authors: P. Yang, S. J. Mandrekar, S. L. Hillman, K. L. Allen, Z. Sun, J. Wampfler, J. M. Cunningham, J. R. Jett, A. A. Adjei, E. A. Perez
Journal: Journal of Clinical Oncology (2006)

13013 Background: The glutathione metabolic pathway is directly involved in the inactivation of platinum compounds. Our earlier work indicated that genotypes corresponding to varied glutathione-related enzyme activities may predict survival in patients with advanced lung cancer. Herein, we evaluated the role of glutathione-related genotypes on clinical outcomes in stage IIIB/IV non-small cell lung cancer patients who were stable or responding from one prior platinum-based chemotherapy. Methods: DNA samples from patients who had tumor regression or stable disease after treatment with one platinum based chemotherapy regimen were analyzed using 6 polymorphic DNA markers that encode 5 important enzymes in the glutathione metabolic pathway. The contrasting genotypes used in the analysis were GCLC (homozygous repeat 77 vs. heterozygous 7*), GPX1 (CC vs. other), GSTP1-I105V (AA vs. other), GSTP1-A114V (CC vs. other), GSTM1 (null vs. present), and GSTT1 (null vs. present). Multivariable Cox proportional hazards models adjusted for age, gender, treatment arm, ECOG performance status, stage, and prior tumor response, were used to evaluate the prognostic significance of the genotypes at each locus. Results: Data from 112 patients with a median follow-up of 10.6 (range: 0.4–56.3) months was used. No significant difference in time to disease progression was observed for any of the genotypes. Among the 6 genomic DNA markers, the GCLC genotype was an important prognostic factor for overall survival after adjusting for other factors. In particular, patients carrying a 77 repeat genotype (homozygous) had a significantly worse survival (Hazard ratio = 1.67, 95% CI: 1.05–2.63). Conclusions: Genotypes of glutathione-related enzymes, especially GCLC, may be used as host factors in predicting patients’ prognosis after platinum-based chemotherapy. Further investigation to define and measure the effects of these genes in chemotherapeutic regimens is needed. (This work was partly supported by NIH research grants CA77118, CA80127, and CA84354.) No significant financial relationships to disclose.
Intraperitoneal recombinant alpha-2-interferon alternating with cisplatin as salvage therapy for minimal residual-disease ovarian cancer: a phase II study.
Authors: M Nardi, F Cognetti, C F Pollera, M D Giulia, A Lombardi, G Atlante, F Calabresi
Journal: Journal of Clinical Oncology (1990)

A phase II study was initiated in March 1987 at the Regina Elena National Cancer Institute of Rome to evaluate the efficacy of alternating intraperitoneal (IP) recombinant alpha-2-interferon (r-alpha 2-IFN) and cisplatin (DDP) as salvage therapy for less than or equal to 5 mm residual-disease (RD) ovarian carcinoma. Fourteen assessable patients entered the study. All had received prior chemotherapy (11 with DDP-based regimens); five patients had macroscopic RD (less than or equal to 5 mm), and nine had microscopic RD (histologically positive random biopsies and/or positive cytology and immunocytochemical tests). The response to IP immunochemotherapy was evaluated by laparotomy. Pathologic complete remissions (PCRs) were achieved in seven patients (50%) who have remained free of disease with a median follow-up of 22+ months (range, 11+ to 30+ months). Six patients achieved a stable disease and one presented disease progression. With the exception of chemical peritonitis-induced adhesions, no limiting toxicity was observed. The results obtained in this small, highly selected series demonstrate that a high PCR rate may be obtained with IP immunochemotherapy with DDP and r-alpha 2-IFN as salvage therapy in residual ovarian carcinoma less than or equal to 5 mm after first-line chemotherapy also including intravenous (IV) DDP. Larger comparative studies must be conducted to establish the potential role of IP DDP and r-alpha 2-IFN as compared with either of the single treatments.
A dose-escalation study of the quinoxaline antitumor agent R(+)XK469 (XK) in patients with refractory solid tumors
Authors: E. Sprague, S. D. Undevia, F. Innocenti, J. Ramirez, L. K. House, H. L. Kindler, D. A. Singh, A. A. Desai, R. L. Schilsky, M. J. Ratain
Journal: Journal of Clinical Oncology (2004)

