tbuckley/cabot-search huggingface dataset:
Evaluation of flare phenomena in advanced colorectal cancer after bevacizumab cessation in the well-responded cases.
Authors: Ali Ayberk Besen, Fatih Kose, Huseyin Abali, Ozgur Ozyilkan, Nurullah Zengin, Nuriye Yildirim
Journal: Journal of Clinical Oncology (2016)

e15019 Background: Angiogenesis, one of the eight cancer hallmarks, is necessary for the development of tumor beyond certain volume, facilitates invasion, and metastases. VEGF is a potent growth factor that has a central role in tumor angiogenesis. Although, the positive impact of bevacizumab on survival parameters, the main effect of bev is cytostatic rather than cytotoxic. This comes with the concern of rapid tumor re-growth after discontinuation of bevacizumab. Methods: We retrospectively evaluated rapid regrowth phenomenon in 105 patients those who were treated with the predefined number of chemotherapy cycles (4-6 month) and grouped according to whether the chemotherapy regimen in the first line setting included bevacizumab, chemotherapy-bevacizumab (CT-Bev) or not chemotherapy (CT). The primary endpoints were to assess PFS 2 (the time from the last dose of bevacizumab (Chemo-Bev group) or chemotherapy (Chemo group) to the first documentation of progression) and OS2(the time from the end of last dose of chemotherapy +/- bevacizumab to death/last control date). Secondary end points were PFS ( the time from the initiation of first-line chemotherapy to the initial sign of progression) and OS (the first dose of chemotherapy administration to death/last control date). Results: Median age was 55 years old. Median overall and progression-free survival times were 27 and 11 months, respectively. Rapid progression rates were 42% and 40% in CT and CT-Bev without no statistically significant difference (p = 0.84). In CT, significantly more patients with stable disease (SD) progressed rapidly compared to patients with complete (CR) or partial response (PR) (53% vs. 27%, p: 0.04). This result was also similar in CT-Bev (48% vs. 30%, p: 0.27) but could not reach to the significant p-value. Overall survival 2 , was significantly shorter in both CT and CT-Bev for patients who showed SD compared to CR or PR (15 vs 38 months) (p < 0.001). Conclusions: In conclusion, the current study showed that cessation of bevacizumab after predefined treatment cycles did not have any negative effect on patients outcome of advanced CRC. This result particularly acceptable for the patients who showed CR or PR to the treatment of CT or CT-bev.
A randomized, double-blind, placebo-controlled study of the safety and efficacy of olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy.
Authors: So Yeon Jeon, Hye Sook Han, Woo Kyun Bae, Moo-Rim Park, Sang-Cheol Lee, Se-Il Go, Hwan Jung Yun, Hyewon Ryu, Yong-Jin Im, Eun-Kee Song
Journal: Journal of Clinical Oncology (2017)

e21699 Background: Olanzapine was found to be effective for preventing acute and delayed emesis in patients receiving highly emetogenic chemotherapy by randomized phase 3 study. However, there is limited data for the efficacy of olanzapine combined with palonosetron and dexamethasone in patients receiving moderately emetogenic chemotherapy (MEC). Methods: We conducted randomized, double-blind, placebo-controlled study to determine whether olanzapine could reduce the frequency of CINV and improve quality of life (QOL) in patients receiving palonosetron and dexamethasone for the prophylaxis of MEC induced nausea and vomiting. Two groups received either 10 mg of olanzapine orally or matching placebo daily on days 1 through 4. The primary end point was the complete response (no emesis and no use of rescue medication) for the acute phase (0-24 hours after chemotherapy). Secondary end points included the complete responses for the delayed (24-120 hours) and overall phase (0-120 hours), proportion of significant emesis (VAS ≥ 25 mm) for overall phase, use of rescue medications, and effect on QOL by Functional Living Index-Emesis (FLIE) questionnaire. Results: Fifty-six patients were randomized and fifty-four patients were evaluable (29 assigned to olanzapine, and 25 to placebo). The complete response rate was not significant between olanzapine and placebo group in the acute (96.5% vs. 88.0%, P = 0.326), delayed (69.0% vs. 48.0%, P = 0.118), and overall phase (69.0% vs. 48.0%, P = 0.118). However, the percentage of patients with significant emesis (17.2% vs. 44.0%, P = 0.032) and the use of rescue medications (0.03±0.19 vs. 1.88±2.88, P = 0.002) were significantly lower with olanzapine than with placebo in the overall phase. Furthermore, olanzapine group experienced a better QOL than the placebo group, as reported on the FLIE questionnaire (P = 0.015). Conclusions: Olanzapine in addition to palonosetron and dexamethasone significantly improved the management of emesis and QOL among previously untreated patients receiving MEC, although the efficacy was limited to reduce the frequency of CINV. Clinical trial information: NCT02400866.
