tbuckley/cabot-search huggingface dataset:
Correlation between clinical response to EGFR inhibition and EGFR mutational status in squamous cell carcinoma of the skin.
Authors: A. Q. Nguyen, W. L. Read
Journal: Journal of Clinical Oncology (2011)

e21081 Background: EGFR (epidermal growth factor receptor) targeted therapies are known to be effective in the management of lung cancer patients carrying mutations in the EGFR gene. In these patients, EGFR inhibitors can produce a complete tumor response even in disease refractory to all other therapies. There is considerable clinical experience with EGFR inhibitors in mucosal carcinomas of the head and neck, a disease in which the response rate to EGFR monotherapy is low and EGFR mutational status irrelevant. Squamous cell carcinoma of the skin (SCCS), however, may be different; we have seen several instances of complete tumor response to anti-EGFR therapy in cases of metastatic or recurrent SCCS. We are not aware of published correlations between clinical response to EGFR inhibitors and EGFR mutational status in SCCS patients. In this study, SCCS specimens from 5 patients with known response to EGFR inhibitor therapy were analyzed for EGFR mutation. Methods: After obtaining local IRB approval for the use of archived tissue for research purposes, tumor specimens from the above listed patients were analyzed using the ResponseDX test developed by Response Genetics Inc. This test identifies EGFR mutations by positive allele-specific PCR amplification using primers specific for the EGFR mutations: G719X, E19del, S7681, E20ins, L858R, and L861Q. Results: All 5 specimens were found to be wild-type and contain no known mutations in the EGFR gene. Conclusions: We did not find an association between EGFR mutation and EGFR-inhibitor efficacy in SCCS patients. Nonetheless, in these SCCS patients, EGFR therapy provided excellent and lasting palliation with minimal toxicity. Clinical trials should be pursued exploring use of EGFR inhibition as a therapeutic option for patients with advanced/recurrent SCCS. Abbreviations: CR, complete response; PR, partial response. Age Site Anti-EGFR agent Best response Duration of response 39 Lung (metastases) Erlotinib PR 8 mo 54 Neck Erlotinib CR 1 mo* Erlotinib CR 1 mo* Erlotinib CR 10 mo 41 Face Gefitinib PR 11 mo Erlotinib PR 10 mo 90 Face Erlotinib PR 6 mo 60 Lip Erlotinib CR 2 mo* Erlotinib CR 5 mo* Erlotinib CR 6 mo * Recurrence upon discontinuation of anti-EGFR treatment.
A retrospective study of gefitinib effective cases in non-small cell lung cancer patients with poor performance status
Authors: H. Nakamura, M. Azuma, S. Namisato, T. Uchihara, A. Saito, M. Furugen, S. Teruya, H. Higa
Journal: Journal of Clinical Oncology (2004)

8177 Purpose: Recent preliminary data in Japan indicate the usefulness of gefitinib to advanced non-small cell lung cancer patients. We investigated those Gefitinib effective examples in non-small cell lung cancer patients with poor performance status (3 or 4). Methods: It was aimed at the patient by whom written informed consent about gefitinib use was obtained among those to whom we judged gefitinib use to be suitable. Results: From July 2002 to December 2003, 53 patients treated with gefitinib 250mg/day. Therapy was continued until disease progression in the absence of significant toxicity. There were 38 men and 15 women, ages ranged from 49–89 years. Performance status (PS) was 0/1/2/3/4 in 6/17/12/14/4. 11 men and seven women were PS3 or 4. The main side effects were skin rash, nausea and diarrhea. Drug induced pneumonia was observed in one case. Bone marrow toxicity was not seen. Improvement of DIC was observed in two cases. Regression of brain metastases was observed in one case. Five cases were confirmed that body fluid collection was decreased significantly. Conclusion: Gefitinib can be prescribed for the patient also in a case with poor performance status comparatively safely, and is useful to condition relief. No significant financial relationships to disclose.
Sequencing the chemokine receptor CXCR4 in individual circulating tumor cells (CTCs) of patients with breast cancer (BrCa).
