bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prescribing decision drivers in patients with recurrent gastrointestinal stromal tumor (GIST) previously treated with adjuvant imatinib: A retrospective chart extract-based approach.
Authors: Guérin Annie , Sasane Medha , Gauthier Geneviève , Schwiep Frances Annelies , Keir Christopher Hunt , Magestro Matt , Wu Eric Q. , Conley Anthony Paul 
Published: March 2020

e21515 Background: Adjuvant imatinib (IM) is the standard of care for primary resectable GIST. However, little is known about prescribing habits following disease recurrence. This study identifies main prescribing decision drivers in recurrent GIST pts following completion of adjuvant IM treatment. Methods: Using an online data collection system, clinical information was retrieved on 410 pts treated with adjuvant IM for ≥6 months for primary resectable KIT+GIST, who discontinued IM treatment, had a recurrence (while off IM), and subsequently restarted IM or initiated sunitinib. Pt-level data were collected at primary diagnosis and at first recurrence. Prescribing decision drivers were identified using logistic regression models. Physicians were also surveyed to identify factors that influence their prescribing decisions. Results: Following initial disease recurrence, 77% of pts restarted IM and 23% initiated sunitinib. IM duration at primary diagnosis was the main prescribing decision driver; pts treated with IM for a shorter period of time (≤18 months) were 7.0 times more likely to restart IM than pts with longer IM duration (p<.01). Pts who took longer (≥12 months) to develop recurrence after IM discontinuation (Odds ratio [OR]=3.4; p=<.01 ), had a low mitotic rate at recurrence (OR=2.8; p=<.01), or had a recurrence inside the gastrointestinal system (OR=2.7; p=<.01) were also more likely to be prescribed IM following recurrence. These findings were consistent with the top survey responses on factors influential to prescribing decisions after recurrence: time to develop recurrence (55%), pt risk profile (53%), and IM duration prior to recurrence (51%). Conclusions: Based on information of pts who restarted IM or initiated sunitinib, IM treatment duration at primary diagnosis, time to develop recurrence after IM discontinuation, tumor location and mitotic rate at recurrence seem to be the main prescribing decision drivers. These findings were consistent with physicians’ main factors reported to influence their prescribing decisions following recurrence.
Practical application of whole genome and transcriptome tumour analysis to guide chemotherapy decision-making for patients with advanced cancers.
Authors: Laskin Janessa J. , Lim Howard John , Gelmon Karen A. , Ho Cheryl , Renouf Daniel John , Yip Stephen , Huntsman David , Tinker Anna , Pleasance Erin , Li Yvonne , Shen Yaoqing , Kasaian Katayoon , Corbett Richard , Mungall Karen , Mungall Andrew , Zhao Yongjun , Schein Jacquie , Roscoe Robyn , Jones Steven , Marra Marco 
Published: March 2020

e22020 Background: We propose that applying personal genomic information prospectively, in a clinically realistic timeframe can aid chemotherapy decision-making and result in more effective cancer treatment. We are investigating this approach in a variety of cancers to examine timeliness, deliverability, and rate of actionable targets identified. Methods: Eligible subjects with incurable cancer and limited chemo options have a tumour biopsy and “normal” blood taken for analysis. Archival specimens are concurrently analyzed to look for changes with time and treatment. Samples are subject to both an Ampliseq amplicon panel and in-depth whole genome DNA and RNA sequencing (WGS). Bioinformatics approaches identity genes with somatic and copy number variations, and expression changes. Variants are integrated into a pathway analysis to identify tumour specific processes that may drive the tumour, these are then matched to drug databases, with manual literature reviews, to indentify drugs that may be useful or even contra-indicated. Results: Between July 2012 -Jan 2013, 9 subjects (of 30 planned) are enrolled: 2 cases each of: colorectal and breast and 1 each of: squamous skin, squamous ethmoid sinus, nasopharyngeal, lung, and CLL-peripheral mantle cell cancer. 5 have completed analyses. Cancer panel results correlated well with WGS; although the panel is more rapid, it provides less comprehensive information and has not been as informative for identifying candidate druggable drivers. Extensive pathway mapping uncovered potential drug targets in each case that would not have necessarily been considered without this analyses. To date, 4 subjects have started chemo based on the analyses and 1 patient has had his diagnosis radically changed. There are significant genomic differences between archival and fresh tumour samples. Conclusions: This approach is feasible and yields actionable targets that can inform real-time chemotherapy decision-making. Archival samples do not appear to adequately represent post-treatment cancers. The impact of WGS vs. panel sequencing will require more subjects but it appears a panel may be insufficient for detailed treatment guidance.
Epithelial-mesenchymal transition and metastatic bladder cancer profile under vinflunine treatment.
Authors: Figueroa Angelica , Abella Vanessa , Aparicio Guadalupe , Haz-Conde Mar , Gayo Javier , Antón Aparicio Luis M. 
Published: March 2020

