bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma kallikrein-kinin system as markers of locally advanced breast cancer prognosis.
Authors: Samaneva Natalia Yu. , Vladimirova Liubov Yu , Frantsiyants Elena M. , Storozhakova Anna E. , Kalabanova Elena A. , Kabanov Sergey N. , Tishina Anna V. , Svetitskaya Yana V. , Shatova Iuliana S. , Vashchenko Larisa N. 
Published: June 2021

e13040 Background: The kallikrein-kinin system is a complex multifunctional signaling cascade. Studies confirm its role in the development of cancer, as well as a role of some of its proteins with pro-inflammatory properties. Criteria for assessing the risk of breast cancer (BC) progression are required. The purpose of the study was to reveal the effect of blood levels of plasminogen, plasmin, precallikrein, and kallikrein in patients with triple-negative BC on the disease course. Methods: The study included 162 patients with triple-negative BC divided into 2 groups: group 1 – 58 patients with an early progression within 6 to 12 months after combination treatment; group 2 – 104 patients without progression during 2 years after combination treatment. Blood levels of plasminogen, plasmin, prekallikrein, and kallikrein were measured by ELISA before anticancer therapy and after 8 chemotherapy cycles. The levels in the blood plasma of healthy donors were reference values. Results were statistically processed using the Statistika 6.0 program with the Student’s T-test. Results: In patients with an early progression, plasminogen levels before the treatment were decreased by 1.7 times (p≤0.05), while plasmin was elevated by 1.9 times (p≤0.05). Kallikrein was increased by 1.9 times (p≤0.05), and prekallikrein was similar to the values in healthy donors. In patients with prolonged remission, plasminogen levels before the treatment were decreased on average by 2 times (p≤0.05). Plasmin was elevated by 2.3 times (p≤0.05), and kallikrein – by 1.8 times (p≤0.05). During this period of the study, prekallikrein levels decreased by 2 times (p≤0.05), compared with healthy donors. After chemotherapy, prekallikrein levels in the group with an early progression decreased by 1.4 times (p≤0.05), compared to the values before treatment, and kallikrein increased on the average by 1.3 times (p≤0.05). In patients with prolonged remission, no changes in the studied indices were registered. Conclusions: Patients with an early progression of BC demonstrated decreased levels of prekallikrein and increased kallikrein after the treatment, which allowed predicting resistance to chemotherapy and further tumor progression.
Efficacy of platinum-based chemotherapy in advanced triple-negative breast cancer in association with homologous recombination deficiency.
Authors: Chen Yimeng , Cui Lina , Zhang Bei , Zhao Xiaochen , Xu Binghe 
Published: June 2021

e13051 Background: Previous studies have identified that at least 50% of triple negative breast cancer (TNBC) harbor mutation characteristics of homologous recombination deficiency (HRD). Thus, more sophisticated research into comprehensive genomic profiling of HRD is urgently needed. Whereas BRCA1/2-deficient advanced TNBC patients are sensitive to treatment with platinum, it is not yet clear whether HRD status could predict platinum response. Methods: 3DMed-HRD algorithm was developed based on loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI) and large-scale state transition score (LST) as previously described. HRD status was defined as HRD positive (deleterious mutation in BRCA1/2 or HRD score ≥30) or HRD negative (no deleterious mutation in BRCA1/2 and HRD score < 30). Tumor samples from 207 TNBC patients were analyzed by next-generation sequencing. Deleterious or suspected deleterious mutations were included for analysis. Among the overall cohort, 34 patients with advanced TNBC treated with chemotherapy were analyzed. Cox regression model was applied to evaluate the relationship between HRD status and clinical outcomes. Results: Deleterious BRCA1/2 mutations were detected in 22.2% (46/207) of TNBC patients as well as 54.6% (113/207) were defined as HRD positive. The most frequent mutations in HRD-positive patients were TP53 (93.5%), MYC (29.0%), PIK3R1 (22.6%), PTEN (22.6%) and MCL1 (19.4%), while TP53 (77.8%), MYC (29.6%), PIK3CA (18.5%), KMT2C (14.8%) and RIT1 (14.8%) enriched in HRD-negative patients. Mutations in DNA Damage Response (DDR), P53, Checkpoint and Receptor Tyrosine Kinase (RTK) pathways were most involved in HRD positive patients. In advanced TNBC cohort, 19 patients received platinum-based and 15 received platinum-free chemotherapy in the first-line treatment. The progression-free survival (PFS) of the platinum-based group was longer than that of the platinum-free group (media PFS 9.1 vs 2.2 months, HR 0.44, 95%CI, 0.20-0.94, P = 0.009). In HRD-positive patients, median PFS was significantly longer in platinum-based group (N = 6) than platinum-free group (N = 8) (media PFS 13.6 vs 1.9 months, HR 0.30, 95%CI, 0.09-0.95, P = 0.008). No significant difference in PFS between platinum-based and platinum-free group (p = 0.332) in patients with HRD-negative tumors. Patients with mutations in homologous recombination (HR) pathway had a worse PFS compared to wild-type in platinum-free group (1.4 vs 3.0 months, p = 0.050). Conclusions: Our findings illustrate the potential of HRD status as a marker to guide chemotherapy in advanced TNBC. In HRD positive patients, platinum-based chemotherapy might be a preferable regimen. Patients with mutations in HR pathway had a shorter PFS in platinum-free group. Prospective study with a larger sample-size is needed for further validation of our findings.
Preliminary data on antitumor activity of extracorporeal subtraction of soluble TNFRs to unleash the activity of endogenous TNFα combined with chemotherapy in treatment-refractory, advanced, triple-negative breast cancer patients.
Authors: Wysocki Piotr Jan , Ostrowski Adam , Segal Robert , Potocki Pawel , Konopka Kamil Wladyslaw , Kwinta Lukasz , Florin Lawrence , Prince Stephen 
Published: June 2021

