bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast cancer screening in patients with cancers other than breast.
Authors: Maurer Stephen M , Leopold Robin Berton , Thomas Alexander W , Concannon Kyle Francis , Correll Alissa Dorothy , LaPenta Catherine M , Sprague Brian L , Herschorn Sally D. , Verschraegen Claire F. 
Published: September 2018

e13095 Background: Screening mammography can detect early breast cancers and reduce subsequent cancer mortality. However, there is a lack of consensus as to what should trigger screening discontinuation. This absence of clear-cut guidelines means that many patients with advanced malignancies continue screening despite unclear benefit. Methods: We performed a retrospective cohort study of female patients diagnosed with a non-breast malignancy to explore the incidence and effects of screening mammography. Female patients, who were diagnosed between 2007 and 2012 with a non-breast malignancy stage II or higher, were cross-referenced with the Vermont mammography screening logs from January 1, 2007 to September 30, 2014. Additional data was collected through chart reviews, in May 2016. Results: Of 1501 women, 398 (26%) who met the above criteria had a screening mammogram within first 5 years of their cancer diagnosis. Of these 398 women, 193 (48.5%) were alive without cancer, 132 (33.2%) had died, and 73 (18.3%) were alive with cancer at the time of chart review. Of those who died, 84 (63.6%) had a stage III or IV cancer. Eighteen (4.5%) had a breast biopsy following a suspicious screening mammogram, resulting in 13 (3.3%) benign diagnoses and 5 (1.3%) breast cancer diagnoses. No patient died of breast cancer. Conclusions: Female patients diagnosed with an advanced non-breast malignancy have a mortality risk that outweighs the known breast cancer mortality benefit from screening mammography. [Table: see text]
Application of liquid biopsy to uncover critical cancer insights using the GeneReader NGS system.
Authors: Andruzzi Luisa 
Published: September 2018

e13102 Background: NGS studies of cancer are primarily based on studies of FFPE samples, the use of which is limited by surgical feasibility, tissue availability and patient preference. An emerging field of study is focused on circulating-free DNA (cfDNA), sometimes termed “Liquid Biopsy”. While holding great promise as the future of cancer understanding and management, the liquid biopsy field is still nascent, lacking an integrated NGS workflow solution with proven performance. Methods: QIAGEN is an established expert in the field of sample preparation for liquid biopsy. The combination of the QIAamp Circulating Nucleic Acid Kit, the GeneReader NGS System using a new proprietary sequencing chemistry, and an optimized bioinformatics solution, provides the first fully integrated workflow specifically designed for analyzing cfDNA. A set of liquid biopsy samples from non-small cell lung cancer (NSCLC) patients and cfDNA reference standards (Horizon), with allelic frequency down to 1%, were used for this study. cfDNA was extracted from the liquid biopsy samples, and run through the QIAGEN GeneReader workflow. Variants were analysed using the QIAGEN Clinical Insight (QCI™) Analyze for liquid biopsy. Results: Expected mutations in all genes (EGFR, KRAS, NRAS, PI3KCA) were identified and verified, at 100% concordance with reported in ddPCR studies. Both single nucleotide and insertion-deletion variants were correctly detected down to a 1% allele frequency threshold which was reproducible between repeat runs. No significant difference was observed between cfDNA reference standards and clinical liquid biopsy samples. Conclusions: These data exhibit high sensitivity and performance consistency of liquid biopsy analysis with the GeneReader system. This study systematically demonstrates the accuracy of a cfDNA assay combined with the robustness of a fully integrated NGS system. As such, laboratories interested in conducting liquid biopsy studies can leverage this study and the system to implement an NGS workflow.
EGFR testing scenario across 111 centres in India: A questionnaire-based survey.
Authors: Prabhash Kumar , Parikh Purvish M. , Rajappa Senthill J , Noronha Vanita , Joshi Amit , Aggarwal Shyam , Bondarde Shailesh Arjun , Patil Shekar , Desai Chirag Jyotiker , Naik Rajesh , Anand Sohit , Chacko Raju Titus , Biswas Ghanashyam , Sahoo Tarini Prasad , Dabkara Deepak , Patil Vijay Maruti , MV Chandrakanth , Das Pratap Kishore , Vaid Ashok K. , Doval Dinesh 
Published: September 2018