e22021 Background: Given the role of vinflunine (VFL) in the microtubule dynamics and the link between microtubules and cell adhesions through cadherins, we have investigated the possible influence of VFL on adherens junctions through its interaction with microtubules. We have studied the implication of VFL on the reversion of epithelial-mesenchymal transition (EMT) in bladder transitional cell carcinoma and explored a possible novel molecular mechanism. Methods: Four human bladder transitional carcinoma cell lines were used to carry out the following experimental procedure: Cytotoxicity assay by using MTT assay, qRTPCR to analyze mRNA markers of the EMT, Western blotting using specific antibodies for EMT markers, and immunofluorescence images, analyzed by epifluorescence microscopy. Results: Cell growth reduction was detected in human bladder carcinoma cells under VFL treatment compared to control. VFL induces mesenchymal to epithelial phenotype and modulates the EMT markers: E-cadherin and Cytokeratin-19 were enhanced under treatment, while significantly reduction of mRNA mesenchymal markers expression (Vimentin, N-cadherin) and EMT-transcriptional factors (Snail and Zeb1) was detected. Strong reduction of Hakai protein was seen under VFL treatment. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin. Epifluorescence images showed that VFL treatment promotes E-cadherin localization specifically at cell-cell contact; while, Hakai expression decreases its expression in the nuclei and cytoplasm. Conclusions: These results suggest that VFL up-regulates E-cadherin contributing to mesenchymal to epithelial transition, and that Hakai modulation might be the molecular mechanism by which the increasing E-cadherin at cell-cell contacts in bladder carcinoma cell lines is detected. Given the relevant in vitro role of VFL on E-cadherin expression and on the reversion of EMT process, we hypothesized that VFL could exert a clinical benefit in delaying the metastasis in urothelial tumors.
Brain microenvironment-induced reduction in microRNAs to promote metastatic tumor growth, drug resistance, and survival.
Authors: Driscoll James , Subramani Arasakumar , Alsidawi Samer , Jagannathan Sajjeev 
Published: March 2020

e22030 Background: Brain metastases remain a serious obstacle that negatively impacts cancer patient survival. Most deaths due to cancer result from the progressive growth of metastatic, drug-resistant lesions. Moreover, the incidence of brain metastases is rising as a result of an aging population, superior imaging modalities, earlier cancer detection and more effective treatment of systemic disease. Methods: To investigate the role of the brain microenvironment in metastasis, tumor cells were co-cultured with astrocytes - the most abundant normal cell type in the metastatic brain tumor niche. This led to increased tumor cell viability, proliferation and chemoresistance. Microarray-based profiling was then performed to address the effect of the brain microenvironment on miRNA expression levels in tumor cells. Results: Profiling revealed that astrocyte co-culture reduced miRNAs-768-3p, 886-5p and 200c in tumor cells. Inhibition of miRNA-768-3p increased KRas expression, and a specific binding site was identified in the KRas 3’UTR and validated using a luciferase construct. miRNA-768-3p levels were reduced in patient-derived brain metastases relative to normal adult brain. Additionally, miRNA-768-3p was also lower in brain metastases compared to the primary tumors in matched paired samples. Our data demonstrates that the brain microenvironment modulates miRNA-768-3p in metastatic lesions to enhance KRas-mediated tumor survival and promote metastasis. Conclusions: The brain microenvironment regulates the expression of individual miRNAs in tumor cells to promote growth, survival and drug resistance. The brain microenvironment down-regulates the level of certain miRNAs to promote oncogenic signaling and tumor growth while our studies indicate that chemically-engineered miRNA mimics can restore the loss-of-function to reduce the viability of cancer cells. miRNA replacement therapy is a promising and novel therapeutic concept that could save thousands of patients from ineffective treatment, improve patient quality-of-life, overall survival and reduce the devastating impact of brain metastases on the healthcare system.
Clonal T-cells and monocytosis in cancer patients and relationship to prognosis, and incidence of autoimmunity, fatigue, and second primary malignancies.
Authors: Snyderman Michael , Mikovits Judy 
Published: March 2020