Authors: F. Fontana, G. Bonizzi, G. Medoro, L. Zorzino, M. Sergio, M. C. Cassatella, E. Peruzzi, S. Gianni, A. Calanca, G. Signorini, F. Nole, G. Giorgini, E. Munzone, N. Manaresi, M. T. Sandri
Journal: Journal of Clinical Oncology (2011)

e21134 Background: Recent efforts of deep sequencing patients tumours have confirmed that clonal populations causing distant metastases are represented within the primary carcinoma. However from large numbers of tumour cells the frequency of mutations in individual clones cannot be inferred. Endocytic recycling of CXCR4, reportedly overexpressed in at least 23 different cancer types, is important for cancer cell motility. The C-terminus of CXCR4 has been reported to contain important motifs for the regulation of receptor trafficking. In this study we aim to establish the methodology for identifying possible mutations from the C-terminus of CXCR4 gene in individual CTCs. Methods: Blood samples from BrCa patients were collected in CellSave tubes and processed with Veridex CellSearch Epithelial Cell Kit. After enumeration, samples of 6 positive patients (2 locally advanced and 4 metastatic, range 13-296 CTC/7.5 ml), were removed from Veridex cartridge and loaded on DEPArray, Silicon Biosystems, a fluorescence and morphology image-based cell sorting system, enabling up to 20 recoveries of single or multiple cells. Recovered cells were then amplified with Ampli1 Whole Genome Amplification (WGA), Silicon Biosystems. An aliquot was used for gene-specific PCR and sequencing by capillary electrophoresis. The overall method was first validated, in blind, spiking KRAS-mutated cells in healthy donor blood samples. Results: On 5/6 (83%) single tumor cells recovered from DEPArray in spiking experiment, KRAS gene was successfully amplified: the blinded mutation was correctly identified and 100% purity was confirmed by DNA fingerprinting. In a duplicate spiking sample sequenced without single-cell sorting and WGA no mutation was detected. In patients, CXCR4 C-terminus sequence was obtained (range 1-9 sequences per patients) for 34/62 (55%) single and 6/11 (55%) multiple CTCs (range 2-8). Conclusions: Mutation sequencing on multiple individual CTCs is possible following single-cell sorting with the method proposed. We succeeded in sequencing the C-terminus of CXCR4 gene from single EpCAM+ CTCs. As the study is still ongoing, these results are preliminary due to the small cohort of patients.
9-years follow up in 121 patients with oligodendroglial tumors: Results of Nice neuro-oncological database
Authors: M. P. Frenay, A. Ramaioli, D. Fontaine, V. Bourg, F. Vandenbos, C. Lebrun
Journal: Journal of Clinical Oncology (2005)

1551 Background: Oligodendroglial tumors are chemosensitive and seems to have a better prognosis than pure low grade astrocytomas. Since 1995, we collected in our neuro-oncological database 1025 primary brain tumors and identified grades II and III oligodendrogliomas according to WHO classification. We analysed data including demographic characteristics, clinical management and survival at 2 and 5 years. Design/Methods: 121 patients were identified: 57 grade II or low grade OG; 64 grade III or anaplastic OG (AOG). After diagnosis, patients were proposed for new surgery, chemotherapy (CT), radiotherapy (RT) or monitoring (after complete removal for OG). Follow-up was performed with clinical assessement, brain MRI and MIBI scintigraphy. Results: patients characteristics were: 81 males; 40 females; mean age at diagnosis: 49.9yrs (OG:46.5; AOG: 53.3). Mean age at first symptom was 47.9yrs (OG:43; AOG: 52.8); First symptom was mostly partial epileptic seizures (73.7% OG, 51.6% AOG), neurological deficit (10.5% OG, 14.1% AOG) or headaches (5.3% OG, 15.6% AOG). Fifty-one patients had gadolinium enhancement (OG:22.8%; AOG:92.2%), only confirmed by MIBI hypermetabolism on brain SPECT for OG (OG+:22.6%, AOG+: 59.7%). Neurosurgical strategy was decided after brain MRI performed with- and without gadolinium enhancement: biopsy only (59.6% OG, 25% AOG); partial resection<90% (21.1% OG, 43.8% AOG); partial resection >90% (8.8% OG, 7.8% AOG); total resection (10.5% OG, 23.4% AOG). Among the 57 OG, 45 patients (78.9%) had second-line treatment (73.3% CT, 17.8% RT, 8.9% new surgery). All AOG patients had a second-line treatment after surgery: 58.1% CT, 41.9% RT). Survival at 2 years was OG:85%; AOG:49%). Survival at 5 years was: OG: 65%, AOG: 20%. Conclusions: (1) OG are younger than AOG patients (2) Epileptic seizure is the most common revealing symptom (3) MIBI SPECT is informative to detect anaplastic component, especially for grade II patients (4) Some OG have gadolinium enhancement on MRI and some AOG had not. No significant financial relationships to disclose.
