tbuckley/cabot-search huggingface dataset:
14-3-3 Integrates Pro-Survival Signals in Hematopoietic Cells Transformed by Diverse Leukemogenic Tyrosine Kinases, and Represents a Common Target.
Authors: Shaozhong Dong, Sumin Kang, Ting-lei Gu, Sean Kardar, Sagar Lonial, H. Jean Khoury, Fadlo Khuri, Haian Fu, Jing Chen
Journal: Blood (2006)
Intratumoral heterogeneity of EGFR mutation and clinical significance in Chinese patients with advanced non-small cell lung cancer.
Authors: Hua Bai, Jie Wang, Zhijie Wang, Jianchun Duan, Lu Yang, Tongtong An, Minglei Zhuo, Meina Wu, Yuyan Wang
Journal: Journal of Clinical Oncology (2012)

7537 Background: Whether exist intratumoral heterogeneity of epidermal growth factor receptor (EGFR) gene mutation remains controversial. This study aims to evaluate intratumoral heterogeneity of EGFR and its clinical significance in patients with non-small cell lung cancer (NSCLC). Methods: Samples were collected from 85 patients with stage IIIa-IV who had palliative surgery resection. All of the bulk tissues had been routinely detected EGFR mutation, in which contained 30 wild-type and 55 mutant-type EGFR. 28–34 tumor foci for each sample were microdissected. EGFR mutation was detected by ARMS. EGFR copy number was detected by FISH. 23 patients received EGFR-tyrosine kinase inhibitor (TKIs) therapy. Results: 1740 tumor foci from 55 EGFR mutant-type (Group-M) and 959 foci from 30 wild-type cases(Group-W) were fractionated. Mean mutation contents were 73.9%(1285/1740) in Group-M and 0 in Group-W. Accordingly, 28.2%(24/85)consisted of cells with both wild-type and mutated-type EGFR, with the proportion of EGFR mutant cells ranging from 1% to 90%, whereas 71.8%(61/85) samples contained pure mutant-type (n=31) or wild-type EGFR cells(n=30). 31 patients (36.5%) presented EGFR FISH positive. The patients with mutation heterogeneity, regardless of high or low mutation contents, presented lower EGFR copy number than those with pure mutation cases (16.7% vs 71.0%,p&lt;0.05). Among 23 patients who received EGFR-TKIs therapy, the mean mutation content was higher in partial response (71.1%) and stable disease group (43.4%) than in progressive disease group (5.0%) (p=0.005). Conclusions: This study showed that the heterogeneity of EGFR mutation was found in introtumoral region with different degree. The response to EGFR-TKIs was correlated with EGFR mutant content.
Palliative ambulatory 14-day infusional ifosfamide in the outpatient setting for treatment of advanced soft tissue sarcomas (STS): “Old wine in a new bottle.”