e22038 Background: Clonal T-cell expansion and monocytosis could explain inflammation, fatigue and autoimmunity seen with cancer if both cell types release excess amounts of cytokines and disregulate the immune system. Cytokines can also have a paracrine effect and increase malignant cell proliferation. Methods: 48 patients with various neoplasms from an oncology practice were studied. Myeloid dyscrasias were excluded to allow interpretation of monocytosis. Clonal TCR rearrangements were done in a reference lab. Cancer-Related Fatigue (CRF) data as defined by the NCCN was available in 34 patients. The study was done 2010–2013. Results: See Table. Conclusions: Presence of a clonal T-cell expansion was associated with the greatest likelihood of high stage disease, second malignancy, autoimmunity and CRF. Monocytosis had a similar effect but less than clonal T-cell positivity. The patients with the least likelihood of high stage disease and CRF had no detectable clonal T-cell expansion and no monocytosis. Of the 25 originally negative or undetectable clonal T-cell expansions, 4 became positive 1-2 years later. The clonal T-cell and monocyte proliferation are unlikely to be reactive because a true tumor-specific antigen is rare and because there appeared to be a negative rather than a neutral or positive impact on multiple parameters. Further investigation to determine the subsets of T-cells and monocytes that are expanded and their production of proinflammatory cytokines, etiology of their proliferation and their role in the progression of neoplasia could lead to new treatments to improve the course and prognosis of cancer patients. [Table: see text]
Anti-retroviral drugs used to treat a patient with chronic lymphocytic leukemia and cancer-related fatigue.
Authors: Mikovits Judy , Snyderman Michael 
Published: March 2020

e22039 Background: The only known human cancer retrovirus, HTLV1 causes adult T-cell leukemia/lymphoma of which some respond to AZT+ alpha interferon. The existence of human retroviruses originating from murine leukemia viruses (MLVs) and their role in human cancer has been debated since the 1970s. A previously untreated 68 y.o. Oncologist with B-cell CLL and Cancer-Related Fatigue (CRF) was studied for retrovirus to determine if he could be treated with anti-retroviral drugs (arvs). His history included autoimmune disorders. Methods: Antibody detection: Alter et al. 2012. Gag detection: Mikovits et al. 2010. Results: Antibody to MLV envelope antigen and Gag RNA was detected. The Gag sequence was similar to MLVs but sufficiently different from the laboratory generated, XMRV which has no natural history in Man to rule it out. Proinflammatory cytokines were elevated. Trisomy 12 was present. By day 571 of his CLL the ALC doubling time decreased to < 1 year and he developed disabling CRF. AZT and raltegravir were started day 899. ALC, cytokine levels and CRF improved. After 9 months CLL parameters relapsed and then responded to adding tenofovir. This response lasted 3 months and then relapsed. Addition of lopinavir induced a response of parameters now ongoing 9 months. Total time on treatment is 29 months without toxicity and with improved CRF. In addition to his CLL there was a measurable T-cell clone and monocytosis both of which rose and fell with relapses and responses of the CLL to arvs but at different rates. Conclusions: A common human neoplasm was successfully treated with arvs. The drugs used were 2 Reverse Transcriptase inhibitors, an Integrase inhibitor and a Protease inhibitor developed for HIV treatment. There is nothing unusual or unique about this patient’s neoplasm and his case should stimulate further research. The role of retrovirus in cancer and CRF and whether arvs could be beneficial to patients identified as having a retroviral associated cancer and CRF should be studied. In addition, the significance of this patient’s clonal T-cell expansion and monocytosis and their production of cytokines should be examined. [Table: see text]
Association of miRNA expression and EGFR mutation status in lung adenocarcinomas.
Authors: Ju Lixia , Zhou Caicun 
Published: March 2020