e13052 Background: Tumor necrosis factor-alpha (TNFα) is a pleiotropic cytokine, with known antitumor activity, produced mainly by activated immune cells. Cancer cells neutralize TNFα by shedding soluble TNF receptors 1&2 (sTNFRs), which act as TNFα-binding decoys. In addition, sTNFRs can directly promote proliferation, survival, and chemoresistance of cancer cells by binding to membrane-bound TNFα and initiating retrograde signaling. Therefore, the reduction of systemic and intratumoral concentrations of sTNFRs represents a novel and unique strategy to reinvent the anticancer use of TNFα. Methods: In this clinical trial (CP7-005; NCT04004910) we evaluated extracorporeal Immunopheresis (subtractive apheresis) with the novel LW-02 immunoadsorption column in advanced chemo-refractory metastatic triple-negative breast cancer (mTNBC). The LW-02 column, which utilizes a proprietary, recombinant single-chain TNFα as the sTNFR-scavenger ligand has received FDA breakthrough designation for cancer treatment. Here we present data on the second cohort of mTNBC patients treated with LW-02 combined with weekly chemotherapy; Cohort 1 (n=10) evaluated Immunopheresis as monotherapy only. In Cohort 2, patients are treated with LW-02 immunopheresis only in week 1 (3 treatments involving processing of 2 plasma volumes (2PV)). From week 2, paclitaxel [60 mg/m2]+carboplatin[AUC2] combination is administered once weekly along with LW-02 immunopheresis (2PV 3x/week). Results: To date, 7 mTNBC patients who failed ≥2 lines of chemotherapy (median=3; 2-5) in the advanced setting have been enrolled. The combination of LW-02 column immunopheresis and chemotherapy resulted in a 29% ORR (1CR, 1PR). In 5 patients who completed at least 4 weeks of treatment, the ORR was 40%. Median OS in the whole population as of this report is 13.3 weeks, and 18.4 weeks in the patients treated for >4 weeks. Treatment-related AEs occurred in most patients; however, most being attributed to chemotherapy - CTCAE G3-4 in 71% (anemia – 71%, neutropenia 29%, thrombocytopenia 29%). Immunopheresis-related G3-4 AEs were CVC complications (29%), hypophosphatemia (14%) and hypercalcemia (14%). Conclusions: The combination of LW-02-column immunopheresis and weekly chemotherapy procedure was shown to be generally safe and provided early, promising signs of antitumor activity in heavily pretreated mTNBC patients with short life expectancy. Further clinical evaluation of the antitumor activity of LW02-based immunopheresis combined chemotherapy is ongoing; however, due to myelotoxicity, the chemotherapy regimen will be adapted accordingly. Clinical trial information: NCT04004910.
Binimetinib activity in PIK3R1-mutant patient-derived xenografts (PDX) implanted into immunodeficient mice.
Authors: Cobleigh Melody A. , Abukhdeir Abde M. 
Published: June 2021

