tbuckley/cabot-search huggingface dataset:
EGFR mutations and pAKT expression as potential predictors of gefitinib efficacy in non-small cell lung cancer (NSCLC) patients (pts)
Authors: V. M. Villaflor, L. Buckingham, M. Gale, J. Coon, A. M. Mauer, T. Muzzafar, K. Kaiser, T. W. Zusag, L. P. Faber, P. Bonomi
Journal: Journal of Clinical Oncology (2005)

7077 Background: Activating mutations in exons 18–21 of the EGFR gene have been found in tumors from NSCLC pts that respond to gefitinib (GEF). The goal of this study was to assess EGFR mutations, as well as expression of EGFR and related molecules by immunohistochemistry (IHC) as predictors of GEF efficacy. Methods: A total of 143 consecutive pts were enrolled in the Expanded Access Trial; 7 pts died and 1 withdrew consent prior to starting treatment. Only pts with > 1 week of therapy were included for analysis. IHC was performed for 64 pts with evaluable tissue specimens. Tissue from 34 pts was analyzed for activating mutations by sequence analysis. Fisher’s Exact Test was used to evaluate associations. Results: 126 pts (64 female, 62 male; median age 68; 67 adenocarcinomas, 59 others) received GEF; median follow-up was 169 days. Overall response rate was 6.4% (1CR, 7PR), and 51 pts (40%) had stable disease (SD). Median Kaplan-Meier survival and progression-free interval (PFI) were 172 and 59 days, respectively. EGFR mutations were found in 9 of 34 tumors evaluated. None of the tumors from 9 pts with PD had mutations; 6/8 (75%) pts with CR or PR, and 3/14 (21%) pts with SD had detectable mutations. A significant association (p<.002) was observed between mutation and response. Median PFI for pts with and without EGFR mutations was 274 and 117 days, respectively (p<.05); no significant difference in survival was observed. Significant positive associations with response were also observed for EGFR (p<.02) and ErbB2 expression (p<.07). Median survival for pts with and without pAKT expression was 373 and 150 days, respectively (p<.02). Significant positive associations with pAKT expression were observed for EGFR (p<.02), ErbB2 (p<.003), pMAPk (p<.04), and IGF-1r (p<.06) expression. Conclusions: Defining molecular profiles predictive of GEF efficacy is still at an early stage. EGFR activating mutations, and detectable EGFR, pAKT, and ErbB2 expression may have predictive value for GEF response; pAKT may have predictive value for survival. Further investigation of molecular markers and mutations is warranted due to the clinical implications with respect to pts with NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, CTI, Genentech, GlaxoSmithKline, Lilly Oncology, Pfizer Abbott Laboratories, Amgen, AstraZeneca, Genentech, Lilly Oncology, Pfizer AstraZeneca, Bristol-Myers Squibb, CTI, Genentech, GlaxoSmithKline, Lilly Oncology, Pfizer AstraZeneca, Bristol-Myers Squibb, CTI, Genentech, GlaxoSmithKline, Lilly Oncology, Pfizer
Prevention of Transfusion-Associated Graft Versus Host Disease (TA-GVHD) by Photochemical Treatment of Platelet Components: Clinical Experience in Routine Use.
Authors: Jean Claude Osselaer, Chantal Doyen, Carlos Graux, Christian Chatelain, Anne Sonnet, Michele Jacquet, Jin Sying Lin, Laurence Corash, Andre Bosly
Journal: Blood (2007)
A phase II trial of trabectedin (T) in patients (pts) with HER2-positive and BRCA1/2 germ-line-mutated metastatic breast cancer (MBC).