e13111 Background: Lung cancer diagnosis now involves routine use of biomarker testing to identify the driver mutations. We conducted a survey of 111 medical oncologists across India to understand the current pattern of EGFR mutation testing at their respective centres. Methods: Medical oncologists from 111 institutes across India were interviewed face to face using a structured questionnaire. They were divided into two groups - Group 1 with in-house EGFR testing and Group 2 who send samples to central/commercial labs. Answers of the two groups were analysed to see the prevailing patterns of EGFR mutation testing and differences between the groups if any. Results: In India, 95% of medical oncologists recommend testing for EGFR mutations in patients with adenocarcinoma histology. 40% would also recommend testing in squamous histology. 80% of medical oncologists request for biomarker testing at the time of primary biopsy. From the time of biopsy, the average time duration to get EGFR test results is 18 days. In centres with in-house testing (Group 1), results are available in 10 days. 96% of the medical oncologists from Group 1 centres request for factoring additional sample for biomarker testing compared to only 69% from Group 2. 69% of medical oncologists in Group 1 centres would prefer to wait for the test results before initiating treatment compared to 46% in Group 2. EGFR TKIs are used in 60% of patients with diagnosed EGFR mutation in the first line. For patients in whom chemotherapy is initiated while waiting for test results, 50% of medical oncologists prefer completing 4-6 cycles before switching to targeted therapy. At the time of progression, rebiopsy is possible in 25% of the patients. Rapid disease progression and poor PS were the two most common reasons given for the low rebiopsy rates. Conclusions: Application of molecular testing is ‎improving. Yield can be improved by training of multidisciplinary team involved in tumor biopsy. There is scope and need to reduce the turnaround time. This will reduce the current scenario of commencing chemotherapy while waiting for test results. Increasing application of liquid biopsy will help in initial diagnosis as well as at relapse, especially for patients with poor PS or difficult access to tumor site.
Antitumor effect of levetiracetam combined with temozolomide in glioma cell lines.
Authors: Chen Zhong-ping , Wu Qing-wu , Wang Jing 
Published: September 2018

e13530 Background: The antitumor effect oftemozolomide (TMZ) is still remitted for portion of glioma patients, and if anti-epilepcy drug levetiracetam (LEV) may help TMZ for anti-glioma is not clear. Methods: The cell proliferation with Cell Counting Kit-8 (CCK-8) assay was performed in two O6-methylguanine DNA methyltransferase (MGMT) positive cell lines (T98G and U138) and two other MGMT negative cell lines (SKMG-4 and U87). The cells were treated with LEV and TMZ alone or in combination. Results: LEV inhibited the proliferation of glioma cell lines but not reach therapeutic effect, especially in U87cell line. The 50% inhibitory concentration (IC50) of TMZ was significantly decreased in cell lines (T98G, U138 and SKMG-4, P< 0.05) which were treated with TMZ and LEV, but no significantly changed in U87 (P> 0.05). Conclusions: LEV may inhibit the proliferation of glioma cell lines (both MGMT- positive and MGMT-negative) and also sensitizes cell lines (T98G, U138 and SKMG-4, but not U87) to TMZ.
Brain tumors: Regulation of angiogenesis.
Authors: Rostorguev Eduard Evgenevich , Frantsiyants Elena Mikhaylovna , Pogorelova Yulia A. , Cheryarina Natalia D. , Kozlova Larisa , Tkalya Lyudmila Dmitriyevna , Tavaryan Irina Stasio , Atmachidi Dmitriy P. , Kavickij Sergey E. , Kuznetsova Natalya S. , Porksheyan David H. , Porksheyan David H. , Kit Oleg I. 
Published: September 2018