PD.2.05 Circulating Tumor DNA Improves Genotypification and Detection of Targetable Alterations in Selected Lung Cancer Patients
Authors: Z. Zatarain-Barrón, F. Barrón, A. Cardona, G. Cruz-Rico, K. Flores-Veles, C. Espenschied, V. Raymond, R. Lanman, C. Vargas, O. Arrieta
Journal: Journal of Thoracic Oncology (2018)
PD.1.06 EGFR Uncommon Mutations Frequency in a 1,688 NSCLC Patients Database in Brazil
Authors: C. Ferreira, M. Zalis, G. Montenegro, M. Custodio, M. Zukin, G. Castro, C. Mathias, C. Haddad, V. De Lima, L. Araujo, C. Baldotto, A. Gelatti, C. Bustamante, A. Souza, M. Reis
Journal: Journal of Thoracic Oncology (2018)
Dendritic cell vaccine (DCVAC) with chemotherapy (ct) in patients (pts) with recurrent epithelial ovarian carcinoma (EOC) after complete response (CR) to 1st-line platinum (Pt)-based ct: Primary analysis of a phase 2, open-label, randomized, multicenter trial.
Authors: David Cibula, Peter Mallmann, Pawel Knapp, Bohuslav Melichar, Jaroslav Klat, Lubos Minar, Zdenek Novotny, Pauline Wimberger, Alexander Hein, Radek Spisek, Jirina Bartunkova, Ladislav Pecen, Hariz Iskandar Bin Hassan, Lukas Rob
Journal: Journal of Clinical Oncology (2018)

e17515 Background: When pts with EOC relapse, their response to subsequent therapy is reduced. We hypothesized that autologous DCVAC could potentiate the antitumor response to ct and delay progression. Methods: Key eligibility criteria were FIGO stage III - IV EOC (serous, endometrioid, or mucinous), PS 0 - 2, CR after 1st-line Pt-based ct that lasted > 6 months, and at least 1 measurable lesion per RECISTv1.1. We randomized pts up to 6 weeks after relapse was confirmed by CT/MRI, 1:1, into arm A (A; DCVAC concomitantly with ct) and arm B (B; ct alone). Pts were stratified by previous bevacizumab use (yes/no) and duration of remission (6 - 12/ > 12 months). Ct consisted of 6 - 10 cycles of carboplatin (AUC 4 - 5; D1) and gemcitabine (1000mg/m2; D1, D8). Pts in A were to receive 10 doses of DCVAC (1 x 107 DCs/dose). The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results: Between November 2013 and May 2015, 71 pts were randomized in 3 countries (A/B, 39/32). Median age was 58.5 years in A and 60.5 years in B. After excluding pts who failed leukapheresis or manufacturing, the intention-to-treat population included 32 pts in each arm. A mean of 9.8 doses of DCVAC were administered in A. Median follow-up time was 28.2 months (range, 23.8 - 41.6 months). Median PFS was 10.9 months in A and 9.4 months in B; HR (95% CI) = 0.74 (0.42 - 1.30), p = 0.29. The corresponding ORR (95% CI) was 87.5% (71.0% - 96.5%) in A and 62.5% (43.7% - 78.9%) in B. In November 2017, median OS was not reached in A, while it was 30 months in B (44% events); HR (95% CI) = 0.62 (0.29 - 1.34). The majority of adverse events (AEs) were related to ct (thrombocytopenia [A: 64.9%, B: 80.6%], anemia [A: 64.9%, B: 67.7%], neutropenia [A: 59.5%, B: 67.7%], and leukopenia [A: 45.9%, B: 32.3%]). There were no grade ≥ 3 AEs related solely to DCVAC. Most common leukapheresis-related AEs were mild pyrexia and moderate hypocalcemia. Conclusions: Primary analysis showed better ORR and a trend towards improved OS in the DCVAC arm. Clinical trial information: NCT02107950.