Multiparametric magnetic resonance imaging in the diagnosis and characterisation of prostate cancer: The PROMIS study.
Authors: Chris Parker, Richard S. Kaplan, Rhian Gabe, Hashim Uddin Ahmed, Khadija Rantell, Mark Emberton
Journal: Journal of Clinical Oncology (2012)

62 Background: Over 1 million US men undergo prostate biopsy each year. About two thirds will test negative. This negative status is uncertain as up to a quarter will have prostate cancer on repeat biopsy. Further, a positive result often fails to discriminate clinically significant from insignificant disease. PROMIS will investigate whether multi-parametric MRI (mpMRI) can discriminate between men with no cancer or clinically insignificant cancer versus those with clinically significant cancer, using template prostate mapping (TPM) biopsies as the most accurate and appropriate reference test in men referred for biopsy. Methods: PROMIS is a multicenter, validating paired cohort study designed to include up to 714 men who will have an mpMRI (index test) and, under general anaesthetic, undergo 10-12 core TRUS biopsy (standard test) and TPM with sampling every 5mm throughout the prostate (reference test). All tests will be assessed independently. Clinically significant cancer on TPM is defined as dominant Gleason pattern ≥4 and/or cancer core length of ≥6mm. PROMIS is powered to measure an absolute increase in sensitivity from 48%, on TRUS biopsy, to at least 70%, by mpMRI. Results: The study will report the proportion of men (i) who could safely avoid biopsy and (ii) correctly identified by mpMRI to have clinically significant prostate cancer. mpMRI will be assessed using an ordinal score of 1 to 5 (highly likely benign - highly likely malignant), with a score ≥3 indicating a positive mpMRI for presence of clinically significant cancer. Secondary objectives will include outcomes based on another definition of clinically significant cancer (non-dominant Gleason pattern ≥4 and/or cancer core length ≥4mm), and cost-effectiveness of using mpMRI prior to biopsy. Conclusions: PROMIS will provide level 1 evidence by comparing mpMRI with the current standard, TRUS biopsy, using an accurate reference test that can be applied to all men advised to have a biopsy. If successful, mpMRI could in the future allow between a quarter and a half of US men referred to safely avoid a biopsy and/or improve the detection of clinically significant cancer by 20%.
