tbuckley/cabot-search huggingface dataset:
Results from a phase I, dose-escalation study of PX-478, an orally available inhibitor of HIF-1α.
Authors: R. Tibes, G. S. Falchook, D. D. Von Hoff, G. J. Weiss, T. Iyengar, R. Kurzrock, L. Pestano, A. M. Lowe, R. S. Herbst
Journal: Journal of Clinical Oncology (2010)

3076 Background: Hypoxia inducible factor-1 (HIF-1) transcription factor is an important regulator of cellular response to hypoxia. Increased HIF-1α is correlated with increased angiogenesis and aggressive tumor growth. PX-478 is a novel agent derived from melphalan by oxidation of the nitrogen mustard moiety. In preclinical models, PX-478 demonstrated antitumor activity and, in contrast to melphalan, inhibited HIF-1α expression. PX-478 was tested in a phase I, dose escalation study in patients (pts) with advanced solid tumors. Methods: Initial accelerated dose escalation cohorts consisted of 1 pt each, with expansion to 3-4 pts following first occurrence of Gr 2 toxicity. Cohorts were expanded to 6 pts if one experienced DLT. A dose was considered not tolerated if 2 or more pts experienced DLT. Study assessments included safety, response, pharmacokinetics (PK), and pharmacodynamics (PD) consisting of measurement of HIF-1α levels in peripheral blood mononuclear cells (PBMCs). Results: Forty pts (age 33-82; median ECOG PS 1) received doses between 1.0 and 88.2 mg/m2 orally on days 1-5 of a 21 day cycle. Treatment was well tolerated with no DLTs between 1 and 58.8 mg/m2. Most AEs were Gr 1/2, including fatigue, nausea, vomiting, anorexia, and anemia. One heavily pretreated pt at 88.2 mg/m2 experienced DLT of prolonged Gr 3 thrombocytopenia without bleeding. Other related Gr 3 AEs were anemia (n=1), acute renal failure (n=1), hypotension, (n=1), and elevated ALT/AST (n=1). Best response was SD in 14/36 evaluable pts (received ≥1 cycle or had documented PD). Pts with SD received a median of 4 cycles (range 2-16); 4 pts received ≥6 cycles (adenoid cystic, pheochromocytoma, prostate and vaginal cancers). PK analyses demonstrate low parent drug levels with evidence for conversion to melphalan and other metabolites. PD studies show HIF-1α inhibition proportional to drug dose. Conclusions: PX-478 has been well tolerated and associated with prolonged SD in pts with advanced cancers. Inhibition of HIF-1α despite low PX-478 levels is consistent with the idea that active metabolites other than melphalan may be responsible for the PD observations. These data support the continued evaluation of HIF-1α inhibition as a therapeutic target. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oncothyreon Oncothyreon
A pooled analysis of the secondary resection for colorectal cancer liver metastases: Comparison of bevacizumab (Bmab) and anti-EGFRs.
Authors: Wataru Ichikawa, Yu Sunakawa, Hirofumi Nakayama, Toshikazu Ikusue, Toshikado Kaneta, Hiromi Imataka, Takashi Sekikawa, Yasutsuna Sasaki
Journal: Journal of Clinical Oncology (2016)

610 Background: Systemic chemotherapies can convert irresectable liver metastases (LM) to resectable in some cases of metastatic colorectal cancer (mCRC). Secondary surgical resection is now considered to be a worthwhile therapeutic aim in mCRC with LM. There is a clear correlation between radiological response and secondary resection rate (SRR) (Jones RP et al. Eur J Cancer 2014). However, it remains unclear which monoclonal antibodies contribute the improvement of SRR, Bmab or anti-EGFRs. Methods: We performed a systematic review of literature published between Jan 1998 and Aug 2015 to analyze the relationship between SRR and antibodies in mCRC treated with 1st-line chemotherapy. Phase II or III trials which obtained the information of response rate (RR) and resection of LM were included in this analysis. The RR, SRR, and R0 SRR were compared between Bmab- and anti-EGFR (cetuximab or panitumumab)-containing regimen groups using Mann–Whitney U test. The correlation between RR and R0 SRR was assessed by Spearman's rank correlation coefficient. Results: A total of 40 studies were enrolled: 33 treatment arms from 16 trials for liver-limited disease (LLD) and 31 arms from 24 trials for non-LLD. The result is shown below. No difference was observed in SRR and R0 SRR between Bmab and anti-EGFR groups. In addition, a preliminary analysis showed that RR had significantly positive association with R0 SRR in anti-EGFR group (R 2 0.74, P=0.027 for non-LLD; R 2 0.88, P=0.018 for LLD) but not in Bmab group (P=0.27 for non-LLD, P=0.12 for LLD). Conclusions: The SRR and R0 SRR were comparable between Bmab and anti-EGFRs, even in mCRC with LLD, while RR correlated with R0 SSR in anti-EGFRs but not in Bmab. These findings warrant validation in ongoing trials to compare the targeted-agents. [Table: see text]
Efficiency of biomarker screening for enriched metastatic colorectal cancer trials: The ATTACC program experience.
Authors: Van Karlyle Morris, Michael J. Overman, Bryan K. Kee, David R. Fogelman, Cathy Eng, Arvind Dasari, Rachna T. Shroff, Laurel Deaton, Shanequa Manuel, Chris R. Garrett, Eduardo Vilar Sanchez, Tunghi May Pini, Imad Shureiqi, Gordon B. Mills, Stanley R. Hamilton, Robert A. Wolff, Funda Meric-Bernstam, James L. Abbruzzese, Dipen M. Maru, Scott Kopetz
Journal: Journal of Clinical Oncology (2014)

