tbuckley/cabot-search huggingface dataset:
MAPK-signaling inhibition as a genome-based precision medicine in refractory osteosarcoma.
Authors: Min Hee Hong, Beodeul Kang, Woo Sun Kwon, Hyo Song Kim, Soo Hee Kim, Woo Ick Yang, Joong Bae Ahn, Hyun Cheol Chung, Sun Young Rha
Journal: Journal of Clinical Oncology (2014)

e22164 Background: MAPK signaling pathways are often dysregulated in tumors and GNAQ mutation enables constitutive downstream MAPK signaling. Inhibition of these pathways with RAF inhibitor, sorafenib was investigated on N of 1 trial design setting for refractory osteosarcoma patient. Methods: The subject of this study was 25-year old male patient with heavily treated metastatic osteosarcoma and no treatment option was available including systemic chemotherapy and radiotherapy at the moment of enrollment. The disease burden of the patient was lung, chest wall and axillary lymph nodes and progressed rapidly with clinical deterioration. Whole exome sequencing of the genomic DNA from peripheral blood mononucleated cells and formalin fixed paraffin embedded tissues of primary tumor and two metastatic tumors with usage of one lane of paired-end, 100bp reads on Illimuna Hiseq. Several novel somatic mutations including GNAQ were identified in metastatic tumors(AACR 2014) and sorafenib 800mg was administered on purpose of inhibiting MAPK pathway. During administration, tumor response and safety of the drug was evaluated. Results: The patient had taken sorafenib 800mg without interruption for 3months and the only adverse event was grade 1 hand-foot syndrome. After taking drugs, the pain and general performance were improved and CT scan taken at 1 and 2 months after initiating sorafenib showed slightly decreased tumor size in chest wall and axillary lymph nodes. However the chest wall metastases were progressed in the end with progression free survival (PFS) of 3 months. Conclusions: Comparing historical data on osteosarcoma and considering PFS of the patient’s previous palliative cytotoxic chemotherapy less than 2 months, sorafenib has shown potential efficacy in tumors with GNAQ mutation. Further exploration of the role of MAPK signaling inhibition such as sorafenib or MEK inhibitors on GNAQ mutation tumors as a genome-based precision medicine is warrented.
Lymphopenia as a predictor of survival in chemoradiation (CRT)-treated stage III non-small cell lung cancer (NSCLC).
Authors: Mahender Yellu, Farhad Fakhrejahani, Jun Ying, Michelle Mierzwa, Ehsan Malek, Sulsal Haque, Arun Sendilnathan, Bradley Joseph Huth, John Charles Morris, Nagla Abdel Karim, Tahir Latif, Kevin P. Redmond, William Barrett, Gregory M.M. Videtic, Nooshin Hashemi Sadraei
Journal: Journal of Clinical Oncology (2015)

e18513 Lymphopenia as the predictor of survival in chemo radiation (CRT) treated stage III non-small cell lung cancer (NSCLC) Background: Despite potential curative CRT treatment for locally advanced NSCLC, survival remains low. A recent phase 3 trial (RTOG 0617) found patients receiving high dose (HD) RT in stage III unresectable NSCLC had worse outcome compared to standard dose (SD). In clinical trial data sets absolute lymphocyte counts (ALC) is not routinely documented. Lymphopenia has been associated with poor immune system and worse oncologist outcome. We hypothesize that the lymphopenia related to treatment and degree of lymphopenia from radiation dose differential may potentially affect the outcome. Methods: All stage III NSCLC patients (pts) treated with curative CRT was retrospectively studied. Pts were categorized into those receiving SD RT ( ≤ 66 Gy) and HD RT ( > 66Gy). Hematologic values including lymphocyte count (LC) was evaluated at diagnosis and at regular intervals. Overall survival and other time to event endpoints were assessed using Kaplan-Meier survival curves and compared between SD and HD groups using log rank tests. Results: Between 2004 and 2014, 151 patients with stage III NSCLC were identified. 77 % pts were males, adenocarcinoma-52 %, and squamous cell carcinoma-41 % . 124 patients received SD RT and 27 received HD RT. HD was associated with significantly higher mortality (P < 0.0001). We have observed a trend towards lower nadir LC in HD vs SD (305/uL vs 390/uL, p 0.116), and a more significant drop in ALC compared to baseline ( -1725/ uL vs. -1472/ uL , p 0.1). Conclusions: Our study demonstratedsurvival disadvantage ofHD RT in stage III NSCLC pts in non-clinical trial setting. LC reached a lower nadir among HD patients. The lower LC may have contributed to the observed poor clinical outcome. Yet this finding is hypothesis generating, therefore a larger multi-institutional study should be considered. Capturing ALC in prospective studies as a potential predictor of outcome could be useful.