Comprehensive molecular profiling of multi-focal prostate cancer and concomitant lymph node metastasis: Implications for tissue-based prognostic biomarkers.
Authors: Simpa Samuel Salami, Daniel H Hovelson, Romain Mathieu, Jeremy B Kaplan, Martin Susani, Nathalie Rioux-Leclercq, Shahrokh F. Shariat, Scott A. Tomlins, Ganesh S. Palapattu
Journal: Journal of Clinical Oncology (2017)

5061 Background: Current tissue-based prognostic biomarker assays claim that assessment of a single biopsy focus is sufficient to predict disease behavior. We analyzed and compared the genetic profiles of multifocal prostate cancer (PCa) with concordant lymph node metastasis (LNM) to determine if expression-based prognostic tests are robust to multifocality. Methods: This IRB-approved study comprised patients who underwent radical prostatectomy and lymph node dissection that revealed N1 or discordant multifocal (low- and high-grade foci) disease. DNA and RNA were co-isolated from each tumor focus pre-identified on formalin fixed paraffin embedded specimens. High depth, targeted DNA and RNA next generation sequencing was performed to characterize the molecular profile of each sample, using the Oncomine Comprehensive (11 patients) or Comprehensive Cancer (DNA, 3 patients) Panels and a custom targeted RNAseq panel comprising genes for deriving prognostic signatures. Results: A total of 67 primary tumor and 17 LNM foci from 14 patients were analyzed. We observed significant intra- and inter-patient molecular heterogeneity. For example, in patient #1, while all 4 regions of high-grade primary tumor showed TP53 somatic mutations and some copy number alterations (CNAs) with two samples from the LNM, tumor areas near the positive margin showed more complete concordance than intraprostatic regions. Critically, a low-grade primary tumor focus in this case showed no somatic mutation or CNA overlap with the high-grade or LNM samples. In patient #4, all tumor and LNM foci shared a large number of somatic mutations, including a frameshift mutation in PTEN, with no high level CNA, consistent with a hypermutated genotype. By targeted RNAseq, low- and high-grade tumors from the same patient showed distinct expression profiles using genes included in prognostic signatures. Conclusions: Our results challenge the claim that expression-based prognostic tests are robust to multifocality. Further studies are needed to better characterize the biologically dominant lesion in multifocal PCa and hold promise for the development of improved prognostic biomarkers.
Premilinary survival results and potential beneficiaries for locally advanced nasopharyngeal carcinoma treated with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy.
Authors: Mei Feng, Jinyi Lang, Lu Li, Yecai Huang, Peng Xu, Yunxiang Qi, Fang Li, Weidong Wang
Journal: Journal of Clinical Oncology (2017)

6030 Background: Neoadjuvant is a promising chemotherapy modality for recurrent nasopharyngeal carcinoma (NPC). However, there is still controversy for locally advanced NPC. We study the survival results of locally advanced NPC treated with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy (NACT) retrospectively, and to explore the potential beneficiaries. Methods: 147 stage III-IVa+b NPC treated with IMRT were included and divided into two groups. NACT group (76) received 2-3 cycles of neoadjuvant chemotherapy with TP or TPF, and then 2-3 cycles of platinum-based chemoradiotherapy (CCRT). CCRT group (71) received 3 cycles of platinum-based chemoradiotherapy. TNM stage, age and whole blood count before treatment were all collected. The stratified analysis was used for distinguishing the potential beneficiaries. Results: median follow-up time was 30 months. For all patients, the 3-year LRRFS, DMFS and OS in NACT and CCRT were 94.5%, 96.8%; 85.8%, 82.8% and 81.6%, 83.4% respectively ( p&gt; 0.05). For stage III patients, the 3-year LRRFS, DMFS and OS were 95.2%, 97.3%; 91.4%, 84.6% and 86.3%, 82.1% respectively ( p= 0.38, p= 0.15, p= 0.58). Though there was no statistical significance, DMFS in NACT was better than it in CCRT. However, for stage IV, the survival rate had no significant difference. The incidence of grade 3-4 bone marrow suppression was higher in NACT ( p= 0.007), and the other toxicities were similar. Univariate analysis showed the percentages of neutrophil and neutrophil-to-lymphocyte ratio (NLR) were significantly correlated with OS ( p= 0.031, p= 0.049). N and clinical stage were the adverse prognostic factors for OS ( p= 0.025, p= 0.007) and DMFS ( p= 0.018, p= 0.001). Clinical stage was the prognostic factors for OS and DMFS in multivariate analyses ( p= 0.019, p= 0.01). Conclusions: NACT had a comparable survival results and tolerable toxicity with CCRT for locally advanced NPC. Stage III might be the potential beneficiaries from NACT, especially for DMFS. Percentages of neutrophil and NLR might be the new adverse prognostic factor for OS. Clinical stage was still the prognostic factor for OS and DMFS.