450 Background: Incorporation of multiple enrichment biomarkers into prospective clinical trials for metastatic colorectal cancer (mCRC) has been proposed or initiated by NSABP, EORTC, NCI Colon Task Force, and UK MRC. The feasibility of large scale screening efforts in mCRC has not been previously assessed. Methods: Patients (pts) with 5-FU refractory mCRC at MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion clinical trials with a therapy targeted to an aberration detected in the patient. Results: Between 8/2010 and 8/2013, 400 heavily pretreated mCRC pts were enrolled onto ATTACC for screening and allocation onto 10 separate Phase I or II companion trials based on banked FFPE tumor testing by IHC, gene sequencing, and CpG island methylation phenotype (CIMP) assay. Outside tissue was obtained with a median of 6 calendar days (8% had insufficient tumor). IHC, sequencing, and CIMP results required a median of 11, 12, and 20 days, respectively. In this population, 53% tumors had KRAS mutations, with BRAF, NRAS, and PI3KCA mutations, and complete PTEN loss present in 8.1%, 8.6%, 21%, and 12%, respectively. CIMP-high status (≥2 markers) was noted in 38% of pts. Given molecular results, trial-specific eligibility, and intermittent study openings, fewer than 25% of screened pts were eligible for enrollment onto a companion protocol. Of these eligible patients, approximately half (13%) enrolled onto a companion trial. Within the entire cohort, 19% enrolled in unenriched trials, and 51% received standard-of-care therapies. ATTACC screening, with an expanding biomarker panel, remains ongoing at a rate of 25-30 patients per month. Conclusions: Universal screening programs such as ATTACC represent an optimal strategy for enrolling patients in multiple biomarker enrichment studies. Even in the setting of multiple companion treatment studies, motivated patients/physicians, and a dedicated screening infrastructure, a majority of patients did not ultimately participate on a companion trial, emphasizing the lack of drugs targeting a number of common aberrations.
Duodenal sparing stereotactic body radiation therapy for the treatment of locally advanced pancreatic cancer.
Authors: Maged Ghaly, Elaine Montchal, Yijan Cao, Mihala Marrero, Lili Vijeh, Eric Xanthopoulos, Vincent Vinciguerra, Neeraj Kaushik, James Sullivan, Beatrice Bloom, Jonathan Knisely
Journal: Journal of Clinical Oncology (2013)

