tbuckley/cabot-search huggingface dataset:
New and emerging therapies for relapse/refractory multiple myeloma: Impact of education on practice behaviors.
Authors: Anne Roc, Wendy Turell, David Dingli
Journal: Journal of Clinical Oncology (2017)

e18096 Background: Newly approved and emerging agents with novel mechanisms of action present unique challenges to treating patients with relapsed/refractory multiple myeloma (RRMM), including keeping abreast of rapid and ever-aggregating data on their safety, tolerability and efficacy. To address these challenges, an education activity focused on new and emerging therapies for RRMM was developed and learner responses were evaluated to determine the impact of education. Methods: A live-online 1-hour video panel discussion with slides, polling, and live questions was produced in 2016 and made available on-demand at OMedLive.com for 6 months. Survey responses (pre-, post-, 8 weeks post-activity), polling responses, and live questions asked were tracked to measure engagement, lessons learned, and additional education gaps. Results: 51 of 288 learners completed all pre/post/follow-up surveys, 67% of which reported the activity positively impacted patient experience or outcome and 61% reported it positively impacted their clinical practice. These learners reported improvements in their ability to: assess the relative safety and efficacy of emerging agents (50%), differentiate available agents and their relative efficacy (50% with proteasome inhibitors, 39% with monoclonal antibodies), see the potential benefit of HDAC inhibitors (35%), use combination regimens (29%), and adjust treatments for patients who’ve experienced disease progression (29%). As the result of education, 95 of 288 learners reported commitments to change in regards to: medical/practice knowledge (95%), care attitudes (89%), practice behavior (76%), and patient clinical outcomes (81%). Learners also demonstrated improved competence via a case scenario which required identifying the optimal next step for a patient with biochemical progression, and improved knowledge on the characteristics of daratumumab, elotuzumab, and selinexor. Conclusions: New and emerging therapies promise to improve the lives of patients with RRMM, but complicates the already difficult task of managing the disease. Ongoing education on RRMM is recommended and can yield immediate and sustained gains in knowledge, competence, and performance.
Advantages of prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: An open-label, randomized, multicenter phase Ⅲ study.
Authors: Jie Xie, Jun Cao, Zhonghua Wang, Biyun Wang, Sheng Zhang, Leiping Wang, Jian Zhang, Zhonghua Tao, Ting Li, JinFeng Zhang, Xi-Chun Hu
Journal: Journal of Clinical Oncology (2016)

e14043 Background: PEG-modification recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) reduces the incidence of febrile neutropenia (FN) and improves the safety of chemotherapy. In China's registration trial of PEG-rhG-CSF, we assessed its efficacy and safety against conventional recombinant human granulocyte colony stimulating factor (rhG-CSF) in breast cancer patients, and prospectively explored its value over multiple cycles of chemotherapy. Methods: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive 100 µg/kg subcutaneous (s.c.) PEG-rhG-CSF, fixed 6 mg s.c. PEG-rhG-CSF or daily 5 µg/kg/d s.c. rhG-CSF 48 hours after chemotherapy.The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2 to 4, the incidence of febrile neutropenia and the safety. Results: For the primary endpoints, a once-per-cycle PEG-rhG-CSF at either 100 µg/kg or fixed 6 mg was not significantly different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2 regarding incidence or duration of grade 3/4 neutropenia, and the difference became bigger over cycles 3 and 4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) of grade 3/4 neutropenia favoring PEG-rhG-CSF. A significant trend towards a lower incidence of all-grade adverse events with PEG-rhG-CSF was noted at 129 (68.98%), 142 (75.53%) and 160 (82.47%) in arms of PEG-rhG-CSF 100 µg/kg, fixed 6 mg and rhG-CSF, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%) and 8/194 (4.12%), respectively (P = 0.0477). Conclusions: Compared with rhG-CSF, PEG-rhG-CSF is a more safe and convenient formulation, and more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy. Clinical trial information: 2006L01305.
Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancers.
Authors: Laia Pare, TomÃ¡s Pascual, Elia Seguí, María González-Cao, Cristina Teixidó, Adela Rodriguez, Blanca González-Farre, Miriam Cuatrecasas, Estela Pineda, Guillermo Crespo, Salvador Martin-Algarra, Elisabeth Perez Ruiz, Begona Mellado, Juan Maurel, Javier Garcia Corbacho, Miguel Angel Molina-Vila, Josep M. Llovet, Noemi Reguart, Ana M. Arance, Aleix Prat
Journal: Journal of Clinical Oncology (2018)