Non-invasive determination of the O<sup>6</sup>-methylguanine-DNA-methyltransferase (<i>MGMT</i>) promoter methylation status in glioblastoma (GBM) using magnetic resonance imaging (MRI).
Authors: Saima Rathore, Spyridon Bakas, MacLean P Nasrallah, Stephen Joseph Bagley, Hamed Akbari, Sung Min Ha, Elizabeth Claire Mamourian, Christopher D Watt, Christos Davatzikos
Journal: Journal of Clinical Oncology (2018)

2051 Background: MGMT promoter methylation is associated with better prognosis and increased benefit from temozolomide in patients with GBM. The methylation status of the MGMT promoter is typically determined by tissue-based polymerase chain reaction assays, which can be limited by inadequate specimen or assay failures. We hypothesized that multivariate analysis of quantitative imaging (QI) features, extracted from multi-parametric MRI (mpMRI), could enable the non-invasive determination of MGMT promoter methylation status. Methods: We performed a retrospective cohort study of 111 GBM patients at the University of Pennsylvania whose tumors underwent MGMT methylation testing (pyrosequencing across 4 CpG sites in the MGMT promoter) and for whom pre-operative structural mpMRI data (T1, T1-Gd, T2, and T2 FLAIR) were available. For each enhancing and non-enhancing tumor sub-region and its peritumoral edema/invasion, we extracted a diverse set of QI features comprising volumetric, morphologic, and texture characteristics, histogram-based signal profiling, and spatial distribution patterns. These features were multivariately integrated via a support vector machine to construct a non-invasive marker of MGMT promoter methylation that was quantitatively evaluated using a 10-fold cross-validation (CV). Results: 40 patients (36%) were positive for MGMT promoter methylation and 71 (64%) were negative. The accuracy of the non-invasive MGMT methylation marker was 88.28% [Specificity = 97.0%, Sensitivity = 75.0%, Area under the curve (AUC) = 0.80]. The most predictive features were consistently selected across the 10-fold CV. Conclusions: Multivariate integrative analysis of QI features extracted from mpMRI yields an accurate, non-invasive marker of MGMT promoter methylation status in GBM. If validated in larger datasets, this marker may allow for early stratification of newly diagnosed GBM trial candidates by MGMT methylation status, non-invasive MGMT methylation testing in patients for whom tissue is inadequate, and potential monitoring of MGMT methylation status during treatment.
Development of targeted radiotherapy for triple negative breast cancer.