254 Background: The proximity of the pancreas to bowel presents a unique challenge for pancreatic cancer SBRT. This study explores the safety and effectiveness of a novel approach optimizing pancreatic tumor coverage and duodenal sparing. Methods: Eighteen patients with locally advanced pancreatic cancer (15 head/3 body) were treated with initial chemotherapy (Gemcitabine or 5-FU/Cisplatin) for 2- 6 months. All underwent endoscopic US-guided fiducial placement in and around the tumor and had a 4D treatment planning CT scan with oral contrast. This CT was used in conjunction with EUS findings, PET, and biphasic CT scans to identify the GrossTumorVolume (GTV) on the expiration phases. The planning target volume (PTV) was created by expanding the GTV by 2 mm. Dose-volume histogram (DVH) endpoints were constructed, keeping V7/15/20 (stomach/duodenum volumes that receive 7 Gy/15 Gy/20 Gy) &lt;40%,/&lt;25%/ &lt;15% ;the dose to 1/3 of the duodenal circumference &lt;20Gy and duodenal point max dose &lt;23 Gy. Additional dose constraints included liver D50&lt;5 Gy, ipsilateral kidney D25&lt;5 Gy, cord Dmax&lt;10Gy. Three 10 Gy fractions, normalized to the 85% isodose were delivered to the PTV on consecutive weekdays using fiducial-based respiratory motion tracking on a dedicated 6 MV linac-integrated stereotactic delivery system . The patients were then offered systemic therapy for 6 months or until tolerance or disease progression. Follow-up occurred at 4 weeks, 12 weeks, and every 3 months. Results: All patients completed SBRT and a median of 5 total cycles of pre-and post-SBRT chemotherapy. Gross target volumes ranged from 14.2-205.7cm 3 (median 39.5cm 3 ). With a median follow-up of 10 months, 1 patient developed transient gastroparesis, 1 G 2 abdominal pain;1 G 2 hematologic toxicity. No late toxicity was observed in 15 patients with longer follow-up (median 12 month). All patients were free of local progression at the last follow-up visit (range 3-12 months). Conclusions: Linac-delivered organ-sparing SBRT with chemotherapy in locally advanced pancreatic cancer resulted in excellent local control and also was well tolerated acutely and subacutely. Longer follow-up is warranted. A phase I dose-escalation study is underway.
High number of peripheral blood circulating endothelial progenitor cells (EPCs) in a patient with erythropoietin (EPO) producing renal carcinoma (RC)
Authors: A. Ulusakarya, F. Haghighi, F. Juin, A. Marconi, X.-H. Liu, D. Machover, G. Uzan
Journal: Journal of Clinical Oncology (2005)

9707
Association of adverse health outcomes with partial and radical nephrectomy: Is it time to reassess the “gold standard” for the small renal mass?
Authors: Brian Shuch, Janet Hanley, Julie Lai, Claude Messan Setodji, Srinivas Vourganti, Wong Ho Chow, Christopher Saigal
Journal: Journal of Clinical Oncology (2013)

363 Background: Partial (PN) and radical (RN) nephrectomy are treatments for the small renal mass. PN is considered the gold standard, as it may protect against renal dysfunction compared to RN. As active surveillance is emerging as a possible strategy, it is essential to understand the adverse health outcomes associated with both interventions. Methods: A retrospective, case-controlled series was performed using the Surveillance, Epidemiology, and End Results-Medicare dataset. Individuals treated with PN or RN for ≤4 cm non-metastatic, renal cell carcinoma (RCC) were compared to two control groups (non-muscle invasive bladder cancer [BCC] and non-cancer patients [NCC]). A Greedy Algorithm matched surgical groups (1:1) to controls by demographics and comorbidity. Medical claims &gt;30 days after treatment were examined for renal, cardiovascular, and secondary cancer events. Results: Patients undergoing PN (1,436) and RN (4,247) were matched to controls and no significant differences were noted in key variables. All cancer groups had 10-year cancer-specific survival &gt;95%. The time to event model demonstrated an increased risk of renal events for both treatments. Compared to BCC and NCC, RN hazard ratios were 2.415 (p &lt; 0.0001) and 6.211 (p &lt; 0.0001), respectively, while PN hazard ratios were 1.513 (p &lt; 0.0001) and 4.926 (p &lt; 0.0001), respectively. Secondary cancers were increased for both PN and RN compared to both control groups (p &lt; 0.0001). Cardiovascular events were increased for both PN and RN compared to NCC (p &lt; 0.0001), but this failed to reach significance when either group was compared to BCC controls. Conclusions: RCC patients treated with PN and RN are at significant risk of subsequent adverse health outcomes. When compared to RN, PN may have better renal outcome; however, when compared to controls, both options significantly increase renal events. The increase in secondary cancers and cardiovascular events with PN and RN is concerning and requires further investigation. As active surveillance is an emerging strategy, it may be time to rethink our current treatment paradigm for the small renal mass.
Ovarian germ cell tumors: 11-year experience in a Mexican university hospital.
Authors: Y. A. Lopez Chuken, J. L. Gonzalez Vela
Journal: Journal of Clinical Oncology (2010)

