bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term survival rates in cancer patients achieved with metronomic chemotherapy (cyclophosphamide and methotrexate).
Authors: Chubenko Viacheslav , Zagorskaya Ludmila , Lukyanchikova Valentina , Moiseenko Fedor Vladimirovich , Abduloeva Nuriniso , Zhabina Albina , Levchenko Natalia , Kramchaninov Mikhail , Shelekhova Ksenia , Zykov Evgenii , Meldo Anna , Kudryavcev Alexey , Napolskaya Elena , Moiseyenko Vladimir 
Published: May 2020

e15519 Background: Metronomic therapy (MT) is one of the most promising advances in cancer treatment strategy focused on both tumor cells and their microenvironment, specifically anti-angiogenic, immune and metabolic regulation. The treatment modality is a durable cytostatic drugs exposure with less toxicity. We investigated the efficacy of MT in point of prolonged duration of response (more than 6 months) in pts with the advanced resistant tumors. Methods: A total of 678 pts have been enrolled in the study and have been treated MT cyclophosphamide 50 mg (qd, PO) and methotrexate 2.5 mg (BID, PO) twice per week dosing schedule until progression. 508 pts (75%) had disease progression during first 6 months. Long-term efficacy (more than 6 months) was assessed in 170 pts (25%). The study population characteristics were female 122 (72%) vs male 48 (28%). Among the enrolled pts median age was 70 years (range from 37 to 91 years). ECOG status ranged from 0 to 4 (median - 1). The majority of pts received MT as a 2nd and 3rd line (57%) of the therapy (range from 1 to 11): 1-2 – 106 (62%), 3-4 - 52 (31%), 5 and more - 12 (7%). The distribution of pts by diagnosis is presented in the table 1. The majority of MT pts were represented by advanced clinical stage III-IV (97,6%): I - 1 (0,5%), II - 3 (2%), III - 7 (4%), IV - 159 (93,5%). MT commonly used in early-stages cancer in elderly patients with multiple comorbidities contraindicated to standard treatment. Most pts had two or multiple metastatic sites. Results: The ongoing long-term effect for MT indication was from 6 to 46 months. The main group consisted of the breast and colorectal cancer, 27% and 15%, respectively. The median time to progression was 9 months (16 months in CR was achieved (0,4%), 11 months and 9 months with a partial response (3,4%) and stable disease (21,2%), respectively). 12 (1,7%) pts are on ongoing long-term follow up more than 24 months. MT was well-tolerated. Drug related adverse events were described upon the study: hematological (10,2%, Gr 3-4 – 3,5%) vs non-hematological (6,6%, Gr 3-4 1,7%) toxicity. Conclusions: MT schedule demonstrated effectiveness in patients with advanced resistant tumors. The median duration of the effectiveness doesn’t depend on the line of therapy, tumor localization and objective response. The role of possible predictive markers of clinical benefit is question of further trials. [Table: see text]
Factors associated with low chemotherapy dosing in high risk breast cancer.
Authors: Hernandez Leilani , Fergestrom Nicole , Charlson John A. , Neuner Joan Marie 
Published: May 2020