e13062 Background: The PIK3R1 gene is genetically altered in ̃3% of breast cancers in the Western and ̃17% in the Eastern worlds. We recently reported that breast cancer cells lacking protein expression of PIK3R1 had elevated levels of activated MEK, sensitizing them to the MEK inhibitor trametinib. To better understand whether MEK inhibition is a therapeutic option for breast cancer patients with mutated PIK3R1, we tested the newer generation MEK inhibitor, binimetinib, in a PDX mouse model. Methods: Two PDx models (table) were tested in athymic nude-foxn1nu (immune-compromised) mice. Both patients had had metastatic, grade 3 breast cancer and expressed moderate RNA levels of PIK3R1. Results: Body weights of treatment arms were unchanged throughout the experiment. The TNBC PDx study was halted early at 13 days because tumors reached the predefined maximum size of 1500 mm2. The binimetinib treated mice experienced slowed tumor growth (522.8 +/- 172.8%) compared to the vehicle control (720.7 +/- 229.1%), (p=0.0693). In the HR+ PDx model, the combination of binimetinib plus tamoxifen resulted in a statistically significant decrease (371.5 +/- 108.1%) in tumor volume compared to tamoxifen alone (525.0 +/- 154.1%; p = 0.0302). Conclusions: Our previous and current results suggest that mutation in PIK3R1 sensitizes cells to MEK inhibitors. Binimetinib inhibited growth in both models. This inhibition was of borderline significance in the TNBC model and was statistically significant in the ER+, HER2- model. To the best of our knowledge, these results provide the first evidence of binimetinib efficacy in PIK3R1-mutant, HR+, HER2- PDX immunodeficient mice. Plans for a phase II trial in patients with PIK3R1-mutant, HR+, HER2- breast cancer are underway.[Table: see text]
Oral etoposide in heavily pre-treated metastatic breast cancer: A retrospective study.
Authors: Jagiello-Gruszfeld Agnieszka I. , Meluch Malgorzata , Kunkiel Michal , Gorniak Anna , Majstrak-Hulewska Anna , Gorska Katarzyna , Konieczna Aleksandra , Nowecki Zbigniew 
Published: June 2021

e13070 Background: Patients with metastatic breast cancer can derive clinical benefit from several subsequent lines of chemotherapy. However, in heavily pre-treated patients, agents with clinical activity, a favourable side effects profile and a convenient administration modality are preferred. Oral etoposide may be an interesting treatment option in this group of patients. Methods: This was a retrospective observational study performed in single institution in 22 patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1-20. Treatment cycles were repeated every 28 days. Results: The median age were 53 years (42-68). The median number of previous chemotherapy lines was 5 (range 2-7). There were no complete or partial responses. Median PFS was 7 months. In 5 patients, the disease stabilized for over 12 months. Interestingly, etoposide activity was unrelated to the number of previous lines and type of metastatic involvement. Oral etoposide was well tolerated with only one patients discontinuing therapy due to toxicity. Conclusions: In real practice oral etoposide is a valuable and safe option for pre-treated metastatic breast cancer patients and might be considered in patients failing other approaches, but still suitable for chemotherapy.
Novel treatment options in advanced adenoid cystic carcinoma of the breast.
Authors: Wenig Evan , Birhiray Reumu E. 
Published: June 2021