Gene expression profiles and tumor locations in colorectal cancer (left vs. right vs. rectum).
Authors: Martin K. H. Maus, Diana L. Hanna, Craig Stephens, Peter Philipp Grimminger, Melinda Epstein, Stephanie H. Astrow, Dongyun Yang, Fotios Loupakis, Jack Hsiang, Gary Zeger, Takeru Wakatsuki, Afsaneh Barzi, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2013)

3527 Background: Recent data suggests that CRC from different locations show distinct genetic profiles. Right-sided tumors have a worse prognosis and may have less benefit from targeted therapies. We investigated the tumor locations and genetic profiles (KRAS and BRAF mutation status and ERCC1, TS, EGFR and VEGFR2 mRNA expression) in 580 CRC tumors. Methods: FFPE tumor specimen from 580 patients with advanced CRC adenocarcinoma were microdissected and DNA and RNA were extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the mRNA expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. These values were analyzed according to tumor location (left vs. right vs. rectum). Results: BRAF mutations were significantly more common in the right colon (15%), followed by rectum (3.8%) and left colon (2.5%). KRAS mutations occurred at similar frequencies throughout the colon. Gene expression of ERCC1 was significantly higher in right-sided than left-sided colon tumors in KRAS wild-type colon cancers. The highest expression levels for all genes were seen in rectum. These differences reached significant levels for ERCC1 (rectum vs. right and rectum vs. left, p&lt;0.001), TS (rectum vs. left, p&lt;0.036) and VEGFR2 (rectum vs. right and rectum vs. left, p&lt;0.001). Conclusions: Tumor location in CRC is associated with specific mutation and expression profiles. Differences in chemosensitivity may be explained by mutation status and mRNA levels in right vs. left CRC. Rectum cancers showed a distinct genetic profile when compared to colon which indicates different tumor biology and may be related to differences in the microflora.
A phase I trial of lenalidomide maintenance after autologous stem cell transplant (ASCT) in patients with high-risk relapsed/refractory lymphomas.
Authors: Jakub Svoboda, Lauren Strelec, Nirav Niranjan Shah, Elise A Chong, Kathleen Montrey, Kristy Walsh, Scott F. Huntington, Anthony Mato, Daniel Jeffrey Landsburg, Sunita Nasta, Stephen J. Schuster
Journal: Journal of Clinical Oncology (2015)

8553 Background: Lymphoma patients (pts) with residual hypermetabolic lesions on PET imaging after salvage chemotherapy have extremely poor outcomes and may benefit from continued therapy after ASCT. Lenalidomide (len) has been used as maintenance in other hematologic malignancies, but its toxicity and efficacy are not well known in lymphoma pts following ASCT. Methods: We conducted a phase I trial of len maintenance after ASCT in lymphoma pts at high risk for relapse defined by residual PET positive lesions of SUV > 2.5 immediately prior to ASCT. Our primary objective was to determine the safety and dose-limiting toxicity (DLT) of len maintenance. A 3+3 de-escalation design was utilized with a starting dose of len at 10 mg on days 1 through 28 of each 28 day cycle (C). Len was initiated 28-100 days post-ASCT and planned for twenty four Cs. DLT was defined as non-hematologic toxicity ≥ grade (G)3 or hematologic toxicity ≥ G4 during the first 28 days of len. Enrollment began in 5/2012; reported data were collected through 1/2015. Results: Eight pts were enrolled and 6 pts are evaluable (4 diffuse large B-cell and 2 Hodgkin lymphomas). One pt withdrew consent and one progressed prior to initiation of len. Median age was 51 yrs (29-61), ECOG PS 0 (0- 1), prior therapies 3 (2-5). Median time on len was 7 Cs (2-24). Len was well tolerated and no DLT was observed at the 10 mg dose. Two pts required dose reduction to 5 mg due to treatment-related toxicities (after C7 and C3). Four pts had ≥ G2 non-hematologic adverse events possibly related to len including fatigue, bronchitis, and thrush. Three pts had transient ≥ G3 neutropenia. Two pts discontinued len (1 due to progression, 1 at investigator’s discretion). No secondary malignancies or study-related deaths were observed. Four of 6 pts remain on len and are progression free; 5 of 6 pts are alive with median follow-up of 195 days. Conclusions: We established safety of len after ASCT in pts with relapsed/refractory lymphomas and determined that len 10 mg daily is a well-tolerated maintenance dose in this setting. Preliminary clinical outcomes observed in this cohort of high-risk lymphoma pts are encouraging and will be validated in the ongoing phase II trial. Clinical trial information: NCT01575860.