e22044 Background: Epidermal growth factor receptor (EGFR) is frequently found to be activated by mutation or amplification in lung cancer. Though most patients with EGFR activating mutation response to EGFR-TKI, there are still about 30% patients showing no response. miRNA expression is deregulated in lung cancer, and miRNAs can regulate EGFR. So it is important to predict the candidate miRNAs that target EGFR and to investigate the availability of these candidate miRNA regulators in lung cancer. Methods: In this study, we investigated the miRNA expression in lung adenocarcinomas cell lines with mutated EGFR (H1650 and PC-9)and wild-type EGFR (H1299 and A549) using the Phalanx Human Whole Genome Microarray. Results: The expression of 1,732 miRNAs was evaluated and expression of individual miRNAs was validated by individual RT-PCR assays. Overall, miRNAs expression were different between these two groups. Hsa-let-7d-3p, hsa-miR-1307-5p, hsa-miR-141-3p, hsa-miR-200c-3p, hsa-miR-203, hsa-miR-3182, hsa-miR-4510, hsa-miR-934 were upregulated and hsa-miR-3196, hsa-miR-4450, hsa-miR-4649-5p were downregulated in the mutated EGFR group. Conclusions: It is suggested that there are different carcinogenic pathways for EGFR mutation tumors. Those miRNAs that associated EGFR mutation can be further explored for their application in target therapy and prognostics.
Cadherin-11 (Cad11) for detection of epithelial-mesenchymal transition (EMT) in circulating prostate cancer (PCa) cells.
Authors: Zurita Amado J. , Bischoff Farideh Z. , Gorlov Ivan , Mayer Julie Ann , Pircher Tony J. , Mikolajczyk Steve , Logothetis Christopher , Lin Sue-Hwa 
Published: March 2020

e22047 Background: CTC are believed to require EMT to metastasize. Cells undergoing EMT may lack or express low levels of epithelial markers such as EpCAM and cytokeratins (CK) and experience a cadherin switch from epithelial to mesenchymal. However, most current detection methods only rely on epithelial markers for enrichment, resulting in failure to recognize other CTC phenotypes. We previously showed that PCa cells expressing the mesenchymal (osteoblast-lineage) marker Cad11 are more likely to home to and colonize bone (Cancer Res 2010). Whether Cad11+ PCa CTC lose CK expression is uncertain. Since Cad11 is an EMT marker relevant to the bone tropism of PCa, we characterized its expression in CTC from patients (pts) with bone metastasis. Methods: Blood from PCa pts (n=86) with different extents of bone involvement was analyzed employing Biocept’s microfluidic CTC technology. For cell capture, we used a PCa CTC-optimized cocktail of antibodies that included epithelial, mesenchymal and putative stem cell markers. Captured cells were scored based on standard stain criteria (CK+/CD45−/DAPI+) and Cad11 expression. To ascertain malignant identity of CK−/CD45−/DAPI+cells, we used FISH to characterize androgen receptor [AR], Myc and PTEN status. Results: Among 69 pts with detectable CK+ CTC, 39% had at least 1 cell co-expressing Cad11. Very rare CK−Cad11− CTC displaying different degrees of aneuploidy were also observed, but only in 4 pts. No single CK−Cad11+ FISH “abnormal” cell was seen. FISH profiling of individual CK+ CTC revealed an association between Myc gain and PTEN loss (P=0.00004). We also found positive correlations between AR and PTEN amplification (r=0.55) as well as AR amplification and Myc loss (r=0.56; both P<10-6). Interestingly, CK−Cad11+cells (range, 1-910) were observed in 45 pts, all with a “normal” pattern of AR, Myc and PTEN expression. Conclusions: Complete loss of epithelial marker expression in CTC (identified by concurrent gene alterations) is a very infrequent event in PCa pts with established bone metastasis. Simultaneous individual CTC profiling of gene gains/losses may provide insights into PCa biology. Evaluation of the identity of CK−Cad11+ cells is ongoing.
Circulating tumor cells (CTC) as a biomarker of response in patients with extensive-stage small cell lung cancer (EX-SCLC).
Authors: Huang Chao H. , Ganti Apar Kishor , Neupane Prakash , Sittampalam G. Sitta , Schmitt Sarah , Nirmalanandhan Sanjit , Williamson Stephen K. , Wick Jo , Smart Janie , Spencer Sarah Ellen , Godwin Andrew K. , Van Veldhuizen Peter J. 
Published: March 2020