e15520 Background: Chemotherapy dose is often reduced or delayed due to adverse effects. However, a low relative dose intensity (RDI) is associated with reduced disease control and survival. There is little data among patients receiving modern breast cancer regimens regarding the risk of low RDI, or factors associated with it. Methods: We used an institutional registry at a large multidisciplinary cancer center to identify subjects with incident invasive, non-metastatic breast cancer diagnosed between 2009-2018. We focused on a subset of high-risk patients for whom chemotherapy is clearly recommended by guidelines: triple negative (estrogen receptor, progesterone receptor and HER2 negative) or HER2-positive subtypes, and either positive lymph node metastases or tumor size > 1.0 cm. We obtained administration dates and doses for the following agents: doxorubicin, cyclophosphamide, paclitaxel, docetaxel, and carboplatin. Our primary outcome was RDI < 85% of guideline-recommended doses of at least one of these agents. Other outcomes included dose of each agent (first cycle dose < 85% or total dose < 85) and timing (delay ≥7 days or early discontinuation). Variables used for analyses included BMI ≥25, race, HER2 status, age ≥55 years, marital status, stage, and Charlson co-morbidity score. Results: More than half of our cohort of high risk breast cancer patients experienced a low RDI of at least one chemotherapy agent. Out of the 237 patients who met our inclusion criteria, 60% had a low RDI, 10% received a low first cycle dose, 38% received a low total dose, and 46% experienced either a dose delay or discontinued treatment. Using logistic regression analyses, we found that being overweight (CI: 1.01-3.54; p = 0.046) and stage 3 breast cancer (CI:1.05-5.96; p = 0.038) were associated with increased odds of having a low RDI. Low total dose was associated with being overweight (p = 0.0181), unmarried (p = 0.0278), and stage 3 (p = 0.0201). HER2-positive status was also associated with a low first cycle dose (p = 0.001) and dose delays or discontinuation (p = 0.0002). Conclusions: Having a BMI ≥25, higher-stage, or being unmarried, which may serve as a proxy for low social support, are factors that may help identify patients who will have guideline-recommended chemotherapy doses reduced.
Taxane induced pulmonary toxicity in breast cancer.
Authors: Varayathu Hrishi , Mathew Hephzibah Sara , Sarathy Vinu , Thomas Beulah Elsa , Kumar Santosh Elluru , Reddy Nitheesha , Mufti Suhail Sayeed , Puii Lalnun , Sangi Lalram , Mathew Smruthy Ann , Koramati Samuel Luke , S Dinesh , Swamy Shivakumar , Naik Radheshyam , Ajaikumar Basavalinga Sadasivaiah 
Published: May 2020

e15522 Background: Taxanes are an integral part of chemotherapy for a broad range of tumor types. The usual toxicities associated with Taxane use are peripheral neuropathy, myelosuppression and musculoskeletal adverse effects. Very few studies have reported taxane induced pulmonary toxicity objectively. In our study we explored Taxane induced pulmonary toxicity based on discrete CT findings. Methods: 40 non-smokers diagnosed with Her-2 negative breast cancer who received Taxane monotherapy from 2017 to 2018 were retrospectively analyzed for pre and post therapy CT changes. Following CT findings were considered significant as pulmonary toxicity; (a) Nonspecific area with ground-glass attenuation, (b) multifocal areas of airspace consolidation, (c) patchy distribution of ground-glass attenuation accompanied by interlobular septal thickening and (d) extensive bilateral ground-glass attenuation or airspace consolidations with traction bronchiectasis. The CT findings were assessed independently by two radiologists and one pulmonologist. Results: Our study showed that 5 patients (12.5%) developed pulmonary changes on chest CT post Taxane therapy as summarized in Table. Conclusions: Our study shows that taxane has more potential to induce pulmonary toxicity than reported in present literature. Given that taxanes are the most widely used chemotherapy, it is of utmost necessity to be cognizant of this under-reported potentially fatal adverse effect in a large population. Further studies should be conducted to better understand the true potential, mechanisms and patterns of taxanes induced pulmonary toxicity. [Table: see text]
Successful mutational profiling of single circulating epithelial tumor cells (CETCs) from patients with solid cancers for guiding therapy.
Authors: Schott Dorothea , Pizon Monika , Pachamnn Ulrich , Pachmann Katharina 
Published: May 2020

e15527 Background: Circulating epithelial tumor cells (CETCs) are an important link between primary tumors and metastases and provide a readily accessible source of tumor material from patients with solid cancer. Therefore, they are representative for primary and metastatic lesions to evaluate treatment response in real-time and to guide therapeutic modifications. Beyond enumeration, information on mutations is extremely important in the clinical setting to monitor the development of the disease over time and to guide drug selection. Isolating single CETCs with high recovery and purity from the high background of blood cells is an indispensable prerequisite to investigate cell heterogeneity and provides a tool for a personalized medicine approach. Methods: Blood from patients with non-small cell lung cancer, colon cancer and malignant melanoma was analysed for CETCs using the maintrac approach. Between 8-20 EpCAM positive cells from each patient were isolated individually using a semiautomated capillary approach and deposited one by one into micro cups. For mutational profiling, EGFR, KRAS and BRAF hotspot mutations were analysed in CETCs after whole genome amplification. Results: DNA could be amplified from all individually isolated cells. EGFR mutations were detected in 17% of isolated tumor cells from patients with non-small cell lung cancer; KRAS mutations were detectable in 28% of cells from patients with colon cancer and BRAF mutations in 50% of evaluable cells. A high heterogeneity in mutation status was observed among CETCs within a patient. Conclusions: Individually isolating CETCs from the peripheral blood from patients with non-small cell lung cancer, colon cancer and melanoma allows not only to detect driver mutations but also to determine genotypic heterogeneity between cells and changes over time. Mutations in the CETCs resemble those detected in primary tumors present only in part of the cells. They can be used to monitor the development of disease and its status over time, particularly for its impact in guiding drug selection.
The application of dynamic monitoring of circulating tumor DNA for detecting minimal residual disease and predicting recurrence in colorectal cancer patients.
Authors: Chan Hiu Ting , Nagayama Satoshi , Chin Yoon Ming , Otaki Masumi , Hayashi Rie , Kiyotani Kazuma , Fukunaga Yosuke , Ueno Masashi , Nakamura Yusuke , Low Siew-Kee Kee 
Published: May 2020