Authors: Salma Moona Alam, Charlotte Benson, David Olmos, Robin Lewis Jones, Scott Mitchell, Omar Al-muderis, Alison Dunlop, Cerys Propert-Lewis, Michelle R. Scurr, Ian Robert Judson
Journal: Journal of Clinical Oncology (2012)

10039 Background: Ifosfamide (IFO) has recognised activity in soft tissue sarcomas. There is evidence for improved cytotoxicity and tolerability utilising a prolonged 14 day infusional outpatient regimen compared with the standard 3-day regimen (Loeffler et al 1990). We undertook a retrospective review of all patients treated with this regimen from September 2008 - December 2011 to determine toxicity and treatment response. Methods: Pts. were identified from our database and demographics, histological subtype, toxicity and survival outcomes were collected. IFO was given via central venous access using 2 x 7 day pumps at 1g/m2/day with mesna for 14 days q 4 weekly. Oral sodium bicarbonate was used to maintain alkaline urine with oral mesna for haematuria, and thiamine for symptoms of encephalopathy as required. Results: 29 patients (pts), with advanced sarcoma, median age 56 years (27-76 yrs), 14F 15 M, median number of cycles = 1 ( 1-9). At baseline: PS 0=1, 1=24, 2=4. 18 pts had de-differentiated liposarcoma (D-LPS), 6 synovial sarcoma, 5 had other subtypes. 12 pts received only 1 cycle, with 5 stopping due to encephalopathy. Ten patients developed encephalopathy, 9 occurring in cycle 1, other toxicity was tolerable, with Gr 2-3 nausea (15 pts) and vomiting (9pts) and only 2 Gr 3 episodes of myelotoxicity for all cycles. 4 patients achieved PR, (2 with D-LPS and 2 with Synovial sarcoma) 11 pts. had SD. Median PFS was 19 months and OS was 12.5 months. 2 pts. with D-LPS had a sustained prolonged response of 15 and 16 months. Conclusions: Infusional IFO is generally well tolerated; however a significant incidence of neurotoxicity was seen. Pts. with D-LPS demonstrated best response to treatment, a sarcoma subtype that has previously failed to respond to systemic therapy. This regime warrants further investigation.
Clinical next-generation sequencing to identify actionable alterations in a phase I program.
Authors: Genevieve Marie Boland, Sarina Anne Piha-Paul, Vivek Subbiah, Lauren Brusco, Shelley M Herbrich, Keith A. Baggerly, Mark Routbort, Keyur Patel, Rajyalakshmi Luthra, Aung Naing, Siqing Fu, Gerald Steven Falchook, David S. Hong, Jennifer J. Wheler, Filip Janku, Kenna Rael Shaw, Kenneth D. Aldape, John Mendelsohn, Gordon B. Mills, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2014)

11115 Background: Due to affordable high-throughput technologies Clinical Laboratory Improvement Amendments (CLIA)-certified next-generation sequencing platforms for genomic characterization have emerged. Given the expansion of molecularly-targeted therapeutics, there is a huge opportunity to use genomic testing for patient selection in clinical trials. We sought to determine the frequency of alterations across tumor histologies in patients with advanced cancer using a deep sequencing approach to assess for mutations in hotspot regions of 46 cancer-related genes. Methods: We examined data from the first 500 patients with advanced cancer prospectively enrolled on an IRB-approved protocol through the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center. Archival tumor DNA was tested for hotspot mutations in 46 genes (Ampli-Seq Cancer Panel) using an Ion Torrent PGM Sequencer (Life Technologies, CA) at the clinical molecular diagnostics laboratory. The data were analyzed using R Statistical Software (R Foundation for Statistical Computing, Vienna, Austria). Results: Patients with 38 tumor types were enrolled. Of 500 patients analyzed, 293 had at least one detectable mutation. The most commonly mutated genes were TP53 (38%), KRAS (11%), and PIK3CA (10%). Of tumor types tested (n ≥ 10), sarcoma (20%) and kidney (30%) had the fewest alterations, while pancreas (100%), colon (91%) and melanoma (87%) had the highest proportion. 46 patients had both primary tumors and metastases analyzed; of mutations seen in primaries or metastases, 91% were seen in both. Across all samples, there was a strong pattern of mutual exclusivity between TP53 mutations and PIK3CA mutations. Alterations in potentially actionable genes were detected in 291 (58%) patients. Both rare mutations in common tumor types and potentially actionable (directly/indirectly druggable) mutations in rare tumor types were identified. Conclusions: Implementation of multiplex testing in the CLIA environment facilitates genomic characterization across multiple tumor types to identify novel opportunities for genotype-driven trials. Matching patients to molecularly targeted therapies is underway.