Authors: Shu-ta Wu, Vijay Gottumukkala, Richard Coelho, Laura Jeffords Moore, Vanessa Kelly, Ohad Ilovich, Rahul Puri, Pinku Mukherjee
Journal: Journal of Clinical Oncology (2018)

e13112 Background: Breast cancer (BC) remains a leading cause of cancer-related deaths worldwide. Triple negative breast cancer (TNBC) is an aggressive phenotype that comprises only 15-20% of all new BC cases but is responsible for a majority of related deaths. Chemotherapy is the current mainstay treatment for TNBC but side effects and drug-resistance remain an issue, so development of targeted therapies for TNBC is critical. Tumor associated mucin 1 (tMUC1), an aberrantly glycosylated transmembrane glycoprotein, is overexpressed in > 90% of TNBCs. We’ve developed a humanized, tMUC1-specific antibody (hTAB004) and radiolabeled it to allow for targeted TNBC treatment. Methods: hTAB004 was conjugated to DOTA-NHS, purified, formulated in a metal free buffer and radiolabeled with Indium-111 or Actinium-225 to produce 111In-DOTA-hTAB004 and 225Ac-DOTA-hTAB004, respectively. In vivo and ex vivo biodistribution studies of 111In-DOTA-hTAB004 were performed in HCC70 xenograft tumor-bearing female NSG mice (n = 3) using SPECT/CT imaging. Therapeutic efficacy of 225Ac-DOTA-hTAB004 was determined in HCC70 xenograft tumor-bearing female nude mice (n = 5/group) and monitoring body weight and tumor sizes. Results: Radiolabeling efficiency of hTAB004 with Indium-111 and Actinium-225 was > 97%. In vivo biodistribution data revealed increased accumulation of 111In-DOTA-hTAB004 in the tumor over 120 hrs. Ex vivo biodistribution data showed 46% ID/g uptake of 111In-DOTA-hTAB004 in the tumor, > 3-fold higher than in the next highest uptake organ, the spleen. Tumor volumes decreased by > 89% in mice treated with a single injection of 225Ac-DOTA-hTAB004 (18kBq), but continued to grow in the control group that received DOTA-hTAB004 alone. Based on Invicro IACUC criteria, 100% of treated mice survived until the end of the study while all mice in control group died by day 35. Conclusions: 111In-DOTA-hTAB004 biodistribution data indicates the excellent tumor targeting capabilities of hTAB004 and 225Ac-DOTA-hTAB004 therapy data shows exceptional clinical benefit in mice bearing human tumors. Given this data, radiolabeled hTAB004 is a promising targeted treatment and imaging option for TNBC. Acknowledgment Funded by NCI SBIR Contract No HHSN261201600013C
A randomized phase III trial between adjuvant docetaxel and surveillance after radical radiotherapy for intermediate and high risk prostate cancer: Results of SPCG-13 trial.
Authors: Pirkko-Liisa Irmeli Kellokumpu-Lehtinen, Marie Hjälm-Eriksson, Lennart Astrom, Timo Marttila, Camilla Thellenberg-Karlsson, Sten Nilsson, Widmark Anders, Teppo Huttunen, Claes Ginman
Journal: Journal of Clinical Oncology (2018)

5000 Background: Docetaxel combined with androgen deprivation therapy (ADT) has improved survival in advanced prostate cancer (PCa). This randomized trial evaluates if six courses of docetaxel improves biochemical disease free survival (BDFS) after radical radiotherapy (RT) for intermediate or high risk PCa. Methods: : A total of 376 patients were randomised in this multinational phase III study, to receive either 6 cycles of adjuvant docetaxel 75mg/m2 every 3 weeks without continuous prednisone (Arm A, n = 188) or surveillance (Arm B, n = 188) after RT (NTC006653848). Neoadjuvant/adjuvant ADT was mandatory for all patients. Primary end-point was a rising PSA ≥ 2 ng/ml above the nadir PSA value. Intermediate or high risk prostate cancer was defined as T2 with Gleason score (GS) 4+3, PSA > 10; T2, GS 8-10 any PSA; or any T3. Patients were followed for 5 years with PSA every 3 months for two years and thereafter every 6 month. Study power was 89% to detect a difference between groups and the sample size calculation accounted for T2/T3 distribution (12%/15% difference in BDFS was assumed for T2/T3 patients). Results: All six cycles were completed in 147 (78.2%) of patients in arm A. Mean age was 66.2 years in Arm A and 66.4 years in ARM B; 75.0 % had T3 disease, 46.3% had GS 8-10. Median follow up was 59.4 months (range 1 to 111 months, one without follow-up). The primary endpoint was reached in 30.7% of patients; 31.0% in Arm A and 30.3% in Arm B. In a Kaplan-Meier analysis there showed no difference between the BDFS curves (p = 0.631) between treatment groups. Febrile neutropenia occurred in 16.1 % of docetaxel patients. No deaths were related to docetaxel treatment. There were 43 deaths during the trial (20 in Arm A and 23 in Arm B) of which 9 and 7 due to PrCa. In a Cox multivariate analysis, GS (p = 0.001) was significant predictor of PSA progression. Hazard Ratio for Arm A (docetaxel) vs Arm B (surveillance) was 1.14 (95% CI 0.79 to 1.64, p = 0.495). Conclusions: Adjuvant docetaxel without prednisone did not improve BDFS after radical radiotherapy with ADT for intermediate or high risk prostate cancer. Clinical trial information: NTC006653848.