e15531 Background: Although the prognosis of colorectal cancer (CRC) has improved in the past decade, a subset of CRC patients may still suffer from relapse due to the progression from minimal residual disease (MRD) after surgical resection. A sensitive and non-invasive method to detect MRD and early diagnosis of recurrence disease is warranted to start therapeutic interventions at an earlier timing and improving the overall survival rate. In this study, we have evaluated the feasibility of circulating tumor DNA (ctDNA) analysis to detect MRD and early detection of recurrence in CRC patients. Methods: Plasma samples were collected prospectively from 38 CRC patients (stage I to IV), who underwent surgical resection. Preoperative blood samples were obtained just before surgery and post-operative samples were collected at multiple time-points to monitor the changes of tumor mutation profiles. Tumor-derived mutations were detected in preoperative blood samples as well as surgically resected-tumor tissues using ultradeep targeted next generation sequencing. Patient-paired peripheral blood cells (PBCs) were sequenced concurrently to exclude clonal hematopoiesis-related mutations. Results: Among the 38 patients, 74 non-synonymous mutations were identified in tumor tissues and 64 mutations in the preoperative plasma samples. Paired PBCs sequencing identified 11 mutations in plasma samples to be clonal hematopoiesis-related mutations. After the exclusion of clonal hematopoiesis-related mutations, 34 (89.5%) of the 38 patients harbors at least one somatic mutation either from tumor tissues or plasma samples to be monitored longitudinally. ctDNA was detectable in 5 of 14 (36%) post-surgical samples of patients who did not receive adjuvant chemotherapy and in 9 of 18 (50%) post-chemotherapy samples. Up to date, 6 patients have been detected with clinical recurrence and ctDNA analysis identified all 6 recurrences before imaging. Serial ctDNA analyses were able to detect disease recurrence up to 6 months before imaging tests. Furthermore, all patients that were ctDNA negative post-operative or post-chemotherapy showed no signs of clinical relapse. Conclusions: Our current results indicate that ctDNA analysis allows the detection of MRD in CRC patients. The integration of ctDNA analysis with current standard monitoring guidelines holds great promise in early detection of recurrence to allow clinical intervention to be applied promptly.
Focused ultrasound ablation of solid tumors: Feasibility of planning tissue-selective treatments.
Authors: Mancia Lauren , Vlaisavljevich Eli , Yousefi Nyousha , Maxwell Adam , Siegel Geoffrey W. , Xu Zhen , Johnsen Eric 
Published: May 2020