Authors: K. L. Tedesco, J. L. Blum, A. Goncalves, J. Lubinski, N. Ben-Baruch, C. R. Osborne, P. Lardelli, J. C. Tercero, F. A. Holmes, S. Delaloge
Journal: Journal of Clinical Oncology (2010)

1038 Background: Single agent T has shown activity in soft tissue sarcoma (STS), ovarian, and breast carcinoma. The European Commission has approved T for STS treatment in adults after failure of standard therapy and for platinum sensitive relapsed ovarian cancer. In 3 phase II studies T showed antitumor activity in pts with pretreated MBC. Preclinical and clinical data suggested T may display specific activity among certain nucleotide excision repair (NER) intact or homologous recombination repair (HRR) deficient MBC, and prompted this phase II trial. Methods: T was given at 1.3 mg/m2 as a 3-hour iv infusion 3qwks to pts with pretreated progressive MBC: Group A: ER/PR/HER2- negative; Group B: HER2 overexpressed (3+), and Group C: BRCA1/2 mutation carriers. Endpoints were objective response rate by RECIST, duration of response, progression free survival (PFS), safety, and pharmacogenomics (PGx). Results: Group A was closed due to low response rate; results have already been presented. A total of 55 pts have been enrolled in groups B (31) and C (24) (median [med] age: 53, ECOG 0/1: 25/30); med number of prior chemotherapy lines: 3 (1-8). Med number of T cycles administered: 3 (1-12+) for both groups. Per external review, of 29 evaluable HER2 3+ pts, 3 confirmed partial responses (PR) were observed. From 21 BRCA1/2 mutation carrier pts, there were 3 confirmed PR. 17 (58.6%) and 8 (38.1%) pts in groups B and C achieved stable disease (SD). Two HER2 3+ pts had SD longer than 6 months. Med PFS was 3.9 months in each arm. The most frequent grade 3-4 laboratory disorders were neutropenia (38%) and (57%), and ALT elevations (57%) and (45%) for groups B and C, respectively. Fatigue, nausea, and vomiting were the most common AEs (51%, 39% and 20% for both groups B and C) of mild to moderate severity in the vast majority of pts. Tissue samples from HER2 3+ pts and BRCA mutation carriers were collected for RNA expression analysis (XPG + ERCC1 + BRCA1). Analyses are ongoing. Conclusions: T showed anti-MBC activity in BRCA1/2 mutation carriers and HER2 3+ pts with a manageable safety profile. Complete efficacy data from groups B and C and PGx results will be discussed to help selecting the MBC patients who are at highest chance for response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PharmaMar PharmaMar
Gemcitabine followed by bortezomib induces apoptosis in human oropharyngeal KB and gemcitabine resistant KB cells by different mechanisms
Authors: V. Chung, B. Zhou, X. Liu, L. Zhu, H.-V. Nguyen, D. K. Ann, Y. Yen
Journal: Journal of Clinical Oncology (2005)

9650 Background: The ubiquitin-proteosome pathway plays a critical role in cellular homeostasis. Some studies have shown a synergistic effect between gemcitabine and bortezomib; however, the molecular mechanisms are not fully understood. Methods: Human oropharyngeal carcinoma KB wild-type (KBwt) and gemcitabine resistant (KBGem) cells were treated with gemcitabine and bortezomib in a time and sequence manner. Results: Gemcitabine followed by bortezomib 4–8 hours later synergistically induced apoptosis in both cell lines and increased the percentage of subG1 cells seen by flow cytometry. Utilizing a luciferase reporter vector, NF-κB activity was found to be five fold greater in KBGem cells and drug treatment decreased NF-κB activity by 44% in KBwt cells and 28% in KBGem cells. By western blot analysis, treating KBwt cells with gemcitabine and bortezomib resulted in cleavage of NF-κB which was not seen in KBGem cells. Cyclin A and B1 expression decreased in KBwt cells following drug treatment; whereas, only cyclin B1 expression decreased in KBGem cells. Since the KBGem cells had higher expression of small ubiquitin modified protein (SUMO), its role was further explored by transducing KBwt and KBGem cells with HIV-based lenti-SUMO-1 and the unconjugatable lenti-SUMO-1aa, respectively, followed by drug treatment. The expression of cyclins A, D1 and E was markedly reduced in KBGem SUMO-1 cells and restored in SUMO-1aa transduced cells. Conclusions: Drug resistance has been a hurdle in the treatment of malignancies and the inducible activation of NF-κB is one pathway that has been implicated. Bortezomib is a novel agent that works on many pathways. For KBwt cells, the NF-κB pathway plays a significant role in inducing apoptosis after drug treatment, whereas in KBGem cells, the role of SUMOylation appears more significant. Sequential drug treatment overcoming gemcitabine resistance through SUMOylation is a unique mechanism. Thus, we have currently developed a phase I clinical trial of fixed dose rate gemcitabine followed by bortezomib (supported by NCI 72767). No significant financial relationships to disclose.