e15558 Background: Ovarian germ cell tumors (OGCT), represent a minority of ovarian malignancies (1%-15%), they're frequently cure by chemotherapy, there is scant evidence from prospective clinical trials. We report our clinical experience with these rare tumors. Methods: Retrospective analysis of the hospital records in the past 11 years, with statistical analysis and conclusions from comparision with literature review. Results: There were 39 patients with OGCT representing 11.3% of ovarian cancers in our institution in the past 11 years. Median age was 20 years (range 1-54 years), 59% were younger than 20 years. Histology was mixed germ cell (38%), dysgerminoma (29%), immature teratoma (15%), other 18% (mature teratoma 3 pt, endodermal sinus 3pt, choriocarcinoma 1 pt). Clinical stage was found to be stage I 57%, stage II 5%, stage III 12%, stage IV 26%. Metastases were 29% liver, 14% lung, 14% brain. Fertility preserving surgery was done in 66%, and radical surgery in 31%. Chemotherapy consisted of BEP (bleomicin, etoposide and cisplatin) 88%, EP (etoposide and cisplatin) 9%. Three patients (stage I) did not receive chemotherapy they are disease free. All patients in stage I and II are well and disease free. Eighty percent of stage III patiens are disease free. Median survival was 62 months. Conclusions: Most patients with OGCT stage I and II had excellent prognosis and fertility preserving surgery is feasable without compromising cure. No significant financial relationships to disclose.
2-deoxyglucose (2DG) bypasses Bcl-2 and Akt mediated resistance in prostate cells
Authors: R. S. Dipaola, D. Dvorzhinski, D. Nelson, V. Garikapaty, E. White
Journal: Journal of Clinical Oncology (2005)

9535 Background: Despite initial success of chemotherapy in advanced prostate cancer, resistance develops secondary to molecular mechanisms of drug resistance including overexpression of Bcl-2 and activation of Akt. Given prior studies demonstrating increased dependence of resistant tumor cells on glycolysis, we hypothesized that acquisition of resistance mechanisms confers sensitivity to agents that inhibit glycolysis, such as 2-deoxyglucose (2DG). Methods: To determine the effect of bcl-2 and Akt on 2DG induced cytotoxicity, we set up an isogenic model using rat prostate epithelial cells transformed with E1A (RP) and transfected with either a human bcl-2 expression vector (RP-B), Myr-Akt, a constitutively active form of Akt, (RP-Akt), the combination (RP-B/Akt), and vector control (RP-V). Results: Using immunoblot, we validated these cell lines demonstrating increased Bcl-2 overexpression in RP-B vs. RP-V, and phosphorylated Akt in RP-Akt vs. RP-V. Using a lactic acid assay, we demonstrated decreased lactate production with treatment by 2DG in all cell lines (p<0.01). Using MTT assay we demonstrated a 51% decrease in cell viability in RP-B, 36% in RP-Akt, 62% in RP-B/Akt, compared to only 12% in the control RP-V (p< 0.001) with 2.5mM 2DG, a concentration achievable in man in prior clinical studies. Conclusions: In summary, 2DG cytotoxicity was increased by overexpression of Bcl-2 and activation of Akt, known mechanisms of resistance in prostate cancer, warranting further study of this renewed paradigm in the laboratory and clinic. No significant financial relationships to disclose.
Glutathione S-transferase P1 I105V (GSTP1 I105V) polymorphism is associated with early onset of oxaliplatin-induced neurotoxicity
Authors: A. Grothey, H. L. McLeod, E. M. Green, D. J. Sargent, C. Fuchs, R. K. Ramanathan, S. K. Williamson, B. P. Findlay, R. M. Goldberg
Journal: Journal of Clinical Oncology (2005)