e15600 Background: Focused ultrasound (FUS) is a noninvasive, nonionizing, repeatable local ablative therapy that induces mechanical fractionation or thermal necrosis of a variety of solid tumors including hepatocellular carcinoma, prostate cancer, and desmoid fibromatosis. Recent feasibility studies in animal models have demonstrated the possibility of designing focused ultrasound treatments that are selective (e.g. spare healthy tissue, nerves, and blood vessels) due to differences in tissue and tumor mechanical properties. Given wide variation in individual tumor and patient characteristics, mechanics-based predictions of ablation zone features in different tissues under a range of FUS device settings are needed to permit personalized treatment planning. Methods: A finite difference computational method is used to simulate FUS ablation of tissues with variable mechanical properties (shear moduli of 0.6 – 200 kPa) under different FUS sonication parameters (frequency and peak pressure). The model calculates strain fields contributing to tissue ablation in FUS treatments which are used to predict ablation zone radii and boundary characteristics. Simulation predictions in model tissues are then compared to histology obtained from FUS-treated porcine tissue samples with similar mechanical properties. Results: The mechanical properties of model tissues and FUS treatment parameters have distinct effects on predicted minimum ablation zone radii. For example, smaller ablation zone radii are achieved in stiffer vessel wall than liver under given FUS sonication parameters. In each tissue, lower frequency and higher peak pressure FUS sonication predict a larger ablation zone. Combined variation of sonication frequency and peak pressure are found to achieve wider variation in ablation zone radius than previously achieved with frequency variation alone. Predicted ablation zone radii and boundary characteristics are consistent with the observed histology of FUS-treated tissues. Conclusions: Results show that simulations accounting for tissue mechanical properties and device settings can predict tissue selectivity and ablation zone characteristics observed in FUS procedures. This study demonstrates the potential of using noninvasive measurements of tissue and tumor properties obtained, for example, via shear wave elastography, in combination with micromechanical tissue ablation simulations to develop personalized, selective focused ultrasound treatments for solid tumors.
Landscape of RAS variations in 17993 solid tumors: A pan-cancer analysis.
Authors: Wu Hao , Zhou Shaoqiang , Zhang Ding , Zhao Jing , Zhao Zhengyi , Wang Guoqiang , Zhang Yuzi , Cui Longgang , Cai Shangli , Bai Yuezong , Chen Dedian 
Published: May 2020

e15615 Background: RAS family genes (HRAS, KRAS and NRAS) were frequently observed in several tumors. The expression of constitutively active RAS proteins mediated by RAS variations promote the development of tumors. KRAS is an important prognostic and drug resistance biomarker. It would also be a promising drug target. AMG 510 which targeting KRAS G12C showed an ORR of 48% in patients with NSCLC. Several trials which evaluating the efficacy of RAS G12C inhibitor in solid tumors are initiated. Herein, we analyzed the alterations status of KRAS/NRAS/HRAS across diverse solid tumors. Methods: The sing nucleotide variants (SNV) and copy number variants (CNV) data of 17993 Chinese patients from 22 types of cancer were obtained in 3DMed database. Genomic profiling of DNA was performed through a next-generation sequencing with 61 cancer-related genes on tissue. Only the pathogenic mutations and likely pathogenic mutations in clinical significance were rolled into our analysis. Results: Among 17993 pan-cancer patients, the total RAS variants frequency was 23.09%. KRAS was the most frequently altered (90.76% of RAS SNV, 84.70% of RAS CNV), followed by NRAS (6.56% of RAS SNV, 8.58% of RAS CNV) and HRAS (2.68% of RAS SNV, 6.72% of RAS CNV). For the SNV, KRAS were most commonly found in pancreas cancer (685/842, 81.35%), intestine cancer (85/175, 48.57%) and colorectal cancer (1609/3329, 48.33%). NRAS occurred most frequently in melanoma (31/196, 15.82%), colorectal cancer (116/3329, 3.48%) and thyroid cancer (2/60, 3.33%). HRAS were most often found in bladder/urinary tract cancer (46/367, 12.53%), prostate cancer (5/137, 3.65%) and head and neck cancer (7/314, 2.23%). Further analysis among KRAS SNV patients showed that the mutation frequency of KRAS G12C, G12D, G12R and G12V was 9.24%, 34.73%, 3.54% and 21.66%, respectively. A total of 21 in 22 types of solid tumors had KRAS G12C/D/R/V pathogenic or likely pathogenic mutation, which occurred most frequently in colorectal cancer, pancreas cancer and lung cancer. Conclusions: Our results suggested that a variety of solid tumors may harbor KRAS G12C/D/R/V mutation. These patients may benefit from KRAS inhibitors.
Repurposing antimuscarinics to treat lethal chemoresistant prostate and lung cancers.
Authors: Bland Tyler B , Wu Boyang 
Published: May 2020