2021 Background: XK is a member of the quinoxaline family of antitumor agents. COMPARE analysis of cytotoxicity data from the NCI-60 cell line screen showed that its mechanism of action is not comparable to that of any marketed cytotoxic agent. In vitro studies suggest that the antitumor activity of XK may be due to inhibition of topoisomerase IIβ, induction of G2-M cell cycle arrest by p53-dependent and mitogen-activated protein (MAP) kinase pathways, and/or pro-apoptotic interactions with the peripheral benzodiazepine receptor. Methods: XK was administered as a 30-minute intravenous infusion for 5 days at 15, 30, 60, 120, and 240 mg/d and every other day for 3 doses at 360, 540, 675, 850, 1100, and 1400 mg/d, repeated every 21 days. The dosing schedule was changed when pharmacokinetic (PK) analysis revealed a long half-life. Results: To date 42 pts (21 male/21 female, median age 60, median Karnofsky performance status 90%) have been treated at 11 dose levels. The principle site of toxicity has been bone marrow. Grade 3 anemia and thrombocytopenia have been observed at 1100 and 1400 mg. Grade 4 neutropenia on the scheduled day 1 of cycle 2 and fever in the setting of grade 4 neutropenia have been the only dose-limiting toxicities (DLT). Non-hematologic toxicities include grade 1–2 alopecia, anorexia, diarrhea, fever, headache, nausea, peripheral neuropathy, rash, stomatitis, and vomiting and grade 3 fatigue. Plasma concentrations of XK decline in a biphasic manner with a long mean terminal phase half-life of 60 h (CV 63%). Steady-state volume of distribution is 13 L (CV 23%); and mean total body clearance (CL) is 0.20 L/h (CV 50%), which is not correlated with dose (p=0.69) or BSA (p=0.93). All pts who experienced DLT had CL < 1 standard deviation (SD) below the mean. Conclusions: XK can be safely administered on a d 1, 3, 5 schedule without BSA-based dosing. As AUC increases with dose and 15% of our pts had CL ≤ 1 SD below the mean, safety concerns preclude further dose escalation > 1100 mg/d on this schedule. Cohort expansion continues at the phase II recommended dose of 1100 mg/d. Pharmacogenomic studies are ongoing to investigate the basis for the large PK variability. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb
Bendamustine, Etoposide, Cytarabine and Melphalan (BeEAM) Followed By Autologous Stem Cell Transplantation Produce a 3-Year Progression-Free Survival Of 75% In Heavily Pre-Treated Hodgkin and Non-Hodgkin Lymphoma
Authors: Giuseppe Visani, Pietro Maria Stefani, Saveria Capria, Lara Malerba, Piero Galieni, Francesco Gaudio, Giorgina Specchia, Giovanna Meloni, Filippo Gherlinzoni, Claudio Giardini, Sadia Falcioni, Roberta Gonella, Francesca Cuberli, Marco Gobbi, Barbara Sarina, Armando Santoro, Felicetto Ferrara, Marco Rocchi, Enrique M. Ocio, Maria Dolores Caballero, Paola Picardi, Teresa Ricciardi, Federica Loscocco, Alessandro Isidori
Journal: Blood (2013)
Final results from ARQ 197-114: A phase Ib safety trial evaluating ARQ 197 in cirrhotic patients (pts) with hepatocellular carcinoma (HCC).
Authors: P. Zucali, A. Santoro, C. Rodriguez-Lope, M. Simonelli, L. H. Camacho, N. N. Senzer, L. Bolondi, M. Lamar, G. Abbadessa, B. E. Schwartz
Journal: Journal of Clinical Oncology (2010)