e13540 Background: Cancer implicates pathological angiogenesis. The problem of treatment for primary and metastatic brain tumors is still unsolved. In addition to main angiogenic functions, VEGF family performs important mediator functions in the immune system. The role of VEGF family in central nervous system tumors is poorly studied. Our purpose was to study the levels of factors of angio- and lymphangiogenesis in tissues of glioblastomas (G), brain metastases (MTS), meningiomas and corresponding peritumoral area. Methods: Tissues of tumor and peritumoral zone (PZ) obtained during the surgery from 22 patients with G, 14 patients with brain MTS from breast cancer and 12 meningioma patients, mean age 39.2±4.8 years, were studied. Levels of VEGF-A, VEGFR-1, VEGF-C and VEGFR-3 were determined by ELISA. The data were processed using Statistica 10 program. The significance of differences was determined by Student's t-test. Results: VEGF-A levels in tissues of G and MTS were higher than in meningioma tissues by 74.7 and 94.5 times, respectively; levels of VEGF-R1 were 2.7 and 3.9 higher, and the VEGF-A/VEGF-R1 coefficient was 28.1 and 24.1 times higher, respectively. Levels of VEGF-C and VEGF-R3 were escalated only in G tissues compared to meningiomas (by 1.7 times on average). The VEGF-С/VEGF-R3 coefficient was similar in all studied tumors. VEGF-A levels were higher in PZ of G and MTS compared to PZ of meningiomas – by 78.2 and 110.7 times, respectively, while VEGF-R1 level was higher in G PZ only (by 5.5 times). The VEGF-A/VEGF-R1 coefficient was 14.5 and 128.5 times higher, respectively. VEGF-C level in PZ of G was escalated compared to meningiomas by 6.5 times, in MTS – by 1.6 times. VEGFR-3 contents did not differ significantly in all PZ samples, but the VEGF-С/VEGF-R3 coefficient was higher in PZ in G by 9 times and in MTS by 2 times. Conclusions: Compared to benign meningiomas, angio- and lymphangiogenesis are activated in glioblastoma tissue and angiogenesis – in metastatic tissue. Lymphangiogenesis is more active in peritumoral zone of glioblastomas compared to metastatic tissue, and angiogenesis is more active in peritumoral zone of metastases.
Kinin system of blood plasma as pathogenesis factor in brain tumors.
Authors: Kozlova Larisa , Frantsiyants Elena Mikhaylovna , Tkalya Lyudmila Dmitriyevna , Rostorguev Eduard Evgenevich , Atmachidi Dmitriy P. , Kavickij Sergey E. , Kuznetsova Natalya S. , Porksheyan David H. , Kit Oleg I. 
Published: September 2018

e13542 Background: The kallikrein-kinin system (KKS) does not only perform its adaptive-regulatory function; it is confirmed to be involved into pathology, neoplastic processes in particular. Our purpose was to study the kallikrein family (KLKs), pro-KLKs and carboxypeptidase N (CPN) in the blood plasma of patients with benign and malignant brain tumors. Methods: We studied citrated blood plasma of 164 patients with brain neoplasms: 37 meningiomas (M), 74 primary glioblastomas (G) and 53 brain metastases (MTS) from breast cancer. The kinetics of KKS enzymatic reactions was determined in the blood plasma before treatment using the U-2900 UV Solutions double-beam spectrophotometer (USA). The results were compared to the values in 39 healthy donors (N). The data were processed using the Statistica 10 program. The significance of differences was determined by Student's t-test. Results: Activity of KLKs in the blood plasma in patients with M exceeded N by 1.3 times (p≤0.05), in G – by 3.9 times, in MTS – by 5.1 times. Levels of pro-KLKs in M were lower than in N by 1.6 times, and in G and MTS they were similar to N. CPN activity in M was decreased compared to N by 3.1 times; in G and MTS it did not differ significantly from N. The pro-KLKs/KLKs coefficient in patients with M was lower than in N by 2 times, in G – by 3.7 times, and in MTS – by 5.1 times. Activity of KLKs in G and MTS was 3 and 4 times higher, respectively, than in M (p < 0.001). It supposed realization of effects of KLKs and produced bradykinin on cells, blood enzymes and microvessel walls in malignant brain tumors to a greater extent than in benign ones. Conclusions: Activation of KKS in the blood plasma in malignant brain tumors is more intense than in benign tumors, it directly and indirectly influences cell migration, increases capillary permeability and causes an imbalance in the related enzyme systems becoming a pathogenesis factor.
Impact of features of brain lesion in prognosis.
Authors: Castaneda Altamirano Carlos , Castillo Garcia Miluska , Belmar Lopez Carolina , Bernabe Luis A. , Sanchez Joselyn , Galvez Renato , Orrego Enrique , Garcia- Corrochano Pamela 
Published: September 2018