Prognostic factor analysis of second-line chemotherapy in advanced biliary tract cancer.
Authors: Sang-Cheol Lee, Kyoungha Kim, Hanjo Kim, Hyun Jung Kim, Se Hyung Kim, Sang-Byung Bae, Chan Kyu Kim, Namsu Lee, Kyu Taek Lee, Sung Kyu Park, Jong-Ho Won, Jina Yun, Dae Sik Hong, Hee Sook Park
Journal: Journal of Clinical Oncology (2012)

e14688 Background: There is no evidence that second-line chemotherapy in advanced biliary tract cancer (BTC) will result in substantial prolongation of survival. The purpose of this study was to evaluate prognostic factors for the survival of patients with advanced biliary tract cancer who was refractory BTC for first-line chemotherapy. Methods: We reviewed 89 patients retrospecitively with advanced biliary tract cancer who had enrolled in two clinical trials at three branches of Soonchunhyang university hospital. They received palliative chemotherapy with 2 regimens (biweekly GEMOX and modified FOLFOX-6). GEMOX is consist of gemcitabine 1,000 mg/m 2 intravenously on day 1 and oxaliplatin 85 mg/m 2 intravenously on day 2 every 2 weeks and mFOLFOX-6 is that oxaliplatin 85mg/m 2 and folinic acid 400 mg/m 2 on day 1 follwed by a 5-FU bolus 400 mg/m2 and 46-h infusion 2400 mg/m 2 every 2 weeks. To evaluate the clinicopathologic factors that affected overall survival, univariate and multivariate analyses were performed on the baseline factors. Results: 89 patients were enrolled from Sep 2006 to Aug 2010. Medain age was 62.14 years (range 35-81). Univariate analysis revealed 4 prognostic factors affecting overall survival after first-line chemotherapy. Performance status of 0-1 vs &gt;2 (p=0.014), salvage chemotherapy (p=0.021), locoregional disease vs disseminated disease (p=0.046) and responder of first-line chemotherapy (p=0.025) was revealed. Multivariate analysis found 2 prognostic factors affecting overall survival. They were salvage chemotherapy and initial responder. Conclusions: This results suggest that 2 nd -line chemotherapy is needed for patients with good performance and responder of initial chemotherapy.
Contents, Vol. 52, 1989
Authors: S. Aritzi, J. Demakis, G. Demakis, J. Fareed, R. Reid, N. Dunkas, S.C. Richardson, G.C. Lyketsos, Giovanni de Girolamo, Giovanni Marchitelli, Rosalia Corbani, Stefano Palazzi, Judith L. Silverstein, J. Passchier, M.B.M. van den Bree, M.L.A. Leijdekkers, F. Verhage, Giovanni A. Fava, Silvana Grandi, Renzo Canestrari, Fernando Lolas, Grigoris Vaslamatzis, Marios Markidis, Klea Katsouyanni
Journal: Psychotherapy and Psychosomatics (1989)
Genetic variation in CYP19A1 and occurrence of adverse events in exemestane treatment with early breast cancer patients in the Dutch TEAM trial.