A phase I trial with a weekly one-hour infusion of flavopiridol (HMR1275), a cyclin dependent kinase (CDK) inhibitor
Authors: N. Mizunuma, E. Nagasaki, K. Hatake, H. Minami, H. Mukai, M. Tahara, K. Kawada, T. Ohtsu
Journal: Journal of Clinical Oncology (2004)

3160 Background: Flavopiridol is a novel synthetic flavonoid that directly inhibits CDKs. We conducted a phase I trial of a 1-hour infusion of single agent flavopiridol to estimate the maximum tolerated dose (MTD), evaluate safety and assess pharmacokinetics and pharmacodynamics. Method: Flavopiridol was administered intravenously at weekly doses of 40, 60 and 80 mg/m2 for 3 consecutive weeks to patients with advanced solid tumors. Safety was evaluated according to the version 2 of the NCI CTC. Results: Twelve patients (pts) with advanced cancer (6 colorectal, 2 non-small cell, and 4 others)have been treated. Median age was 54 years (range 40–71) and ECOG performance status was 0 (6 pts) and 1 (6 pts). DLTs were Grade (G)3 hyponatremia in 1 pt at 60 mg/ m2, and G3 neutropenia with infection and G4 neutropenia lasting 5 days in 1 pt each at 80 mg/ m2. Both neutropenia episodes developed 7–8 days after flavopiridol treatment. The mean Cmax at 80mg/m2 was 5276nM and the mean AUC was 28471nMxhr with the 1-hr infusion; this was 8.0- and 1.5-fold higher, respectively, than reported with the 24-hr infusion('02 ASCO Y. Sasaki et al.). Cmax at all dose levels were above the IC50 of 300 nM for inhibition of CDKs and the IC50 for most human cancer cell lines in vitro. Flavopiridol Cmax and AUC tended to increase in a dose-dependent fashion; however, flavopiridol glucuronide conjugate Cmax and AUC did not. Three pts had stable disease (SD), with one SD lasting >90 days. Conclusions: The major DLT of flavopiridol administered as a 1-hr infusion was reversible neutropenia. The MTD and RD for phase II studies were determined to be 80 mg/m2 and 60 mg/m2 weekly for 3 weeks, respectively. No significant financial relationships to disclose.
Phase II trial of irinotecan plus bevacizumab for heavily pretreated recurrent ovarian cancer.
Authors: Salvia Sanjay Jain, Yan G. Makeyev, Franco Muggia, James L. Speyer, John Patrick Curtin, Stephanie V. Blank, Leslie R. Boyd, Bhavana Pothuri, David Fishman, Xiaochun Li, Judith D. Goldberg, Amy Tiersten
Journal: Journal of Clinical Oncology (2012)

5016 Background: Irinotecan and bevacizumab have single agent activity in platinum sensitive (PSen) and resistant (PRes) ovarian cancer patients (pts). We sought to evaluate the efficacy and toxicity of irinotecan plus bevacizumab in these pts. The trial was designed to evaluate whether the progression free survival (PFS) at 6 months is at least 40% and with secondary objectives of estimating response rate (RR), duration of response (DoR), time to progression and toxicity. Methods: No limitation on number of prior regimens was placed, and prior use of study drugs was allowed. Irinotecan 250mg/m2 and bevacizumab 15mg/kg every 3 weeks were given. Due to treatment-related grade 3 toxicity (diarrhea and neutropenia) experienced by the first 5 pts on the study, the dose of irinotecan was amended to 175mg/m2. Results: 20 pts with recurrent ovarian cancer [PSen 5, PRes 15] of a planned 35 have been recruited thus far. Median age is 59 (45-78). Median number of prior regimens is 5 (3-12) with 9 pts demonstrating progressive disease (PD) on prior topotecan-containing regimens and 7 pts exhibiting PD on prior bevacizumab-containing regimens. 4 pts discontinued treatment before 2 cycles (2 for protocol defined toxicity, 2 by patient/physician choice). Partial response (PR) was observed in 2 PSen pts and 1 PRes pt, while stable disease (SD)was seen in 9 (2 PSen, 7 PRes) out of the 15 pts assessable for response at this time. 3 pts demonstrated PD after 2 cycles of treatment. 12 of 13 pts with PR or SD by RECIST also had response by CA125 criteria. Median DoR thus far (SD plus PR) is 18 weeks (4-37). 6 pts have ongoing response (4-18 weeks). Of 19 pts that received &gt; 2 cycles, 3 had grade 3 diarrhea (2 before protocol amendment and 1 after). 2 pts had grade 3/4 neutropenia (1 before and 1 after protocol amendment). Median PFS is 9.6 months (mts). Median overall survival is 15.5 mts. PFS rate at 6 mts is 61% with 95% confidence interval: (40%, 92%). Conclusions: Results of the trial to date suggest the hypothesis that the PFS at 6 mts is less than 40% can be rejected. Activity of this regimen is encouraging given the heavily pretreated nature of the pts. Dose-limiting diarrhea and neutropenia required protocol amendment. We continue to accrue study subjects at the amended dosing.