e13549 Background: Brain metastasis (BM) is an event with poor prognosis. Different scores predict outcome in patients with BM. One of them is Graded Prognostic Assessment (GPA) score and includes clinical features like age and performance status of the patients. The frequency of patients with available tissue from brain lesions is increasing because of improvement of surgical techniques. It allows to include the evaluation of pathological features in order to improve prognosis determination. Our study aims to evaluate if tumoral proliferation and lymphocyte infiltration in brain lesions can improve prognostic accuracy of clinic-pathological features in patients with BM. Methods: We obtained BM samples from 113 cases that came to the Instituto Nacional de Enfermedades Neoplasicas from 2001 to 2015. We evaluated clinicopathological features from patient files and prospectively evaluated pathological features: Ki67 and lymphocytes in 64 BM lesions from slides scanned in a BX63-Olympus. The image analysis software use for calculating KI67 index and CD3 was Tissuemorph, with a median count of 5135 cells and 5391 cells, respectively. We calculated GPA score and evaluated the value to add pathological features of BM. We also evaluated distribution of mononuclear cells. Results: Median age at first diagnosis of BM was 52 years (range 11–75 years), 35.4% were male. BM at debut and extra-brain disease was found in 33.6% and 39.3%. The most frequent primary tumor location was breast (31%) and lung (18.6%). Most frequent procedure for brain lesion was biopsy (9.8%), subtotal resection (8.9%) and total resection (81.3%). Distribution of lymphocytes was perivascular in 57 cases. Median ki67 and CD3 TIL were 30 and 44, respectively. GPA 0-1, 1.5-2.5, 3 and 3.5-4 were found in 18 (16.2%), 61 (55.0%), 27 (24.3%) and 5(4.5%), respectively. Higher GPA (p = 0.196) had a trend to shorter survival. Higher ki67≥ 15% (p = 0.013) index was associated with shorter survival. The CD3 lymphocytes count was not associated with survival (p = 0.754). Adding ki67 index to GPA was associated with better outcome (p = 0.033). Conclusions: Our results find that patients with high ki67 index in brain lesions carry a worse prognosis and adding this information to GPA score can improve prognostic accuracy of the tool.
Survival analysis of a phase IB/II study of everolimus and metformin for patients with advanced cancer.
Authors: Molenaar Remco Jurriaan , van de Venne Tim , Weterman Mariette , Mathot Ron , Klumpen Heinz-Josef , Richel Dirk , Wilmink Johanna 
Published: September 2018

e14020 Background: Fundamental research suggests that a combination of everolimus and metformin has synergistic anti-tumour effects with lower chances of drug resistance. Methods: 9 patients with advanced refractory cancer received everolimus and metformin in a 3+3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results: We enrolled 9 patients who stayed on the study for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. 4 out of 9 patients experienced a DLT and we terminated patient enrollment. Metformin was eliminated slower and metformin trough concentrations were higher when co-administered with everolimus than as single-agent (half-life: 9.3 h vs 4.3 h; P= .03 and Ctrough: 0.47 mg/l vs 0.2 mg/l; P =.01). After 9 weeks of treatment, 3 patients were still on study and all had stable disease as evaluated using CT scans and RECIST criteria. The 3 patients that received everolimus and metformin for at least 9 weeks had a significantly longer survival than the 5 patients who had to stop study treatment prematurely due to toxicity (median overall survival: 184 days vs 82 days; P= .048). Conclusions: The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. This may be due to pharmacokinetic interactions between everolimus and metformin and has implications for diabetic cancer patients that are treated with these drugs. Patients that tolerated the combination survived longer than patients who did not, suggesting that the combination of an mTOR inhibitor and metformin is clinically effective against cancer. This advocates for future clinical trials with combinations of other mTOR inhibitors and biguanides. [Table: see text]
Comparison of adverse events beyond cycle 1 between cytotoxic combination and molecularly targeted phase I trials.
Authors: Jordan Emma J. , Spicer James F. , Sarker Debashis 
Published: September 2018

e14028 Background: Traditionally, only grade 3 and 4 adverse events (AEs) occurring during cycle 1 are used for dose escalation decisions in phase I oncology trials. With the shift in cancer drug development away from cytotoxic chemotherapy towards molecularly targeted agents (MTAs), assessment of lower grade AEs and those in later cycles is considered to be of increasing relevance. This study evaluated differences in AE incidence between trial types (combination cytotoxic vs. single MTA) and cycle number (1 vs. 2-6). In line with previous work suggesting ethnic and age related differences in toxicities, we evaluated AE incidence across a range of patient demographics. Methods: Retrospective analysis of toxicity data in patients enrolled onto phase I clinical trials at a single UK centre between 2006 and 2016. All AEs in the first six cycles of treatment deemed at least ‘possibly related’ were recorded. Results: A total of 912 AEs (664, grade 1; 194, grade 2; 54, grade 3 and 4) were identified in 127 patients across 15 different trials (420 treatment cycles). Mean AE totals for patients on cytotoxic combinations and MTAs respectively were 4.51 and 2.94 in cycle 1, 3.47 and 3.04 in cycles 2-6. Patients on cytotoxic combinations experienced a significantly higher mean number of AEs in six cycles compared to those on MTAs (7.98 vs. 5.98, p = 0.0135). Of the patients experiencing grade 3-4 AEs, 57% (cytotoxic combinations) and 75% (MTAs) occurred for the first time after cycle 1. No significant difference in incidence of AEs was found between any subgroups of patient demographic variables. Conclusions: Incidence of AEs is less in MTAs than for cytotoxic combinations across cycles 1-6. The significant incidence of first grade 3-4 AEs occurring from cycle 2 onwards supports incorporation of AE assessment beyond cycle 1 into recommendations for phase II doses in MTAs.
Efficacy of a repeat dose injection of CLR 131 (I-131-CLR1404) in U87-MG tumor-bearing athymic nude mice.
Authors: Oliver Katherine , Longcor Jarrod , Kandela Irawati 
Published: September 2018