Authors: Danny Houtsma, Duveken Fontein, Tahar van der Straaten, Renee Baak-Pablo, Judith A.M. Wessels, Caroline Seynaeve, Cornelis J. H. Van De Velde, J. W. R. Nortier, Hans Gelderblom, Henk-jan Guchelaar
Journal: Journal of Clinical Oncology (2013)

e22152 Background: Aromatase inhibitors (AI) are an important part of treatment of endocrine sensitive breast cancer. Adverse events in patients treated with AI’s often cause treatment discontinuation. The most common adverse events, such as arthralgia, myalgia and hot flushes are probably caused by estrogen deprivation and predict treatment efficacy. It is unclear which patients are at risk to develop these adverse events. The aim of this study was to examine if SNP’s in the CYP19A1 gene can predict the occurrence of adverse events in breast cancer patients treated with adjuvant exemestane. Methods: Patients of whom tissue was available and were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. DNA was isolated from tumor samples and 30 SNPs were identified using a tagging SNP approach, aiming for 80% coverage of CYP19A1. Genotypes were determined with taqman assays. Primary endpoint of the study was the occurrence of adverse events. Secondary endpoints were the occurrence of hot flushes, arthralgia, and myalgia. Results: 807 patients were included in the analyses and genotypes were obtained in 722 cases. One SNP, rs8031311, was associated with a higher incidence of adverse events with an odds ratio of 2.8. Four SNP's were associated with an increased incidence of hot flushes: rs934635, rs4775928, rs16964189, rs6493496 with odds ratio’s of 2.9, 1.8, 1.8 and 2.6 respectively. No association was found between variation in CYP19A1 and the occurrence of arthralgia or myalgia. Conclusions: Germline variation in the CYP19A1 gene is related to the occurrence of adverse events, specifically hot flushes, in early breast cancer patients treated with exemestane. These findings may contribute to the individualization of hormonal therapy in breast cancer. [Table: see text]
Absolute Lymphocyte Count At Day+15 and +30 Post-ASCT As Predictors of Early and 1-Year Mortality for Patients with AL Amyloidosis Treated with a Single Autologous Stem Cell Transplant
Authors: Victor Hugo Jimenez-Zepeda, Donna Reece, Suzanne Trudel, Christine I. Chen, Norman Franke, Andrew Winter, Rodger E. Tiedemann, Vishal Kukreti
Journal: Blood (2012)
Cetuximab and bevacizumab in addition to chemotherapy first-line for left-side metastatic colorectal cancer: A cost-effectiveness analysis.
Authors: Yanqiao Zhang, Tongsen Zheng, Maobai Liu, Te Li, Bin Wu
Journal: Journal of Clinical Oncology (2017)

732 Background: To test the cost-effectiveness of cetuximab and bevacizumab treatment as first-line treatment for patients with left-side metastatic colorectal cancer (mCRC). Methods: A Markov model was developed to Chinese clinical practice. The model incorporated clinical and utility data from published literatures, resource utilization and unit prices based on local charge. The lifetime horizontal was used and sensitivity analyses were carried out to test the robustness of the model results. The impact of patient assistance program (PAP) was also evaluated in scenario analyses. Results: Baseline analysis showed that the addition of cetuximab gained additional 0.364 QALYs with more $39,450 relative to bevacizumab therapy, resulting in an ICER of $108,287 /QALY. When PAP was available, the incremental cost decreased to $2,464, which yielded an ICER of $6,764 /QALY, which indicated that the strategy might be very cost-effective at a willingness-to-pay (WTP) threshold of 3 times the per capita GDP of China ($22,200/QALY). Sensitivity analyses found that the costs of cetuximab and bevacizumab were the most influential parameters. Conclusions: When PAP was available in Chinese context, cetuximab treatment is likely to be cost-effective versus bevacizumab therapy for patients with left-side mCRC.
Quantitative CT imaging features for hepatocellular carcinoma (HCC) with b-catenin (CTNNB1) gene mutation.