Clinical and translational studies of depsipeptide (romidepsin), a histone deacetylase (HDAC) inhibitor, in patients with squamous cell carcinoma of the head and neck (SCCHN): New York Cancer Consortium Trial P6335
Authors: M. Haigentz, M. Kim, C. Sarta, R. S. Keresztes, R. V. Smith, T. J. Belbin, J. M. Mariadason, J. M. Greally, G. I. Shapiro, R. I. Haddad
Journal: Journal of Clinical Oncology (2007)

6065 Background: Unresectable recurrent and metastatic SCCHN is incurable and associated with dismal prognosis. Our objective is to evaluate the clinical activity of depsipeptide (DEP) and its effects of on PBMCs, SCCHN tumors and oral mucosa tissues in an NCI/CTEP sponsored phase II trial. Methods: Eligibility criteria include PS 0–2, any number of prior therapies and no history of significant cardiovascular disease. DEP was administered at 13 mg/m 2 IV over 4 hrs on days 1, 8, and 15 of 28 day cycles. A two-stage design was utilized, with commencement to the second stage (total 46 pts) if at least 8 of 18 pts achieve disease control at 8 weeks by RECIST. Results: To date, 10 pts (7M/3F) have been accrued, all with samples for correlative studies. Two pretreated pts (2 and 4 prior therapies for recurrent/metastatic disease) have achieved disease stabilization, including one with clear histone H3 hyperacetylation in PBMCs immediately following the first 4 hr infusion of DEP. Common toxicities to date have included fatigue and weakness, usually mild. Myelosuppression is uncommon. Aside from G3 hypotension in 1 pt, no cardiovascular toxicities have been attributed to DEP. To date, 2 of 2 pairs of pre- and post-treatment (cycle 1, day 16) biopsy specimens have demonstrated increased expression of p21 Waf1/Cip1 by immunohistochemistry post-DEP, consistent with HDAC inhibition by DEP in tumor cells. Additionally, 3 pairs of tumor biopsies and 4 pairs of mucosal brush biopsies have been analyzed by differential gene expression profiling using microarrays containing 27,323 cDNA clones; 208 cDNA clones of interest appear to be upregulated in response to DEP in at least 3 of the 7 comparisons. Analysis also includes CpG island methylation status of candidate tumor suppressor loci in tumor and mucosal tissues. Conclusions: DEP appears well tolerated by SCCHN pts, with infrequent myelosuppression and minimal if any cardiovascular toxicity in pts without pre-existing disease. Effects of DEP on PBMCs, tumor and mucosal tissues are consistent with HDAC inhibition in vivo. Accrual to the clinical trial is ongoing. Supported by ASCO Career Development Award, NIH CA110342 and N01-CM-62204. No significant financial relationships to disclose.
Increase in the incidence of differentiated thyroid carcinoma in children, adolescents, and young adults (AYA): A population-based study.
Authors: Lucas B. Vergamini, A. Lindsay Frazier, Fernanda L. Abrantes, Karina Braga Ribeiro, Carlos Rodriguez-Galindo
Journal: Journal of Clinical Oncology (2012)

9523 Background: Studies have shown an increase in thyroid cancer incidence among adults since the 1990s. However, few studies have evaluated this occurrence among children and AYA. Increases resulting from enhanced detection are most likely to involve small tumors. The objective of this study is to investigate trends in incidence of differentiated thyroid carcinomas in children and AYA by size and sex. Methods: This is an ecological time-trend study. Cases of differentiated thyroid cancer (1984-2008) in patients younger than 30 years old were selected from SEER 9 cancer registries using International Classification of Diseases for Oncology 3rd edition (ICD-O-3) codes for papillary and follicular cancers (codes 8050/3, 8052/3, 8130/3, 8260/3, 8290/3, 8330-8332/3, 8335/3, 8340-8344/3, 8450/3 and 8452/3). Patients who had multiple primary tumors were excluded from the study. SEER*Stat software was used to calculate age-standardized rates (estimated per 1,000,000 persons; World Standard