e14089 Background: CLR 131 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Study was to evaluate the therapeutic effect of CLR 131 when administered as a repeat dose intravenous injection in U87-MG tumor bearing mice. Malignant gliomas are associated with a low survival rate, and treatment with chemotherapy, external beam radiation, or surgery have shown limited effectiveness. In this study, therapeutic effect was evaluated by measurement of tumor volume increase and by survival of CLR 131 treated animals compared to animals dosed with a I-127-CLR1404 control. Methods: The U87-MG cell line (human glioma) was purchased from American Type Culture Collection (ATCC, Rockville, MD) and maintained in MEM media supplemented with 10% fetal bovine serum. Twenty female athymic nude mice (Harlan, Indianapolis, IN) weighing between 16-20 g were anaesthetized with isofluorene and inoculated subcutaneously in the right flank with 1 x 106 U87-MG tumor cells suspended in 50 μL PBS. The mice were given potassium iodide at a concentration of 0.1% in their drinking water to block possible free iodide in the drug formulation, with the addition of 0.4% (w/v) sweetener (Sweet and Low) to aid palatability, three days prior to injection and continuing through two weeks post injection. Doses of 95.7µCi and 109.0 µCi of CLR 131were given at Day 0 and Day 7 (N = 8 per group). Control doses of I-127-CLR1404 were given at the indicated dose and was injected via tail vein on Day 0 and Day 7. Results: The control group’s tumors increased 25-fold over a period of four weeks and the treatment group’s tumors increased 12-fold over the same period. There was a significant difference between the control and treatment tumor volumes. Mean survival time was 24.5 days and 31.9 days post injection, respectively. Conclusions: CLR 131 represents a unique, first in class targeted radiotherapeutic currently in clinical development. This study shows that CLR 131 dosed twice provides significant inhibition of tumor growth in a U87-MG tumor model which is known for very aggressive growth. Additionally, CLR 131 provided an overall survival benefit over the control group.
Evaluation of advanced lung cancer inflammation as potential prognostic markers in patients with colorectal cancer.
Authors: Rowe Julie Haewon , Kamil Fathima , Yu Andre , Wray Curtis Jackson , Cen Putao , Jafri Syed Hasan Raza 
Published: September 2018

e15142 Background: The Advanced Lung cancer Inflammation (ALI) prognostic index evaluates the degree of systemic inflammation in cancer patients and has been validated in small cell lung and esophageal cancer. The “sidedness” of the colon primary has prognostic implications with left sided tumors having longer survival rates than right sided. Our hypothesis is that right sided colorectal cancers (CRC) will have a lower ALI. Methods: We conducted a retrospective review of newly diagnosed CRC patients who were seen and evaluated at a tertiary Cancer Center from 1/1/2005 to 12/31/2015. ALI is calculated as ALI = BMI x (serum albumin/NLR). NLR is the neutrophil to lymphocyte ratio. Logistic regression models were used to determine the association between primary colon cancer location and ALI. Results: A total of 279 patients were included in this study. 53% of patients were male and mean age was 63.4 years (SD 13.7). 52% of cancers were located on the right side. Using an ordered logistic regression, ALI was predictive of higher stage disease (p = 0.04). In those patients with stage III (n = 64) or IV (n = 136) disease, the likelihood of a low ALI was significantly higher for right-sided colon cancers (OR 2.12, 95%CI:1.18-7.76). Conclusions: The Advanced Lung Cancer Inflammation index appears to be related to both CRC stage and primary cancer location. Ongoing studies are needed to determine the relationship between ALI and CRC survival.