e15636 Background: Advanced non-small cell lung cancer (NSCLC) and prostate cancer (PCa) remain leading causes of cancer-related deaths in the United States and worldwide. The current study investigates the ability of antimuscarinics to resensitize chemotherapy resistant NSCLC and PCa to chemotherapy-induced apoptosis. Methods: The chemotherapy drug docetaxel (DTX) resistant human NSCLC and PCa cell cultures were established to recapitulate clinical emergence of chemoresistance. These cultures were used to harvest total RNA and protein for qPCR and Western blot analyses, respectively. DTX’s ability to induce apoptosis was measured with crystal violet survival assay and TUNEL assay. Results: DTX-resistant NSCLC (A549R) and PCa (DU145R) cells show increased expression of the muscarinic acetylcholine receptors 1 and 3 (CHRM1 / CHRM3). Treatment of these DTX-resistant cells with the CHRM1 antagonist dicyclomine (Dic) or the CHRM3 antagonist darifenacin (Dari) resensitize these cells to DTX-induced cell death. This treatment repurposes Dic and Dari, which are currently used in the clinic to treat irritable-bowel syndrome and overactive bladder, respectively. Decreased cell survival was observed with crystal violet survival assay, which led to increased cell death at a lower concentration of DTX compared to cells treated with DTX alone (A549R [DTX IC50]: DTX = No response, Dic + DTX = 5.2 nM, Dari + DTX = 2.2 nM / DU145R [DTX IC50]: DTX = No response, Dic + DTX = 4.2 nM, Dari + DTX = 1.4 nM). Furthermore, cells treated with Dic + DTX or Dari + DTX show increased apoptosis measured by TUNEL assay compared to cells treated with DTX alone (A549R [TUNEL positive %]: DTX = 0.9%, Dic + DTX = 22.2%, Dari + DTX = 88.2% / DU145R [TUNEL positive %]: DTX = 3.6%, Dic + DTX = 96.4%, Dari + DTX = 90.1%). Conclusions: We show that chemoresistant NSCLC and PCa have high expression of CHRM1 and CHRM3 and that antimuscarinics effectively resensitize these lethal forms of cancer to chemotherapeutics. Our data support the rationale of repurposing these therapies to treat chemoresistant NSCLC and PCa, allowing quick entry into a Phase II clinical trial and further translation into clinical practice, in a more cost-effective and less financially risky way, to benefit cancer patients.
X-ray crystal structure analysis of elacestrant (RAD1901), a novel selective estrogen receptor degrader (SERD), bound to estrogen receptor alpha ligand binding domain.
Authors: Fanning Sean W. , Greene Geoffrey , Conlan Maureen G. 
Published: May 2020

e15647 Background: Antiestrogens are a mainstay of treatment for estrogen receptor positive (ER+) breast cancer in both the adjuvant and the advanced/metastatic settings. Elacestrant is a mixed activity selective estrogen receptor (SER) alpha (ERα) antagonist, acting as a SER modulator (SERM) at low doses and a SER degrader (SERD) at high doses. It has shown activity in hormone sensitive wild type (WT) ERα and insensitive estrogen receptor gene 1 (ESR1) mutation-harboring (Y537S and D538G) ERα breast cancer, both in preclinical models and in clinical studies. It also possesses a unique pharmacology compared to other competitive ER antagonists in its ability to cross the blood brain barrier. Competitive ERα antagonists are typically comprised of a core that sits in the ligand binding pocket and an arm that manipulates the structure to achieve SERM or SERD activities. In these molecules, the arm is attached in the same position as the triphenylethylene core of tamoxifen. However, elacestrant possesses a novel site of attachment. As such, we hypothesized that elacestrant adopts an alternative binding orientation in the ERα ligand binding pocket to achieve its unique pharmaceutical profiles. Methods: X-ray crystallography was used to solve a co-crystal structure of elacestrant in complex with WT ERα ligand binding domain to 2Å. Results: Overall, elacestrant promotes the formation of a canonical ERα ligand binding domain antagonist conformation, whereby helix 12 (H12) is docked into the activating function-2 cleft. However, elacestrant adopts a novel vector in the ERα ligand binding pocket that places it in close proximity to helix 12. As a result, it forms a bifurcated hydrogen bond that is not observed in other competitive antiestrogens and samples a chemical space known to increase H12 mobility and induce SERD activity. This novel vector also places it near positions 537 and 538, the two most common sites of somatic mutation. Conclusions: The high-resolution x-ray crystal structure of elacestrant suggests that the unique binding mode it adopts enables novel pharmacology and positions it to achieve potency in the WT and activating somatic ERα mutated breast cancer setting.