4137 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-MET, the exclusive receptor tyrosine kinase for hepatocyte growth factor implicated in tumor cell migration, invasion, proliferation and angiogenesis. Over-expression of c-Met and HGF is associated with poor prognosis in HCC pts. ARQ 197 has been evaluated in over 300 cancer pts. This study evaluates the safety, pharmacokinetics, biomarkers, and preliminary evidence of efficacy in HCC pts who received ≤ 2 prior systemic chemotherapy regimens. Methods: Multicenter, single cohort phase 1b trial. ARQ 197 is administered at the oral dose of 360 mg bid. Treatment is continued until disease progression or unacceptable toxicity. Results: As of December 31, 2009, 20 pts with HCC (2 F/ 18 M; range 47-80 median 69.9 years) were enrolled and treated. Of these, 12 and 8 pts presented with ECOG 1 and 0 respectively, while 16 and 4 pts presented with Child-Pugh A and B cirrhosis respectively. Drug- related adverse events (AEs) were reported in 16 (80%) pts. The most commonly reported AEs (> 10%) included fatigue (11 cases, 55%), anemia (6, 30%) neutropenia (4, 20%), leucopenia (4, 20%), thrombocytopenia (3, 15%), alopecia (3, 15%), anorexia (3, 15%), and diarrhea (3, 15%). Four pts experienced drug-related serious AEs including 2 cases anemia (grade 3), 1 case leucopenia, and 1 case neutropenia (grade 3, 4). Two of these, following drug holiday and growth factor support, 2 of these pts remained on study at a reduced dose. Of 15 RECIST evaluable pts, 5 achieved stable disease > 4 months (1 with minor radiographic response) with TTP ranging from 3.1 to 42.3 weeks. PK data analysis shows day 1 mean Cmax (n = 10) of 1,714 ± 771 ng/mL and AUC(0-12) of 15,693 ± 6,842 hr*ng/mL. Final results including PK, biomarker, and efficacy data will be available for presentation. Conclusions: ARQ 197 appears safe and well tolerated in this previously-treated and cirrhotic HCC patient population. To date, no drug-related worsening of liver function is reported and there appear to be early indications of activity. A phase II randomized trial comparing ARQ 197 to best supportive care is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ArQule ArQule
Sorafenib fourth-line treatment in imatinib-, sunitinib-, and nilotinib-resistant metastatic GIST: A retrospective analysis
Authors: P. Reichardt, M. Montemurro, H. Gelderblom, J. Blay, P. Rutkowski, B. Bui, J. T. Hartmann, D. Pink, S. Leyvraz, J. Schütte
Journal: Journal of Clinical Oncology (2009)

10564 Background: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors usually caused by mutations in the KIT or PDGFRA gene. Advanced disease generally cannot be cured by surgery nor by tyrosine kinase inhibitors (TKI), but TKIs have considerably improved outcome for patients (pts) with advanced GIST. Patients failing TKI treatment with imatinib (IM), sunitinib (SU) or nilotinib (NI) have a poor prognosis. Sorafenib is a multi kinase inhibitor that blocks not only receptor tyrosine kinases such as KIT, VEGFR and PDGFR but also serine/threonine kinases along the RAS/RAF/MEK/ERK pathway. Recently, clinical activity of sorafenib in third-line treatment in patients with GIST after IM and SU failure has been shown (Wiebe et al. ASCO 2008, #10502). Methods: We report herein preliminary data of 32 pts treated with sorafenib in nine European centers. Centers were selected based on their previous and known experience in GIST and reported all pts treated. Pts received sorafenib after failure of IM, SU and NI in fourth-line treatment. Baseline characteristics and treatment details have been retrieved via questionary. Results: Median age at sorafenib treatment start was 62 years (range 33–81 y), and the majority of pts were male (63 %). Primary tumor site was gastric or small intestine in 25% and 41% of pts, respectively. All pts had failed IM, SU, NI. 19 % of pts achieved partial remission and 44% disease stabilization. Approximately half of the pts had an improvement of symptoms and/or performance. Half of the pts were on treatment longer than 4 months (actuarial data) and 41% of pts continue to receive sorafenib. Median progression-free survival is 20 weeks and median overall survival 42 weeks (Kaplan-Meier), at a median follow-up of 22 weeks (range 3–54). Conclusions: This is the largest series assessing efficacy of sorafenib fourth-line treatment for IM, SU and NI refractory GIST reported yet. Sorafenib displays significant clinical activity in this heavily pretreated group of patients. [Table: see text]
Lenalidomide in High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia with Chromosome 5 Abnormalities.
Authors: Lars Möllgård, Lars Nilsson, Lars Kjeldsen, Ingunn Dybedal, Inge Hogh Dufva, Hege Garelius, Jan Maxwell Norgaard, Olle Linder, Elisabeth Ejerblad, Jan Astermark, Eva Hellström-Lindberg
Journal: Blood (2009)