3076 Background: In advanced cancer, the overall response rate (ORR) following anti-PD1 monotherapy is variable (0% to 50%). Here, we hypothesized that this observation is partly explained by different amounts of the drug target (i.e. PD1) in the tumor. Methods: RNA-seq data from 10,078 tumors representing 34 cancer-types were obtained from TCGA. The expression of PD1 and 566 immune-related genes/signatures were evaluated. Correlations between each gene/signature and ORRs reported in the literature were calculated. We included only studies of anti-PD1 monotherapy that enrolled at least 20 patients (pts) who were not selected for PDL1 expression. To translate the in-silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 694 formalin-fixed paraffin embedded (FFPE) tumor samples from 16 cancer-types. Finally, we evaluated FFPE-based PD1 mRNA from an independent dataset of 102 pts with advanced solid tumors treated with anti-PD1 monotherapy. Results: PD1 expression varied significantly across TCGA (p < 0.001) with 0% to 84% of tumors within a cancer-type being PD1-high (H) (defined as %ile 80). Interestingly, % of PD1-H tumors within a cancer-type were found highly correlated with ORRs reported in the literature (correlation coefficient [CC] = 0.91), suggesting that 83% of the differences in the ORR across cancer-types may be explained by the abundance of PD1. Lower CCs were identified with different PD1 cutoffs, other genes/signatures and tumor mutational burden. To translate these findings in clinical samples, the expression of PD1 was evaluated in 773 FFPE tumor samples across 17 cancer-types. Using the optimal cutoff (%ile 80), similar proportions of PD1-H tumors within each cancer-type were identified in our in-house FFPE-based cohort compared to TCGA (CC = 0.92). Finally, the optimal PD1 FFPE-based cutoff was found significantly associated with ORR (PD1-H 42.8% vs. PD1-low 17.6; P = 0.018) in 102 pts with advanced cancer treated with anti-PD1 monotherapy. Conclusions: Our findings highlight the strong relationship between PD1 mRNA expression and the activity of anti-PD1 therapies across multiple cancers.
Abstract 19399: Wave Condition Number is Useful in Predicting Risk for Coronary Heart Disease From Framingham Heart Study Data
Authors: Marianne Razavi, Niema M Pahlevan
Journal: Circulation (2017)

Introduction: Wave condition number (WCN) is a non-dimensional number that can predict the optimum arterial wave reflection for left ventricle pulsatile workload minimization across mammalian cardi...
Multi-clonal mutation signatures in primary breast malignancies and their axillary lymph node metastases.
Authors: Jiaqi Liu, Xin Wang, Wenyan Wang, Jie Wang, Zeyu Xing, Shudong Yan, Menglu Zhang, Xiang Wang
Journal: Journal of Clinical Oncology (2018)