Correlation of killer-cell Ig-like receptor (KIR) haplotypes and Fcγ-receptor polymorphisms with survival of high-risk relapsed/refractory neuroblastoma patients treated by long-term infusion of anti-GD2 antibody ch14.18/CHO.
Authors: Holger N. Lode, Sascha Troschke-Meurer, Dominique Valteau-Couanet, Alberto Garaventa, Juliet Gray, Victoria Castel, Isaac Yaniv, Christian Jensen, Christin Eger, Madlen Juettner, Silke Kietz, Karoline Ehlert, Evelyne Janzek, Hans Loibner, Nikolai Siebert, Ina Mueller, Ruth Ladenstein
Journal: Journal of Clinical Oncology (2016)

10548 Background: Receptors expressed on natural killer (NK) cells and their ligands on target cells involved in antibody-dependent cell-mediated cytotoxicity (ADCC) may predict outcome in patients (pts) with high-risk relapsed/refractory neuroblastoma (NB) treated by long-term infusion (LTI) of anti-GD2 antibody ch14.18/CHO. Methods: 53 pts received 6x106 IU/m2 sc IL-2 (d1-5; 8-12), LTI of 100 mg/m2 ch14.18/CHO (d8-17) and 160 mg/m2oral 13-cis-RA (d19-32) in a closed single center program (53 pts) (APN311-303). Polymorphisms in Fcγ-receptor genes 2A (H131R), -3A (V158F) and -3B (NA1/NA2), and KIR- as well as KIR ligand expression (HLA-C1; HLA-C2; HLA-Bw4+) were determined by real-time PCR. Results: The survival update of the APN311-303 cohort revealed a 5-y OS of 56.4±7.1% (mean OS 4.35y [0.3-6.2y]) and a 5-y PFS of 29.1±6.3% (mean PFS 2.4y [0.1 - 5.9y]). Median TTP/PFS was 1.35 y (95% CI: 0.21-2.48 y). This result is clearly superior to historical controls not treated with ch14.18/CHO with a 5-y OS of 14.8±6.8% (p < 0.005), indicating clinical efficacy of the treatment. In this cohort, we identified 21/53 pts with the NK- stimulatory KIR haplotype (2DS2+) who had superior OS- and PFS-rates compared to 16/53 pts with an inhibitory haplotype and KIR/KIR-ligand match (2DS2-, 3DL1+, Bw4+) (p < 0.02). Similarly, we found 33/53 pts with low affinity FCGR alleles (FCGR2A-H131R/R and/or FCGRA3A-V158 F/F). These patients showed lower PFS rates compared to 19/53 patients with high affinity FCGR polymorphisms (p < 0.01). Importantly, ADCC analysis on day 15 of cycle 1 showed higher levels in the pt group with NK- stimulatory versus NK- inhibitory KIR/KIR ligand haplotypes (27±5 % vs. 12±3%, p < 0.01). A similar effect was observed in pts with high affinity FCGR polymorphisms with an ADCC increase of 21±7% compared to 11±2% in the low affinity FCGR control. Conclusions: KIR-haplotypes and FCGR- polymorphisms correlated with the functional immune parameter ADCC and clinical outcome, and may therefore be useful biomarkers for LTI with ch14.18/CHO.