Gemcitabine, oxaliplatin, 5-FU and folinic acid as an outpatient first-line therapy in patients with inoperable esophageal cancer: A phase I study
Authors: J. M. Stieler, A. Hilbig, U. Pelzer, L. Roll, A. Helm, M. Gövercin, H. Riess, H. Oettle
Journal: Journal of Clinical Oncology (2004)

4250 Background: In patients (pts.) with esophageal cancer (EC) chemotherapy is considered in the palliative situation or for downstaging. Cisplatin/5-FU combinations (partly combined with radiotherapy) are among the most commonly used drugs but do require hospitalization to guarantee sufficient hydration. Oxaliplatin (Ox) is a less nephrotoxic platin derivative which reduces the need for hydration. In this study we tried to define dose limiting toxicity (DLT) and the maximal tolerable dose (MTD) of Ox when combined with Gemcitabine (Gem), 5-FU and folinic acid (FA). Methods: 13 (11m/2f) pts. with inoperable EC (3 adenocarcinoma/10 squamous cell cancer) were included. Median age was 59 (46–77) years, median Karnowski performance status was 70 (80–90)%. Therapy consisted of Ox (60/70 mg/m2) (2,5h), Gem 1000 mg/m2 (30 min), FA 200 mg/m2 (30 min) and 5-FU 750 mg/m2 (24h IV) given on day 1,8, q d 22. DLT was defined as WHO Grade IV neutropenia for >=5 days, neutropenic fever, WHO grade 4 thrombopenia for more than 5 days or associated with bleeding or necessity of platelet transfusion, > WHO grade 2 non-hematologic toxicity except for nausea/emesis and alopecia or a delay in the subsequent cycle for more than 3 weeks. Further severe toxicities could be regarded as DLTs according to investigators decision. MTD was defined as appearance of DLTs in at least 2/6 pts. during the 1st cycle of therapy. Results:At a dose level (DL) of 70 mg Ox /m2, 1/6 pts. developed WHO grade 4 thrombopenia and urosepsis grade 4 during the 1st cycle and 2 other pts. showed WHO grade 3 neuropathy after 3 cycles which by decision of investigator was regarded as a DLT, too. In the DL of 60 mg/m2, 1/6 pts developed grade 3 neuropathy after 6 cycles. Therefore, MTD was reached at 70 mg/m2 and DL 60 mg/m2 will be subjected to further evaluation. 11 pts. were evaluable for response with 1 CR, 3 PR, 3 MR, 2 SD and 2 PD. Median duration of response was 10,4 weeks (4,7–14,7). Median survival was 7,1 months . Conclusions:The combination of 60 mg Ox, 1000 mg Gem, 200 mg/m2 FA and 750 mg/m2 5-FU is a feasible outpatient drug combination that should be further evaluated in a phase II setting. No significant financial relationships to disclose.
Phase II and pharmacogenomics study of enzastaurin plus temozolomide and radiation in patients with GBM.
Authors: N. A. Butowski, K. Lamborn, M. C. Polley, J. L. Clarke, A. Nicole, M. Page, S. Nicol, D. Thornton, S. M. Chang, M. Prados
Journal: Journal of Clinical Oncology (2010)

2050 Background: ENZ suppresses signaling through PKCβ and the PI3K/AKT pathways. Primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS). PGx parameters were assessed for correlation to clinical outcomes. Methods: Pts enrolled with newly diagnosed GBM or GS and Karnofsky performance status (KPS) ≥ 60. Treatment started < 5 weeks after diagnosis with RT 60 Gy given over 6 weeks and TMZ 75 mg/m2 given daily during RT and then adjuvantly at 200 mg/m2 on days 1-5 of a 28-day cycle. ENZ 250 mg/day was given daily during RT and adjuvantly. Twelve adjuvant cycles were planned. PGx biomarkers included: MIB, MGMT, MMR, PKC isoforms, MAPK, pCREB, EGFR, PTEN, GSK3β, VEGF, and pS6. PFS and OS were estimated by Kaplan-Meier method. Comparison to UCSF historical data used a Cox proportional hazard model to adjust for known prognostic