Patterns of primary therapy for prostate cancer in elderly men: Analysis of data from CaPSURE
Authors: B. Konety, J. Cowan, J. Duchane, P. Carroll
Journal: Journal of Clinical Oncology (2006)

4577 Background: It is generally acknowledged that men who are most likely to derive benefit from therapy for prostate cancer are those with a life expectancy of greater than 10 years. We examined the patterns of primary treatment for prostate cancer in men ≥75 years of age who would have a life expectancy of approximately 10 years. Methods: We examined data from the multi-institutional CaPSURE database on type of primary therapy received for prostate cancer in men &lt; and ≥75 years. Primary therapy was defined as watchful waiting (WW), radical prostatectomy (RP), brachytherapy (BT), BT plus external beam radiotherapy (BT+EBRT), EBRT or primary androgen deprivation therapy (PADT). Chi square tests and multinomial logistic regression analysis were performed to identify predictors of type of primary therapy. Results: The median age of the entire population (n = 10,764) was 67 years and 18% of the dataset were patients ≥75 years. A greater proportion of patients ≥75 years were white, single, had multiple co-morbidities, had low income and low education levels and were classified as high risk (43% vs. 25%) compared to those &lt;75 years. Men ≥75 years were more likely to have received EBRT, PADT or WW (all p &lt; .01). In a multivariate analysis adjusted for socio-demographic factors, diagnostic risk category, and number of co-morbidities at diagnosis, patients ≥75 years were less likely to be managed with primary therapy than with WW regardless of risk category or level of co-morbidity: BT (OR 0.21, 95%CI 0.15–0.31), BT/EBRT (OR 0.21, 95%CI 0.16–0.28), EBRT (OR 0.29, 95%CI 0.22–0.37), PADT (OR 0.64, 95%CI 0.51–0.81), and RP (OR 0.01, 95%CI 0.01–0.02). Conclusions: Older patients are far more likely to received WW as primary therapy regardless of burden of co-morbidity or risk level of primary cancer. A more tailored approach to prostate cancer therapy taking into account co-morbidity and functional level to decide primary therapy may be more appropriate in elderly men. Well selected older patients with high risk disease, particularly those with low co-morbidity levels, may derive survival benefit from primary therapy other than WW. [Table: see text]
Allogeneic immunotherapy by hematopoietic stem cell transplantation (ASCT) after reduced intensity conditioning (RIC) following high-dose chemotherapy for patients with acute myeloblastic leukemia (AML) in first complete remission (CR1): Reduced toxicity
Authors: D. Blaise, R. Tabrizi, C. Faucher, M. Mohty, J. Bay, G. Marit, S. Furst, A. Charbonnier, C. Chabannon, N. Vey
Journal: Journal of Clinical Oncology (2007)

7098 Background: RIC-based ASCT can be used after intensive chemotherapy in pts with CR1AML(Blaise, Cancer, 2005). Initial disease control was high and was not related to selection bias (Mohty, Leukemia, 2005).Here, we investigated if this control was maintained after a long follow-up. Methods: 37 pts (age: 51 (26–60)) with high risk clinical characteristics (70%) (Age = 50 (N=22, 59%); severe comorbidity (30%)) and/or poor risk leukemic features (65%) (Cytogenetics (35%); 2 induction courses (27%); secondary leukemia (11%), High white blood cell counts(14%) or partial remission (3%)) were treated. After CR1, pts received at least either 1 course of high dose cytarabine (24 g/m 2 ) and anthracycline (HIDAC: N=21) or HIDAC + 1 course of. melphalan (140 mg/m 2 ) (HDMEL) with auto-SCT Pts (HIDAC +HDM N=16). All pts were then scheduled to receive ASCT prepared with RIC (fludarabine (180 mg/m 2 ), busulfan (8 mg/kg), Thymoglobulin (2.5 to 10 mg/kg)) followed with BMT (28%) or PBSC (72%). Results: With a Median follow-up of 3 years (16–70 mths). 