Authors: Ahmed M. Khalaf, David T. Fuentes, Kareem Ahmed, Reham Abdel-Wahab, Manal Hassan, Ahmed Omar Kaseb, John D. Hazle, Khaled M. Elsayes
Journal: Journal of Clinical Oncology (2017)

253 Background: To determine whether CT imaging features can provide quantitative biomarkers to differentiate HCC with pathologic B-catenin gene mutation and those without mutation. Methods: Quantitative imaging features were extracted from a database of manually labeled liver with enhancing and non-enhancing tumor tissue,which were established using multiphasic CT images from 17 patients. CT studies were done before each patient underwent surgical removal of the HCC, which were subjected to pathologic analysis to evaluate B-catenin mutation.The mean period between the CT studies and the pathologic analyses was 18 days. According to the pathology results, the patients were divided into two groups: HCC with CTNNB1 mutation and HCC without. Image feature extraction included image gradients, co-occurrence matrix, and pixel neighborhood statistics of the first, second, and third moments. Pairwise analyses of the imaging features were performed on the mutated and non-mutated HCC images and the background liver tissue of both groups. Independent samples t-test and Mann Whitney U test were performed to quantitatively compare between the means of the imaging features extracted from the tumor tissues of both groups and those extracted from the background liver tissue of both groups. Results: Imaging feature analysis of the pairwise difference between the mutated and non-mutated HCC scans for multiple pixel-neighborhood image features are statistically significant.The top stratifying image features include the skewness (p = 0.02), energy (p = .03), and entropy (p = .03) during the venous and arterial phase. Conclusions: This preliminary study demonstrates the feasibility of quantitative imaging feature extraction from CE-CT imaging to differentiate between HCC with proven B-catenin gene mutation and those without mutation. Non-invasive methods of identifying HCC with B-catenin mutations may be clinically beneficial since B-catenin is an important potential target in novel cancer therapies, and identifying B-catenin mutations may also help provide information regarding prognosis.Verifying the quantitative features in larger patient populations is needed to confirm the results of this study.
Comparison of magnetic resonance imaging and histopathological response to neoadjuvant chemotherapy in locally advanced rectal cancer: The GEMCAD 0801 trial.
Authors: Gina Brown, Uday Bharat Patel, Jesus Santos Cores, Maria Isabel Gil Garcia, Juan Ramón Ayuso, Iciar Puchades Roman, Fernando Mas Estelles, Noelia Risueno, Antonieta Salud, Juan Maurel, Jorge Aparicio, Carles Pericay Pijaume, Vicente Alonso, M. José Safont, Manuel Gallén, Ruth Vera, Jaime Feliu, Marta Martin-Richard, Carlos Fernandez-Martos
Journal: Journal of Clinical Oncology (2012)

e14097 Background: MRI methods for rectal cancer response assessment post chemoradiotherapy include post treatment T staging(ymrT), tumor regression grading(mrTRG) and length change/modified RECIST measurement. The usefulness of MRI in evaluating response to neoadjuvant chemotherapy has not been investigated. We assessed the reproducibility and agreement of these three parameters with histopathological T and TRG stage(ypT, pTRG). Methods: 28 eligible patients were enrolled in a prospective phase II trial to evaluate safety and efficacy of neoadjuvant CAPOX-B in patients with MRI defined T3 rectal adenocarcinoma. Patients received 4 cycles of Cap 2000 mg/m2(d1-14),Ox 130 mg/m2(d1) and B 7.5 mg/kg(d1) every 3 weeks(last cycle without B). Seven radiologists assessed MRIs using the following categories: ymrT (T0-T4 using T3 substaging), mrTRG (1-5), and length change(Stable disease, Complete response,Partial response). Agreement was assessed by kappa (central reviewer data verses each local centre reviewer).Agreement between central reviewer MRI results and both pathology endpoints was also assessed. Results: 24 patients had evaluable pre and post chemotherapy imaging and pathology (4 did not have post treatment MRI). Thirteen patients had good response (ypT0-3a) and 11 had poor response (&gt;ypT3a). Sixteen patients had good pTRG(2-4) and 8 had poor pTRG(0&amp;1). ymrTRG showed a moderate level of reproducibility;K=0.45-0.58. ymrT showed a fair to moderate level of agreement;K=0.2-0.53. Length assessment also showed a fair level of agreement; K=0.21-0.38. ymrTRG showed 75% agreement with ypT(16/22); K=0.49(0.13-0.84) and 79% agreement with pTRG(19/24); K=0.55(0.22-0.88). ymrT showed a fair level of agreement with ypT;K=0.21, pTRG;K=0.2, length assessment showed slight agreement with ypT;K=0.1, pTRG;K=0.1. Conclusions: This is the first study to show MRI can evaluate response of rectal cancer following neoadjuvant chemotherapy. As mrTRG showed best agreement with pathology, we recommend mrTRG as the preferred method of post treatment assessment in this setting.