factors. Correlation of biomarker data with clinical outcomes was assessed by log-rank test. Results: Sixty-six pts were included; 60 phase II pts (enrolled 9/07 to 11/08) and 6 pts given ENZ 250 mg from the prior phase I; 54 pts had progressed; 41 pts had died. Treatment produced a low incidence of toxicity. Median follow-up for survivors was 88 weeks (range: 38-163). Median PFS was 36 weeks (95% CI: 30-48); 6-month PFS rate was 65% (95% CI: 55-78). Median OS was 76 weeks (95% CI: 64-83); 52-week OS rate was 77% (95% CI: 68-88). Adjusting for age, KPS and resection extent, the current study had better PFS and OS than two UCSF historical trials (Int J Rad Oncol Biol Phys: Chang, 2004; Butowski, 2005). Preliminary results suggest PFS and OS may not be significantly improved compared to a more recent trial combining the TMZ/RT regimen with erlotinib (Prados, JCO, 2009). MGMT-methylated pts (n = 13) had longer OS (p = 0.007) and PFS (p = 0.04) than MGMT-unmethylated pts (n = 30). Pts (n = 24) with MIB index ≤ 25.3 (median) had prolonged OS (p = 0.04), but not PFS (p = 0.5) compared to pts > median (n = 27). Conclusions: The ENZ/TMZ/RT regimen was well tolerated and active in pts with GBM. Correlation of biomarkers with OS may be useful in future trials. Detailed biomarker analyses will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly Lilly
Abstract 12893: Left Atrial Appendage CT Contrast Defects Correlate With CHADS2 Score and is a Prognostic Indicator for Embolism in Subjects With Atrial Fibrillation or Flutter
Authors: Nobusada Funabashi, Hiroyuki Takaoka, Masae Uehara, Koya Ozawa, Yoshio Kobayashi
Journal: Circulation (2014)

Introduction: Early phase CT contrast defects in the left atriium (LA) and left atrial appendage (LAA) are often observed in atrial fibrillation (AF) or atrial flutter (AFL) despite absence of thrombi. However their clinical significance is unclear. Hypothesis: In order to investigate this correlation we compared CT, transesophageal echocardiology (TEE), CHADS2 score, and occurrence of embolism (including cerebral infarction). Methods: A total of 32 AF or AFL subjects who underwent CT and TEE within 3 months were enrolled. 5 subjects with LAA thrombi by TEE were excluded. A total of 27 subjects were retrospectively analyzed (persistent AFL 10, persistent AF 9, chronic AF 3, paroxysmal AF 3, permanent atrial standstill 2, 22 male, 61±11 years, occurrence of embolism 26%, median CHADS2 score 1). We measured velocity in the LAA by TEE. We also measured CT attenuations in the LAA and LA, and calculated LAA/LA ratios. Results: CT LAA/LA ratios were significantly lower in subjects with embolism than without (0.44±0.30 vs 0.74±0.24). CT LAA/LA ratios were smaller when CHADS2 score was ≥2 (0.57±0.31 vs 0.75±0.24). CT LAA/LA ratios correlated with TEE LAA velocity (R=0.44). According to receiver operating characteristic (ROC) curves, at a best cutoff of 24.3m/sec (TEE LAA velocity), sensitivity and specificity for occurrence of embolism were 70% and 86%, respectively (Area under the curve (AUC) 0.69). Another ROC curve, at a best cutoff of 0.41 (CT LAA/LA ratio), produced a sensitivity and specificity for occurrence of embolism of 90% and 71%, respectively (AUC 0.78). In logistic regression models using LA diameter, left ventricular ejection fraction, presence of moderate to severe mitral valve stenosis or regurgitation measured by TEE, the odds ratio for CT LAA/LA ratios was 0.017 (P=0.043) for prediction of embolism. Conclusion: CT LAA/LA ratio correlates with TEE LA velocity and is a prognostic indicator for the occurrence of embolism in AF or AFL subjects without LAA thrombosis.