15 pts experienced aGVHD (grade 2–4 aGVHD cumulative incidence (CI):22% (9–35). 10 and 14 pts presented a limited and extensive cGVHD respectively (CI cGVHD:65 % (50–80). 3 deaths were attributed to non-relapse causes (NRD) (AGVHD: 1; CGVHD: 2° (NRD CI: 8% (0–17). In all, 9 pts relapsed at 5 mths (2–19) (24% (9–35). Relapse was associated with the absence of cGVHD (cGVHD: 8 (0–19), no cGVHD 44% (12–76), p=.05). 25 pts are still alive in CR1 for overall survival and leukemia-free survival (LFS) probability estimates at 4 years of 65 % (48–79%) and 66% (49–80%) respectively. When restricting the analysis to the 33 pts evaluable for cGVHD, cGVHD remained the only independent risk factor positively influencing LFS (cGVHD: 81% (59–92); no cGVHD (56% (27–81), p=.05) Conclusions: We conclude that RIC Allo-SCT preceded by adequate prior intensive chemotherapy might offers a relatively low NRD while exerting a sustained leukemia control even in high risk pts deserving prospective evaluation against standard strategy of conventional Allo SCT. No significant financial relationships to disclose.
Comparative study of multiparametric MRI of intraprostatic lesion detection: Correlation with transrectal ultrasound-guided and template biopsies.
Authors: V. M. Mullassery, A. R. Padhani, P. J. Ostler, N. Anyamene, P. Hoskin
Journal: Journal of Clinical Oncology (2010)

e15003 Background: Multiple MRI techniques (T2W, dynamic contrast enhancement (DCE), diffusion-weighted (DW) and spectroscopic imaging (MRSI)) can detect the intraprostatic location of cancer. This study compares the diagnostic performance of each alone and in combination for detecting cancer in men with raised serum PSA levels. Methods: 20 patients (PSA 6.5ng/ml; range 4.5- 47.9ng/ml; previous negative systematic TRUS=11) underwent multifunctional MRI studies. T2W, DCE, DW and MRSI MRI findings were correlated with TRUS or template biopsies. Each prostate was divided in multiple sectors according to biopsy site. For TRUS biopsy correlations, only the posterior 1.5cm (needle length) of each gland was evaluated. A radiologist blinded to biopsy results evaluated each sequence, scoring each sector 1(definite normal)-5(definite cancer) using literature based criteria. ROC analysis was used to compare diagnostic performance of each technique alone and in combination. Results: 329 biopsies from 100 sectors were reviewed (median 3/sector; range 1-12). 15 sectors had cancers (prevalence 15%; pre-test likelihood). 2 sectors had Gleason 3+4 cancer and 13 sectors had Gleason 3+3 cancer. Only T2W (AUC 0.67, P=0.03; sen 40%, spec 94%) and DW-MRI (AUC 0.72, p=0.005; sen 67%, spec 69%) were able to detect cancer. DCE-MRI and MRSI were poor at cancer detection (p=NS). Combining T2W+DW-MRI was not better than DW-MRI alone (AUC 0.71, p=0.008; sen 60%, spec 76%). The post-test likelihood of cancer being present/sector (positive predictive value) increased by 45%, 10% & 15% for T2W, DW-MRI & T2W+DW-MRI respectively. 8 of 9 T2W/DW false negative sectors had small volume tumor (length less or equals 2mm/involved core). Negative predictive value (NPV)/sector was high for T2W/DW-MRI (increasing by 5% to 90% for both). Presumed tumor foci in non-biopsied TRUS regions were seen in 3/16 patients (diameter 8mm-20 mm). Conclusions: Only T2W and DW-MRI are useful for detecting cancers in patients with previous negative systematic TRUS prostate biopsies and persistently raised PSA levels. The high NPV/sector suggests a role for MRI in guiding biopsies. No significant financial relationships to disclose.