3509 Background: Sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, the integral component of the FOLFOX regimen which has emerged as standard therapy in colorectal cancer. Variations in genes potentially involved in the detoxification (glutathione system: GSTP1, GSTM1) or the cytotoxic mechanism (nucleotide excision repair: ERCC2, XRCC1) of oxaliplatin could serve as genetic predictors of susceptibility to oxaliplatin’s neurotoxic effects. Methods: Germline DNA was extracted from whole blood of 299 patients (pts) who received FOLFOX4 on Intergroup study N9741. Four genetic variants (GSTP1 I105V, GSTM1 del, ERCC2 K751Q, XRCC1 R399Q) were tested for association with the time to development of grade 2/3 sNT and sNT as reason for treatment discontinuation. In addition, pts who developed grade 2 (3) neurotoxicity before a cumulative oxaliplatin dose of 600 (800) mg/m2 was reached were compared to an equal number of pts that tolerated extremely high cumulative doses of oxaliplatin. Results: Pts with GSTP1 I105V C/C polymorphism were more likely to discontinue FOLFOX due to sNT (23.7%) than pts with T/T (9.2%) or C/T (10%) variants (p=0.039). Pts with GSTP1 I105V C/C also had lower cumulative dose to onset of grade 3 sNT compared to T/T or C/C pts (p=0.05). Pts carrying at least one GSTP1 I105V C-allele (C/C or C/T) were more likely to experience rapid onset grade 3 neurotoxicity than T/T pts, who were more likely to be able to tolerate high doses (p=0.027 for grade 2, p=0.030 for grade 3). No significant correlation of GSTM1, ERCC2, and XRCC1 polymorphisms with the onset of sNT on FOLFOX was observed. Conclusions: Our study provides early evidence that genetic variations in GSTP1 may serve as predictors of susceptibility to oxaliplatin-mediated sNT. These findings require prospective validation before GSTP1 polymorphisms can be used to identify pts in whom neurotoxicity prevention strategies on oxaliplatin-based chemotherapy are warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis
Targeting FVIII Expression to Human Platelets Corrects the Hemophilic Phenotype in An Immunocompromised Hemophilia A Mouse Model Transplanted with Genetically Manipulated Human Cord Blood Stem Cells
Authors: Qizhen Shi, Erin L. Kuether, Scot A. Fahs, Jocelyn A. Schroeder, Robert R. Montgomery
Journal: Blood (2011)
Locoregional control following external beam radiotherapy for recurrent, I-131 refractory thyroid 26061 cancer
Authors: G. A. Payne, G. W. Warren, J. Valentino, T. J. Gal, S. M. Arnold, K. B. Ain, C. A. Given, Y. M. Brill, M. R. Kudrimoti
Journal: Journal of Clinical Oncology (2008)

6061 Background: When thyroid cancer recurs and is refractory to radioactive iodine, it is usually in a less differentiated state with a greater propensity for local recurrences as well as metastases. External beam radiotherapy (EBRT) is believed to be useful in maintaining locoregional control (LRC) in this group of patients. Presented herein is a retrospective analysis of this type of thyroid cancer treated with EBRT at a single institution. Methods: Patients presenting to the University of Kentucky Department of Radiation Medicine with thyroid cancer between 1992 and 2007 were analyzed by retrospective chart analysis. Clinical response, survival, and toxicity (using NCI CTAE criteria) are reported. Results: Twenty-eight patients with recurrent, radioactive iodine refractory thyroid cancer were treated with EBRT for locoregional disease (LRD). The median age at diagnosis was 43.5 (range 12 to 83). Of these patients, 64% were female, 25 were papillary histology (6 tall cell, 2 diffuse sclerosing, 1 Hürthle cell, and 1 clear, Hürthle, and tall cell) and 3 were follicular histology (2 Hürthle cell, 1 insular). Stage at diagnosis included I - 13, II - 3 (2 with metastatic disease), III - 2, IVA - 9, and IVC - 1. Extra-thyroidal extension was noted in 50%. Iodine avid disease was present in 27 patients at diagnosis and all were treated with a median I-131 dose per treatment of 158 mCi (range 25 to 650 mCi) in a median number of 2 doses. All patients were treated with EBRT to a median dose of 63 Gy (range 30 to 71 Gy) using 3-D based planning. Complete response was noted in 23 patients, partial response in 2, and persistent disease in 2; one was not evaluable. Grade 3 acute toxicity was noted in 32% of patients (7 of skin nature, 2 of esophagus nature), while Grade 4 acute toxicity (1 of nausea/vomiting nature, 4 of esophagus nature) was observed in 18%. Esophageal strictures developed in 5 patients (18%). With a median follow-up of 25.5 months (range 3 to 104 months), LRC was maintained in 19 patients (70%). Conclusions: EBRT for recurrent, radioiodine refractory thyroid cancer is associated with a high LRC rate, and should be actively considered for this group of patients. No significant financial relationships to disclose.
DEK Regulates Hematopoietic Stem and Progenitor Cell Fate By Activating AKT and ERK Mediated Signaling through CXCR2/Heparan Sulfate Proteoglycans
Authors: Maegan L. Capitano, Nirit Mor-Vaknin, Maureen Legendre, Scott Cooper, David Markovitz, Hal E. Broxmeyer
Journal: Blood (2016)