e13526 Background: Breast cancer is the most common malignant disease in women worldwide. Axillary lymph node metastasis often represents the first step of the metastatic process and represents a major adverse progress. However, the mechanism of lymph node metastasis is still under exploration. Methods: Whole exome sequencing was performed on primary tumors, lymph node metastases and white blood cells from 10 synchronous patients with breast cancer and axillary lymph node metastasis. Single nucleotide variants (SNVs) and copy-number variants (CNVs) were generated and compared within individual patients. The significant differences in the number of SNVs and the length of CNVs were determined by Student’s t-tests. The PyClone2 was applied to infer clonal dynamics during lymph node metastases. Results: The samples were sequenced to high, uniform coverage. An average of 5.6±2.6 somatic SNVs per megabase (Mb) in primary tumors and 5.5±2.7 somatic SNVs/Mb in lymph node metastases were identified, corresponding to similar mutation burden between two malignant sites (p = 0.81). There was also no difference in the length of CNVs (p = 0.33). Moreover, 48.1%±13.8% of somatic SNVs and 61.7±35.0% of CNVs in primary tumors, and 49.4%±12.3% of somatic SNVs and 72.0±24.3% of CNVs in lymph node metastases were overlapping. Intriguingly, 82.1±14.4% of the overlapping somatic SNVs were with the similar allele frequencies (AFs). The dominant clonal variants that progressed from tumor to node with increasing AFs of more than 10% were significantly enriched in the P53 pathway feedback loops (p = 0.04) and significantly associated with tumor cell invasion. Furthermore, the multiple clonal subclones in both malignant sites were identified. Conclusions: Our study reveals a direct genomic lineage between the primary breast tumor and lymph node metastases and further show that most SNVs and CNVs were overlapping in these two malignant sites. The overlapping variants are associated with tumor invasion, which supports the early genetic variability in the metastatic process. These results prove the concept of the multi-clonal metastatic model, in which more than one clones migrate into the axillary lymph node to establish the metastases.
Paclitaxel combined with ramucirumab as the second-line chemotherapy for elderly patients with advanced gastric cancer.
Authors: Tetsuya Kusumoto, Hideo Uehara, Kenkichi Hashimoto, Yoshihiko Fujinaka, Keiji Yoshinaga, Eiji Kusumoto, Chiaki Shinzato, Yoshihisa Sakaguchi, Koji Ikejiri, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2018)

e16088 Background: In recent years, the proportion of elderly patients has increased in Japan. Paclitaxel plus ramucirumab (PTX/RAM) was currently proved to be one of the most effective regimens for patients with metastatic or locally advanced gastric cancer (AGC) as the second-line treatment, based on the several prospective randomized clinical trials. Methods: We herein examined the clinical significance and validation of PTX/RAM practically as the 2nd-line treatment in elderly patients with AGC. From June 2015 to Aug 2017, 48 patients with AGC received RAM-containing chemotherapy in our institute. We conducted a retrospective review of the data of 25 patients with AGC who received more than 2 cycles of PTX/RAM as the 2nd-line regimen. These patients were categorized into a younger group ( < 75 years of age, n = 21) and an elderly group (≥75 years of age, n = 4). Adverse events, tumor responses, and survival data were analyzed. Results: Only 2 patients (1 of each group) quitted the continuation of PTX/RAM except for the progressive disease. The rates of hematological toxicities of higher than grade 3 were 33% and 75% for the younger and the elderly group, respectively. The ORR and the DCR were 50% and 50% for the elderly group, 32% and 78% for the younger group, respectively. The survival data showed that the median PFS and the OS were 131 days and 290 days, respectively. The median OS from the administration of the first-line was 589 days. Conclusions: PTX/RAM might also be one of the best regimens for elderly patients with AGC as the second-line treatment following fluoropyrimidine-containing chemotherapy.
Parameters of lipid peroxidation in tumors of the upper jaw.
Authors: Yulia V. Ulianova, Oleg Ivanovich Kit, Marina Engibaryan, Elena M. Frantsiyants, Viktoriya L. Volkova, Irina V. Aedinova, Natalia A. Chertova, Mamuka V. Bauzhadze
Journal: Journal of Clinical Oncology (2018)