A randomized phase II and coagulation study of bevacizumab alone or with docetaxel in patients with previously treated metastatic pancreatic adenocarcinoma
Authors: I. A. Astsaturov, N. J. Meropol, R. K. Alpaugh, J. D. Cheng, N. L. Lewis, M. Beard, A. Rogatko, Z. Xu, L. M. Weiner, S. J. Cohen
Journal: Journal of Clinical Oncology (2007)

4556 Background: Vascular endothelial growth factor (VEGF) is overexpressed in pancreatic cancer and interacts with coagulation to promote angiogenesis. We performed this randomized phase II study of bevacizumab (BEV) alone or with docetaxel (DOC) in patients (pts) with previously treated metastatic pancreatic adenocarcinoma to investigate their clinical activity and interaction with coagulation. Methods: Eligible pts had one prior gemcitabine regimen, PS 0–1, measurable disease, and no bleeding/thrombosis. BEV was given at 10 mg/kg IV Q 2 weeks alone (Arm A) or with DOC (Arm B) at 35 mg/m 2 IV on days 1, 8, and 15 Q 28 days. CT scans were obtained every 2 cycles. The primary endpoint was progression-free survival (PFS), with secondary endpoints response rate and overall survival (OS). Peripheral blood was obtained for coagulation parameters, basic fibroblast growth factor (bFGF), VEGF, and circulating endothelial cells (CEC). A two-stage design with a target median PFS of =4 months in either arm and early stopping for futility was utilized. Results: Thirty pts (15 per arm) received 88 cycles of therapy (44 per arm, median 2, range &lt;1–10). Pt characteristics: median age 61.5 (range 38–81), ECOG 0/1 (11/19). Seven pts in Arm A and 8 in Arm B had grade 3/4 events. Serious adverse events were 5 DVT/PE (3-Arm A; 2-Arm B) and 2 bowel perforations (1 per arm). Best reponse was 4 pts with stable disease in Arm A and 5 pts with stable disease and one unconfirmed PR in Arm B. Median PFS and OS were 43 and 181 days in Arm A and 45 and 123 days in Arm B (p=0.5 for PFS, p=0.8 for OS). The study was stopped after only 2/15 pts per arm had PFS of =4 months. In multivariate analysis, higher bFGF (HR=1.4, p=0.008) and thrombin/antithrombin complex (TAT) levels on treatment (HR=1.75, p&lt;0.001) were associated with worse OS. D-dimer, tissue factor and TAT levels on d15 were associated with increased venous thrombosis and GI perforation (p=0.04). VEGF plasma levels and CEC at all time points were not associated with clinical outcomes. Conclusions: BEV alone or with DOC has minimal antitumor activity in gemcitabine-refractory pancreatic cancer. Increased plasma bFGF and coagulation markers during therapy predict for worse OS and increased perforation and thrombosis. [Table: see text]
Studies of L1210 Leukemia. I. Ultrastructure of Solid and Ascites Cells&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: David Branded, M.D., Brian Schofield, Ruby Slusser, Elsa Anton, M.D.
Journal: JNCI Journal of the National Cancer Institute (1966)

The solid and ascites forms of the L1210 leukemia were studied by electron microscopy. Various types of virus particles were seen in the cells, either free in the cytoplasm or in association with membrane systems, such as the endoplasmic reticulum, the inner cytoplasmic membrane, and the plasma membrane. Differences in the aggregation of ribosomes were noted between the cells from the ascites and solid forms. Such differences may be due to the type of nutritional environment provided by the host.