Population) and annual percentage changes (APC) were calculated using Joinpoint model. Results: Rates ranged from 2.77 (1990) to 7.45 (2002) for males and from 17.19 (1987) to 41.3 (2008) for females. Overall, a significant increasing trend in incidence was observed for females (APC=3.20, 95%CI 2.80, 3.60). When a stratified analysis based on tumor size was performed, significant increasing trends were noted for the following categories: 0.5-0.9 cm (Males: APC=3.50, 95%CI 1.50, 5.40; Females: APC=7.30, 95%CI 5.90, 8.80), 1.0-1.9 cm (Males: APC=3.20, 95%CI 1.00, 5.40; Females: APC=2.90, 95%CI 2.20, 3.70), and ≥ 2cm (Males: APC=1.30, 95%CI 0.30, 2.40; Females: APC=2.50, 95%CI 1.70, 3.20). However, no statistically significant trends were noted for tumors &lt;0.5 cm (Males: APC=2.50, 95%CI -0.30, 5.40; Females: APC=2.0, 95%CI -6.90, 11.80). Conclusions: Incidence rates for differentiated thyroid carcinoma are also increasing among children and AYA in the United States. The absence of increasing trends for small tumors (&lt; 0.5cm) rules out diagnostic scrutiny as the only explanation for the observed results. Environmental, dietary and genetic factors should be investigated.
Impact of enhanced reimbursement on provider participation a cancer care quality program and adherence to cancer treatment pathways in a commercial health plan.
Authors: Jennifer Malin, ANN NGUYEN, Stacey E. Ban, Vincent Willey, Ralph Quimbo, John Barron, Paula Inches, Boris Spevak, Michael Fisch
Journal: Journal of Clinical Oncology (2015)

6571 Background: Payment for treatment planning and care coordination for cancer care in the U.S. has been largely funded through the margin between the acquisition cost and reimbursement of cancer drugs. The Institute of Medicine has called for new payment models to align reimbursement to support patient-centered, high-quality affordable cancer care. Methods: In July 2014, 6 commercial HPs in the Midwest and Georgia implemented a cancer care quality program that included additional reimbursement for treatment planning and care coordination when oncologists selected regimens that were on a pathway. Cancer treatment pathways were developed using an evidence-based process with expert advisors from academic centers and community practices for breast, lung and colorectal cancer (available at www.cancercarequalityprogram.com). Practices provided clinical data on HP members starting systemic therapy through a web portal, including tumor type, stage, line of therapy, biomarkers, performance status, and planned treatment. Using program data linked with HP data, rates of participation and pathway adherence for the initial 6 months of the program were estimated. Results: Between July and December, 616 practices registered 5538 patients in the program, with a mean of 8.7 patients per practice (SD 23.8, range 1 to 275). The most commonly cancer types were breast and lung cancer (29% and 15%, respectively, of all registered regimens) followed by colorectal cancer (13%) and lymphoma (10%). Based on chemotherapy claims for members incurred in September and October, 64% (95% CI, 62%-65%) of members (n = 2,989) were registered with the program, ranging from 8% to 100% patients within participating practices. Among registered patients, pathway adherence was 43% for breast cancer, 65% for colorectal cancer, and 51% for non-small cell lung cancer. Conclusions: A new payment model that supports quality affordable cancer care through enhanced reimbursement for treatment planning and care coordination when treatment adheres to a cancer treatment pathway is feasible. Additional interventions may be needed to increase program participation and pathway adherence.
Pharmacodynamic biomarkers from phase II study of the SMAC (Second Mitochondrial-Derived Activator of Caspases)-mimetic birinapant (TL32711; NSC 756502) in relapsed platinum-resistant epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC) (NCT01681368).