e18097 Background: There is a close relationship between the peroxidation activity parameters and the metabolic activity of the tumor, which is considered informative for assessing the effectiveness of antitumor treatment. Methods: Accumulation of the lipid peroxidation products (conjugated dienes, malondialdehyde, sulfhydryl groups, superoxide dismutase, catalase, vitamins A and E) was determined in 20 samples of tumors of the upper jaw to study their metabolic activity. Results: The conjugated diene levels in tumor tissues were increased by 38.6% compared to intact tissues, while levels of malondialdehyde were decreased by 38.7%. Levels of total, non-protein and protein sulfhydryl groups in tumor tissues were 18.2%, 28.4% and 13.3% lower, respectively, than in intact tissues; the activity of antioxidant enzymes – superoxide dismutase and catalase – was inhibited by 20% and by 3 times, respectively, and their ratio 2.5 times exceeded the normal value. Levels of vitamin E were unchanged, while vitamin A was 2 times decreased; their ratio reflecting the oxidative ability of tissue membranes was increased. Conclusions: Tumor tissues of the upper jaw demonstrated the initiation of free radical processes before treatment (accumulation of primary products of lipid peroxidation (conjugated dienes), decrease in the vitamin A level and decrease in the number of reduced forms of thiols). A low level of malondialdehyde accumulation indicated either that the oxidation chains were terminated after the initiation of free radical processes due to the reserve of antioxidants, or that tumors of the upper jaw were defective in the content of substrates for the malondialdehyde formation – arachidonic and linolenic acids. The increase in the activity of superoxide dismutase, catalase, thiol-dependent peroxidases and the number of thiols indicated the resistance of tumors of the upper jaw to the damaging effect of antitumor drugs.
Surgical re-excision vs. observation for dysplastic naevi
Authors: K.T. Vuong, J. Walker, H.B. Powell, N.E. Thomas, D.E. Jonas, A.S. Adamson
Journal: British Journal of Dermatology (2018)

Pathologists, doctors who study the causes and effects of diseases, look at samples of skin under the microscope. Unusual moles of the skin, called histologically dysplastic nevi (HDN), are checked for cancer. HDN are present in 2‐10% of the white‐skinned population and may look like melanoma, a possibly deadly form of skin cancer. However, doctors disagree whether melanomas develop directly out of HDNs. As a result, some doctors advise removing more skin after a biopsy to make sure HDNs are completely removed. Recent research suggests that simple viewing of the HDN biopsy, might be a safe option instead of surgical removal. The aim of this study, from the University of North Carolina in the U.S.A., was to look at past studies for how often melanomas develop in patients who either had their HDNs surgically removed or simply viewed by experts. The authors found 12 studies with over 2,600 HDN either observed or removed. The rate of melanoma development was low in both the observed (0.39%) and the removal (0.44%) groups. The authors concluded that most HDNs can be safely observed with low risk for melanoma development at the site of the HDN biopsy. However, the quality of the evidence reviewed was low, therefore more research is still needed to guide decision‐making by doctors.
OS3.2 The origin of humanglioblastoma(IDH wildtye) is not the location of the tumor but the subventricular zone
Authors: S Kang, J Lee, J Lee, S Kim, J Kahng, S Yoon, J Lee, E Kim, Y Ju, J Chang, J Lee
Journal: Neuro-Oncology (2018)