Weekly nab-paclitaxel in combination with carboplatin as first-line therapy in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Mark A. Socinski, Corey J. Langer, Isamu Okamoto, Jeremy K. Hon, Vera Hirsh, Shaker R. Dakhil, Ray D. Page, James M. Orsini, Hui Zhang, Markus F. Renschler
Journal: Journal of Clinical Oncology (2012)

7590 Background: The median age of advanced NSCLC pts in the US is 71 years; yetelderly pts (≥70 years) are generally undertreated, with only ≈30% receiving systemic therapy. Hence, better, more tolerable therapeutic options are needed for this cohort. In a phase III trial nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C, significantly improved ORR, the primary endpoint (25% vs 33%, P = 0.005), with a 1-month improvement in OS (P = NS) and improved safety. This analysis evaluated efficacy and safety in pts ≥70 and &lt;70 years old. Methods: Pts with untreated stage IIIB/IV NSCLC and with an ECOG score of 0/1 were randomized 1:1 (stratified by age [≥70 vs &lt;70 years], region, stage, gender, and histology) to C AUC 6 day 1 and either nab-P 100 mg/m 2 on days 1, 8, 15 or sb-P 200 mg/m 2 day 1 q 21 days. ORR and progression-free survival (PFS) were determined by blinded centralized review. Results: Of the phase III study population, 15% were elderly (156/1052; 74 pts in the nab-P/C and 82 in the sb-P/C arms). Most elderly pts were male (72%), Caucasian (71%), and had stage IV disease (64%). In pts both ≥70 and &lt;70 years old, ORR was higher in the nab-P/C vs sb-P/C arm (≥70: 34% vs 24%, P = 0.196; &lt;70: 32% vs 25%, P = 0.013). In pts ≥70 years old, PFS trended in favor of nab-P/C (median 8.0 vs 6.8 months, HR: 0.687, P = 0.134); OS was significantly improved (median 19.9 vs 10.4 months, HR: 0.583, P = 0.009). In contrast, PFS (6.0 vs 5.8 median months, HR: 0.903, P = 0.256) and OS (11.4 vs 11.3 median months, HR: 0.999, P = 0.988) were similar for both treatment arms in pts &lt;70 years old. Adverse events were similar in pts ≥70 years old vs the entire study population, with less grade 3/4 neutropenia (P &lt; 0.05) and neuropathy (P &lt; 0.05) and increased thrombocytopenia (P = NS) and anemia (P &lt; 0.05) in the nab-P/C vs sb-P/C arms. In pts ≥70 years old, patient-reported FACT-taxane subscales revealed significantly less neuropathy, pain, and hearing loss in the nab-P/C vs sb-P/C arms (P &lt; 0.001). Conclusions: In elderly pts with advanced NSCLC, nab-P/C as first-line therapy was well tolerated and led to improved ORR and PFS, with significantly longer OS vs sb-PC.
Four-Year Survival and Durability Results of Brentuximab Vedotin in Combination with CHP in the Frontline Treatment of Patients with CD30-Expressing Peripheral T-Cell Lymphomas
Authors: Michelle A Fanale, Steven M Horwitz, Andres Forero-Torres, Nancy L Bartlett, Ranjana H Advani, Barbara Pro, Robert W Chen, Andrew J Davies, Tim Illidge, Mayur Uttarwar, Dirk Huebner, Hong Ren, Andrei R Shustov
Journal: Blood (2016)