e13071 Background: Adenoid cystic carcinoma (ACC) accounts for less than 0.1% of all breast cancer cases. The disease typically remains localized and indolent, and frequently occurs with triple negative status. Methods: In patients with locally advanced or metastatic disease, chemotherapy for triple negative breast carcinoma is seldom effective. Thus new treatment paradigms are desired. Drug targeted analysis derived from next generation sequencing and identification of driver mutations may offer a bright future in treatment options in chemo-resistant malignancy. Results: A 53 year old woman presented with breast mass and mastectomy with stage pT3N0M0 triple negative ACC of the breast resulting in observation. She later relapsed with chest wall disease, resulting in resection and radiation therapy. Shortly thereafter, she relapsed with pulmonary metastatic disease. She was treated with carboplatin and doxorubicin which were discontinued due to disease progression. Liquid assay revealed an IDH2 mutation, prompting treatment with enasidenib with ongoing evidence of disease control at 4 months. Patient tolerated treatment well without grade 3 or 4 adverse reactions. A 48 year old woman presented with an increasing 9.5 cm unresectable breast mass without distant metastasis. Pathology showed triple negative ACC of the breast, resulting in chemotherapy with doxorubicin, cyclophosphamide, and paclitaxel with clinically progressive disease. She represented with necrotic and ulcerating changes of the breast. Foundational genomic testing showed an FGFR2 mutation. After four months of treatment with erdafitinib, she had resolution of pain and cessation of pain medication. Her therapy led to a grade 2 adverse event related to hyperphosphatemia. She underwent surgical resection with negative margins. Conclusions: These examples illustrate a potential treatment paradigm for a rare malignancy for which there is no standard of care. Here we present two desperate cases, one of which had a driver mutation of IDH2, and the other FGFR2 for which there are targeted therapies approved in other disease states. The use of these two agents resulted in clinical benefit. A patient with metastatic disease treated with enasidenib has ongoing disease control for over 4 months with minimal adverse reaction. A patient with advanced local disease requiring narcotics and gabapentin for pain control treated with erdafitinib had significant symptomatic control with successful cessation of pain medications and ability to undergo potentially curable mastectomy with negative margins despite progression on prior chemotherapy. In summary, ongoing research of ACC of the breast will be required. Alternative therapeutic options related to targeted treatment may offer promise to clinical outcomes in the future. For cases of locally advanced or metastatic disease, the use of targeted therapy may offer new therapeutic options.
Utility and acceptability of the EXCEEDS algorithm for oncology stakeholders: Results of a Delphi study.
Authors: Covington Kelley Renee , Marshall Timothy F , Sharp Julia L , Kendig Tiffany , Williams Grant Richard , Pergolotti Mackenzi 
Published: June 2021

e13538 Background: The Exercise in Cancer Decision Support (EXCEEDS) algorithm is an evidence-based, risk stratified framework. This framework allows for enhanced decision making for exercise pre-participation medical clearance and triage to cancer rehabilitation or exercise services across the cancer continuum. We conducted a Delphi study to examine utility and acceptability of the EXCEEDS algorithm for oncology stakeholders. Methods: Delphi study participants were randomized to two case studies, then made pre-participation medical clearance (yes/no) and intervention triage recommendations (cancer rehabilitation, clinically-supervised exercise, cancer-specific community-based exercise, and unsupervised exercise) in two conditions: independent (IND) and using EXCEEDS. Immediately following, participants rated algorithm acceptability in four domains using 4-point Likert scales (1- strongly disagree, to 4- strongly agree). We dichotomously coded accuracy (correct/incorrect) for each medical clearance and triage recommendation, then calculated the proportion of correct answers for each case to determine accuracy. We compared triage decision time (seconds) between conditions (IND vs. EXCEEDS) using paired-samples t-tests. We calculated the proportion of participants who ‘agreed’ (i.e., score ≥3) with each acceptability domain. Results: Oncology stakeholders (N=33) were mostly female (69.7%), 35-44 years old (42.4%), located in the United States (60.6%), and had at least 10 years of experience (60.6%). When using EXCEEDS, accuracy for medical clearance decisions improved in 3 of 4 cases (75%), triage decision accuracy improved in 4 of 4 (100%) cases, and triage time (seconds) improved significantly in 3 of 4 cases (75%, p<.05). Table shows average improvement in decision accuracy and triage time for each case study. Most participants agreed that the algorithm was acceptable in each domain: “meets my approval” (n=21, 63.6%), “is appealing” (n=29, 87.9%), “enjoyable to use” (n=19, 57.6%), and “welcomed in my discipline or practice” (n=24, 72.7%). Conclusions: Accuracy and efficiency of decision-making for medical clearance and triage to cancer rehabilitation or exercise services was enhanced when using the EXEECDS algorithm. Most participants agreed the algorithm was acceptable. Future research is needed to validate the tool and explore avenues for dissemination and clinical implementation. % difference between EXCEEDS and Individual condition (EXCEEDS – IND) for medical clearance decision, triage decision and mean (M) and standard deviation (SD) of triage decision time.[Table: see text]
Extracting knowledge of NCI research directions from funding data using language processing.
Authors: Beidler Peter , Nguyen Mark , Kang John 
Published: June 2021