Two hypotheses about the origin of human glioblastoma (GBM) genesis are known to be dedifferentiation of cancer cells and orthodox differentiation of cancer stem cells. However, little is known about whether the direction of the human GBM genesis begins at the site of the tumor or at the subventricular zone (SVZ) where normal neural stem cells (NSCs) are present. Here, we describe direct molecular genetic evidence from patient brain tissue and genome-edited mouse models that show astrocyte-like NSCs in the SVZ to be the cell of origin that harbors the driver mutations of human GBM. The patients enrolled in our study underwent supra-total resection or other surgical resection of tumors located primarily in the temporal lobe, providing access to normal SVZ tissue away from the tumor mass, under the assistance of a magnetic resonance imaging-navigation. We performed deep sequencing of triple-matched tissues, consisting of i) normal SVZ tissue away from the tumor mass, ii) tumor tissue, and iii) normal cortical tissue (or blood), from 28 patients with GBM, isocitrate dehydrogenase-wild type (IDH-wildtype) or other types of brain tumors. Next, we performed single cell cloning or isolation with targeted sequencing in tumors carrying shared driver mutations with SVZ tissue in patients with GBM of IDH-wildtype to examine: i) micro-invasion of cells harboring driver mutations from GBM into SVZs or ii) clonal evolution of cells harboring driver mutations from the SVZ to GBM. We performed immunostaining and laser capture microdissection in order to isolate separately the three layers of SVZ in two GBM patients to determine the origin cell type of GBM. To examine the etiology of somatic mutations in tumor-free SVZs, we attempted to analyze genetic signatures. Finally, we generated a mouse model of p53, Pten, and EGFR mutations in NSCs from the SVZ through genome editing to prove human genetics evidence. We found that normal SVZ tissue away from the tumor in 56.3% of GBM IDH-wildtype patients contained low-level GBM driver mutations (down to ~1% of the mutational burden) that were observed at high levels in their matching tumors. Moreover, via single cell sequencing, laser microdissection analysis of patient brain tissue and mutational signature analysis, we discovered clonal evolution from SVZ to tumor in GBM, hot mutational area (astrocytic ribbon area) in SVZ and clockwise mutational signature at SVZ. By genome editing of a mouse model, we discovered that astrocyte-like NSCs carrying driver mutations migrate from the SVZ and lead to the development of high-grade malignant gliomas in distant brain regions. Our results highlight NSCs in human SVZ tissue as the cell of origin that harbors the driver mutations of GBM. In addition, the origin of human glioblastoma is not the location of the tumor but the subventricular zone.
Is symptom worsening (SW) associated with RECIST response in patients (pts) with desmoid tumors (DT)?
Authors: Nuria Kotecki, Armelle Renaud, Mariem Ben Haj Amor, Anne-Sophie Thomassin Defachelles, Thomas Ryckewaert, Vincent Gamblin, Yves Marie Robin, Sophie Taieb, Nicolas Penel
Journal: Journal of Clinical Oncology (2016)

e22534 Background: DT is a rare, locally infiltrative tumor. Front-line 'watch-and-wait' policy with monitoring by MRI is recommended. Methods: We retrospectively reviewed data from 27 consecutive pts with histologically-proven DT from 01/2007 to 12/2015. The study aims to investigate if SW is correlated with disease progression according to RECIST 1.1, volumetric changes or contrast enhancement (CE) over time. Clinical and MRI characteristics were assessed at diagnosis and at last follow up. Results: The cohort consisted in 6 men (22%) and 21 women (77%) with a median age of 33 (10-77). The most common location was the abdominal wall (11, 40%). Median follow-up was 40 months (5-98). 15/27 (55%) pts received at least 1 systemic treatment including NSAID, tamoxifen, imatinib or methotrexate based chemotherapy. Increasing in pain, retraction, functional impairment were seen respectively in 11 (40%), 10 (37%) and 10 (37%) patients. Objective response, stable disease and disease progression according to RECIST 1.1 was found in 7 (26%), 13 (48%) and 7 (26%) pts, respectively. Objective response, stable disease and progressive disease according to volumetric changes was found in 8 (30%), 10 (37%), 9 (33%) pts, respectively. Size and volume changes were highly correlated (p < .00001.). We have described 2 “false” progressions characterized by increased of only 1 axis and decrease of other axis; this could be related to tumor retraction along the muscle fibers. We found that response assessment according RECIST was not associated with SW (Table). CE was assessable in 26 pts, with decrease CE in 10 pts (38%) and stable CE in 16 pts (62%). CE change and RECIST response were not correlated (p = 0.697). CE changes were not associated with worsening of pain (p = 0.676), retraction (p = 0.126) and functional impairment (p = 0.126) Conclusions: SW was not associated with the response according to RECIST, volumetric or CE changes. Innovative methods for monitoring pts are needed. Objective responses (7) Stable disease (13) Progressive disease (7) p Increase in pain 3 5 3 0.974 Increase in retraction 2 4 4 0.438 Increase in functional impairment 2 3 4 0.438
TCT-455 Transfemoral TAVI in patients with “unfavorable conditions for TAVI” following the European Guidelines of Valvular Heart disease
Authors: Leire Unzue, Eulogio García, Francisco Jose Rodriguez Rodrigo, Belen Diaz-Anton, Francisco Javier Parra, Miguel Rodriguez del Rio, Alberto Rubio, Maria Jesus Fernandez del Cabo, Blanca Zorita, Juan Medina
Journal: Journal of the American College of Cardiology (2018)