Authors: Kristen Paige Bunch, Anne M. Noonan, Jung-min Lee, Ciara Catherine Maria O'Sullivan, Nicole D. Houston, Irene Ekwede, Jin-Qiu Chen, Michelle Herrmann, Liang Cao, Naoko Takebe, Jennifer Burns, David Edward Weng, Elise C. Kohn, Christina M. Annunziata
Journal: Journal of Clinical Oncology (2014)

5585 Background: Inhibitor of apoptosis (IAP) proteins prevent apoptosis in part by inhibiting caspases. IAPs also activate pro-survival NFkB signaling. SMAC is their endogenous inhibitor. Cancers, long known to avoid apoptosis, show IAP gene amplification and protein over-expression, or SMAC gene deletion and reduced protein. Birinapant (B) is a first in class bivalent peptidomimetic of SMAC. B mimics SMAC’s modulation of IAPs including cIAP1, cIAP2, XIAP and ML-IAP. In preclinical models B depleted cIAP1, activated caspase 3 and inhibited growth of tumor cells. Methods: Phase II CTEP-sponsored single agent study of B in relapsed EOC, PPC or FTC. Patients received B 47mg/m2 IV on days 1, 8 and 15 of a 28-day cycle. Percutaneous tumor biopsy was performed prior to cycle 1, and repeated on cycle 2 day 15. Plasma and PBMC were collected for additional research studies. Results: We collected pre-treatment biopsies on 11 patients, and paired on-treatment biopsies on 7 patients. Four cores were harvested at each timepoint; two cores were flash-frozen and two were fixed in formalin and embedded in paraffin. Correlative studies verified on-target activity of B and developed biomarkers of drug effect: Clinical trial information: NCT01681368. Conclusions: Birinapant is a promising novel therapeutic with clear evidence of IAP suppression in vivo. The biomarkers developed in this study will be incorporated into future clinical trials in order to better understand mechanisms of response and resistance to apoptosis-inducing therapies. Sample type Number collected Analysis Markers Frozen tumor 11 pre, 7 on B Simple western cIAP1, cIAP2, caspase 3, caspase 8, PARP, NFkB-p65, NFkB-p100/p52, IkBa, cFLIP, RIP Drug levels -- Fixed tumor 11 pre, 7 on B IHC TNF, TRAIL, CD3, CD19, CD56, CD68 Plasma 11 (x6) cycle 1 PK Drug levels -- Plasma 11 (x2) pre/on B Cytokines TNF, TRAIL, IL-6, IL-8 PBMC 11 pre, 8 on B Simple western cIAP1, cIAP2, caspase 3, caspase 8, PARP, NFkB-p65, NFkB-p100/p52, IkBa, cFLIP, RIP Whole blood 11 pre, 9 on B T, B, NK cell counts CD3, CD4, CD8, CD19, CD56, CD16
A phase II trial evaluating weekly docetaxel and capacitabine in patients with metastatic or advanced, locally, recurrent head and neck cancer
Authors: J. Zhang, J. S. Lee, S. Urba, F. Worden
Journal: Journal of Clinical Oncology (2009)

6051 Background: Docetaxel has documented clinical efficacy in head and neck cancer and the synergy between docetaxel and capacitabine has been shown in preclinical studies. Phase I studies combining docetaxel and capacitabine demonstrated anti-tumor effects in breast, colon, and bladder cancers. We therefore test this combination in patients with metastatic or locally advanced head and neck cancer. Methods: To be eligible for this single arm safety/efficacy phase II study, patients must have documented measurable advanced, locally recurrent or metastatic head and neck cancers, which were untreatable by surgical resection or radiation therapy, a Zubrob performance status of 0–2, adequate marrow, hepatic and kidney functions. Prior chemotherapy with non-docetaxel containing regimen was allowed. Docetaxel 30 mg/m2 was given on day 1, 8 and 15, while capecitabine 1,000 mg bid was given on days 5–18 of the 28 days cycle. Response to treatment was assessed after every 2 cycles. Patients with complete response (CR) received 2 additional cycles of therapy. Patients with partial response (PR) or stable disease (SD) continued to receive the therapy until they developed CR or progressive disease (PD). Patients with PD or unacceptable toxicity will be off the study. Results: 39 patients (33 male, 6 female) with a median age of 58.4 years were enrolled between September 2003 and April 2008. At baseline, 14/39 patients (36%) had local regional disease, 17/39 (44%) had distant metastasis, and 7/39 (18%) had both. 31/39 (79%) of the patients had prior chemotherapy. Responses at 4 months were analyzed on 36 patients: 5 patients (13%) had confirmed responses (2 CR, 3 PR) and 8 patients (20%) had stable diseases. Progression-free survival at 6 month was 34% (95% CI 19% - 49%). Major grade 3 and 4 toxicities were lymphopenia (8/39, 20%), infection without neutropenia (5/39, 13%) and fatigue (4/39, 10%). Conclusions: Weekly docetaxel and capacitabine are well tolerated and the disease control rate (33%) is comparable with the historical controls in patients with metastatic or advanced, locally, recurrent head and neck cancers. No significant financial relationships to disclose.