e13547 Background: In fiscal year (FY) 2019, 42% of the $6 billion NCI budget went towards nearly 5,000 research project grants, of which about 60% are R01 type. Given the enormity of allocated resources, there is a need for the scientific community to have a more rigorous understanding of the cancer research landscape. While the NCI Budget Fact Book publishes statistics based on pre-designated codings, it is unclear if this method yields the best representation of fields within oncology. Open questions include: how many distinguishable areas of cancer research are being funded? Are there differences in growth rate, publication rate and geographic distribution among those areas? Addressing these questions in a systematic manner is a well-suited problem for unsupervised machine learning. Methods: We analyzed 55,362 R-type grants from FY 2010-2021 (up to 1/31/21) from NIH ExPORTER. Preprocessing was done on ‘Project Terms’ to weight their importance using TF*IDF vectorization and principal component analysis. We used minibatch K-means clustering repeated 100 times, with the best iteration chosen by Calinski-Harabasz clustering quality score. Over 100 repetitions, the Adjusted Rand Index was 0.9907±0.0037 (mean ±standard deviation), indicating robustness to initial conditions of K-means. For publication rate analysis, FY 2020 and 2021 grants were excluded, and 2021 grants were excluded for trajectory analysis. Optimal cluster number was determined based on a combination of inertia, Calinski-Halabasz, and silhouette scores. Results: We found the optimal number of 24 clusters to best represent separation of the R-type grant research directions. These 24 clusters clearly represent topics such as immunotherapy, cohort risk-factor studies, and imaging. Notable trends include increased funding of immunotherapy and targeted inhibitor clusters averaging +$9.9M and +$9.2M growth per year respectively over 10 years, and decreased funding of pathway regulation and genetics clusters averaging -$7.8M and -$5.7M per year. These examples suggest a broader trend that funding is shifting from basic to translational science. Further analysis shows that the targeted inhibitor cluster is most geographically skewed, with 30% of grants going to institutions in just three cities. The number of journal articles (per grant) also shows a bias, with development/training and genetics clusters having publication rates of 32.6 and 20.8 and randomized control trials having a publication rate of 6.3. The average publication rate of NCI was 14.8. Conclusions: Using a novel framework for unsupervised clustering of NCI grant key-phrases, we can organize research projects more holistically than keyword searching, and more efficiently than manual categorization. Our model identifies growing and shrinking areas of research and points out biases in location and publication rate across these areas.
To determine correlation of inter reader variability in sum of diameters using RECIST 1.1 with end point assessment in lung cancer.
Authors: Sharma Manish , Singareddy Anitha , Bajpai Surabhi , Narang Jayant , O'Connor Michael , Jarecha Rudresh 
Published: June 2021

e13557 Background: Lung cancer is the leading cause of cancer death in the world including more than 160,000 deaths in the US. The purpose of the study was to determine whether inter reader variability in Sum of Diameters (SOD) of tumor burden has any correlation with variability in end point assessment in lung cancer progression. RECIST 1.1 is based on the SOD of target lesions seen on imaging studies. Response criteria for evaluation of target lesions include - Complete response (CR), Partial response (PR), Progressive disease (PD) and Stable disease (SD). The key determinant of patient response is based on Target Lesion response which in turn is determined by SOD. Inter reader variability study plays an important role in the development of reliable diagnostic tools and understanding of imaging outcomes given the confounding factors like effusion, atelectasis and consolidation in lung cancer that affect Target Lesion selection. Methods: Retrospective analysis of 470 patients was carried out using RECIST 1.1. Double read with adjudication is the preferred read model for submission studies where images are read by two independent reviewers blinded to treatment allocation. As per RECIST 1.1, lesions were measured in the longest diameter for non-nodal and short axis for nodal lesions. This was followed by the calculation of SOD for total tumor burden. If these two primary reviewers disagree, then a third radiologist, the “adjudicator”, reviews the assessments performed by the first two radiologists and selects between the more accurate one. For further analysis, patients were divided into 2 groups, the one with no adjudication i.e. agreement between both readers and the second group with adjudication i.e. disagreement between both readers and ANOVA was used to perform analysis of Variance. Results: Of 470 patients, 332 patients with disagreement were adjudicated, while there was agreement on 138 patients assessments between both readers. SOD of baseline visits for all patients was assessed using ANOVA - single factor with following results: F ratio of 4.76 for Disagreement group was more than F crit (3.86) with P-value 0.03, while for Agreement group F value was less than F crit. Conclusions: There is a direct relationship of variability in SOD at baseline between two readers to the possibility of disagreement in their end point assessment. Additional rules around selection and measurement of Target Lesions should be proposed in protocol to reduce variability and improve endpoint assessment outcomes.[Table: see text]