Phase I study of 5-aza-2’-deoxycytidine in combination with valproic acid in patients with NSCLC
Authors: M. J. Karpenko, Z. Liu, J. Aimiuwu, L. Wang, X. Wu, M. A. Villalona-Calero, D. Young, K. Chan, M. R. Grever, G. A. Otterson
Journal: Journal of Clinical Oncology (2008)

3502 Background: Epigenetic silencing is an important event in thoracic malignancies. The synergism between DNMT and HDAC inhibitors suggests the possibility of combination treatment in patients (pts) with NSCLC. We performed a phase I trial of the DNMT inhibitor 5- aza-2’-deoxycytidine (5-aza-CdR) with the HDAC inhibitor valproic acid (VA) in patients with metastatic NSCLC. The objectives were to determine the safety and tolerability of these agents, to assess alterations of methylation after treatment and to analyze pharmacokinetics (PK). Methods: Pts had progressive NSCLC, PS 0–2, and normal organ function. Pts were treated with escalating doses of 5-aza- CdR (5 - 15mg/m2) IV for 10 days in combination with VA (10 - 20 mg/kg/day) PO on days 5–21 of a 28 day cycle. Sequential samples for PK and pharmacodynamic analysis was performed on peripheral blood or buccal epithelial cell samples at pretreatment, day 1, 5, 8, 15 and 22 of the first cycle. Results: Of the 8 pts, 2 were treated at dose level 0 (5-aza-CdR at 5mg/m2, VA 15mg/kg/d) and both experienced Gr3 neurologic DLT. 6 pts were then treated at the de-escalated dose level -1 cohort (5-aza-CdR, 5mg/m2, VA 10mg/kg/d). Pts received 1–4 cycles. 1/6 pts developed DLT (7 days Gr4 neutropenia) at this dose level and d -1 was determined as the MTD. Observed Gr3 toxicities included: neutropenia (5/8), muscle weakness (3/8), and pleural effusion (2/8). 1 Pt had stable disease after 3 cycles but developed PD after 4 cycles. HbF levels were elevated in 5/7 Pts after treatment. Serum gene methylation analysis showed that detectable MGMT methylation decreased during treatment in one pt with detectable serum methylation. PK analysis were fitted to a two-compartment model, and interestingly suggested that Css and AUC NSCLC pts treated with decitabine were lower than that observed for AML pts though there was no difference in terminal half life or clearance. Conclusions: IV 5-aza-CdR in combination with PO VA is well tolerated and shows promise in gene demethylation. Due to the degree of neutropenia at the 10 day schedule we will further study 5-aza-CdR at a five day schedule in combination with HDAC inhibitors. No significant financial relationships to disclose.
Polymorphism in NQO1 pro187ser and survival of non-small cell lung cancer
Authors: S. Y. Song, H. J. Park, S. M. Yoon, S. S. Shin, S. D. Ahn, J. H. Kim, Y.-C. Hong, E. K. Choi
Journal: Journal of Clinical Oncology (2005)

9596 Background: NAD(P)H:quinone oxidoreductase 1 (NQO1) has been known to function on reduction of oxidative status as a cytosolic flavoenzyme that catalyzes the electron reduction of substrates. It was reported to play a role in the prognosis of lung cancer patients treated with chemotherapy. We studied to assess that the NQO1 pro187ser polymorphism is associated with progression-free or overall survival of non-small cell lung cancer (NSCLC) patients treated with radiotherapy. Methods: One hundred and ninety-nine patients with squamous cell carcinoma or adenocarcinoma were recruited at the Asan Medical Center from 2000 to 2003. We determined the genotypes of the NQO1 gene by single base primer extension assay using SNapShot Kit. Kaplan-Meier survival curves and the log-rank test were used to analyze the effects of genotypes on survival. Hazard ratios were calculated using the Cox-proportional hazard model. For functional study, fluorocytometry analysis for cell cycle and NQO1 level after irradiation were evaluated using one hundred and ninety-nine evaluated cell lines. Results: Patients carrying pro/pro or pro/ser genotypes had a significantly longer progression-free survival than those carrying ser/ser genotype (P = 0.033), but not significantly for overall survival (P = 0.452). Particularly, histological types showed a significant effect on progression-free and overall survival (P = 0.004 and P = 0.051). Both progression-free and overall survival was longer for patients carrying squamous cell carcinoma than those carrying adenocarcinoma. There was a tendency to show increased G2 arrest and high NQO1 level after irradiation in these good prognostic groups. Conclusions: NQO1 polymorphism used as prognostic marker for non-small cell lung cancer patients treated with radiotherapy. No significant financial relationships to disclose.