Adjuvant chemotherapy with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin (FL) in patients with locally advanced rectal cancer after preoperative chemoradiotherapy followed by surgery: A randomized phase II study (The ADORE).
Authors: Yong Sang Hong, Byung-Ho Nam, Kyung Hae Jung, Jae-Lyun Lee, Kyu-Pyo Kim, Young Suk Park, Joon Oh Park, Sun Young Kim, Tae-You Kim, Jee Hyun Kim, Joong Bae Ahn, Tae Won Kim
Journal: Journal of Clinical Oncology (2013)

3570 Background: Preoperative chemoradiotherapy (Pre-CRT) with fluoropyrimidines (Fp) followed by surgery is one of the standard treatments for patients (pts) with locally advanced rectal cancer (LARC); however, the role of adjuvant chemotherapy is still controversial. The aim of this study is to investigate the efficacy of adjuvant FOLFOX for LARC pts who underwent Fp-based Pre-CRT and complete total mesorectal excision (TME). Methods: This randomised phase II study accrued LARC pts whose ypStage was II (ypT3-4/ypN0) or III (any ypT/ypN1-2) after Fp-based Pre-CRT followed by TME. Pts were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (5-FU 380 mg/m 2 , leucovorin 20 mg/m 2 on D1-5 q 4 weeks X 4 cycles) or FOLFOX (oxaliplatin 85 mg/m 2 , leucovorin 200 mg/m 2 on D1, 5-FU bolus 400 mg/m 2 on D1, 5-FU infusion 2400 mg/m 2 for 46 hours q 2 weeks X 8 cycles). The primary endpoint was disease-free survival (DFS). Results: A total of 320 pts were randomly assigned (161 FL and 159 FOLFOX) between November 2008 and June 2012, the arms were balanced. By intent-to-treat analysis, estimated 2-year DFS rate was 82.0% in FOLFOX arm and 69.4% in FL arm (HR 0.46 [95% CI, 0.28-0.76], p=0.002) after the median follow-up duration of 22.5 months. The statistical improvements of DFS were maintained regardless of ypStage: 2-year DFS rate was 89.7% (FOLFOX) vs 76.4% (FL) in pts (n=122) with ypStage II (HR 0.32 [0.10-0.98], p=0.035), and 78.1% (FOLFOX) vs 64.4% (FL) in pts (n=198) with ypStage III (HR 0.49, [0.27-0.86], p=0.011). All grade leucopenia (32% vs 22%), neutropenia (70% vs 46%), thrombocytopenia (26% vs 2%) and sensory neuropathy (71% vs5%) were more frequently observed in FOLFOX arm; however, grade 3/4 adverse events (AE) were not different between arms. Conclusions: Adjuvant FOLFOX improved 2-year DFS relative to FL for LARC pts whose ypStage II or III after Fp-based Pre-CRT followed by TME. Significant AEs were not different between arms. The DFS results will be updated in the presentation. Clinical trial information: NCT00807911.