e22048 Background: SCLC, a variant of lung cancer marked by early metastases, accounts for 13% of all lung cancers diagnosed in US. Despite high response rates to treatment, it is an aggressive disease with a median survival of 9-11 months for patients with EX-SCLC. Detection of CTCs is a novel laboratory technique currently in use to determine response to therapy and to predict prognosis in breast, colorectal and prostate cancer. We initiated a study to study the role of CTC as a biomarker of response and relapse in patients with EX-SCLC. Methods: We collected blood sample from chemotherapy naïve patients with EX-SCLC prior to initiation of therapy, following completion of systemic therapy, follow up every 6-8 weeks and at relapse. The CTC was determined using the Cell Search system in a central laboratory. The study was conducted in 4 different sites and it was reviewed and approved by respective Research Review Committee and IRBs. Results: We enrolled 27 patients with EX-SCLC, 1 was excluded due ineligibility, all patients were treated with platinum and etoposide. We observed partial response in 16 patients (61%), stable disease in 3 patients, 1 with progression of disease and not assessed in 7 patients (5 deceased, 2 not available); the baseline CTC of 2 patient were not measured (one due instrument failure and one due insufficient blood). The overall median number of CTCs in 24 patients measured at baseline and post-tx was 75 (range 0 to 3430) and 2 (range 0 to 526), respectively. A significant reduction in CTCs from baseline to post-tx was identified; for the 14 subjects with pre and post treatment CTC, the median reduction was 51.5% (51.5% decrease, range -2904% to +5%, p< 0.001). Conclusions: We were able to demonstrate feasibility of using CTC as a biomarker of response in patients with EX-SCLC in clinical setting. CTC could be a useful biomarker in the management of SCLC to predict response to therapy.
A new tumor biomarker: Serum protein peak at 3144 m/z in patients with node-positive breast cancer.
Authors: Chen zhan-Hong , Xu Shen-Hua , Su Dan , Liu Wei , Yang Hongjian , Xie Shang-Nao , Meng Xuli , Lei Lei , Jia Wang Xiao 
Published: March 2020

e22050 Background: To explore the association of the 3144 m/z and the clinicopathological features and its clinical value in the diagnosis and prognosis of breast cancer. Methods: Using SELDI-TOF-MS, we analyzed serum 3144 m/z in 298 patients patients with node-positive breast cancer after mastectomy. The association between 3144 m/z and clinicopathological features was evaluated. We also evaluated their prognosis value in survival using univariable and multivariable statistical analyses. Results: The positive rate was higher in 3144 m/z than CA153 (36.6% versus 11.5%, p <0.001). The 3144 m/z positive rate was no difference in patients with CA153 negative or positive (35.3% versus 29.6%, P =0.563). 3144 m/z was higher elder cases (> 50 years old) than young group(<or=50 years old). There were no correlation was found between 3144 m/z and other clinicopathological features, except for the age (42.8% in > 50-year-old and 31.2% in young,χ2=4.227, P=0.040). The patients with 3144m/z negative (n=189) had higher 3-year OS rate than positive (n=109), 89.5% versus 81.7% (P=0.034). Also in young (P=0.024), postmenopasual (P=0.025), small tumor (P<0.001), node(-) or less (P<0.001), early stage (P<0.001), good molecular type (P=0.019), normal CA153 (P<0.001), neoadjuvant chemotherapy (P=0.001). Using Cox proportional hazards model,analysis showed that basal-like type (worse, P=0.038), CA153 positive (worse, P=0.015), adjuvant chemotherapy (better, P=0.028) and adjuvant radiotherapy (better, P=0.032) were independent prognostic factors in patients with node-positive breast cancer. but the 3144m/z was not. Conclusions: Serum protein peak at 3144 m/z provides a new, practical biomarker for diagnosis and prognosis of breast cancer.
Metabolomic analysis of dynamic response and drug resistance of gastric cancer cells to 5-fluorouracil.
Authors: Sasada Shinsuke , Miyata Yoshihiro , Tsutani Yasuhiro , Hihara Jun , Okada Morihito 
Published: March 2020

e22053 Background: Metabolomics has developed as an important new tool in cancer research. It is expected to lead to the discovery of biomarker candidates for cancer diagnosis and treatment. The current study aimed to perform a comprehensive metabolomic analysis of the intracellular dynamic responses of human gastric cancer cells to 5-fluorouracil (5-FU), referencing the mechanism of drug action and drug resistance. Methods: Small metabolites in gastric cancer cells and 5-FU–resistant cells were measured by liquid chromatography-mass spectrometry. Candidates for drug targets were selected according to the presence or absence of resistance, before and after 5-FU treatment. In addition, the gene expression of each candidate was assessed by reverse transcription-polymerase chain reaction. Results: The number of metabolites in cancer cells dramatically changed during short-term treatment with 5-FU. Particularly, proline was reduced to one-third of its original level and glutamate was increased by a factor of 3 after 3 h of treatment. The metabolic production of glutamate from proline proceeds by proline dehydrogenase (PRODH), producing superoxide. After 5-FU treatment, PRODH mRNA expression was upregulated 2-fold and production of superoxide was increased by a factor of 3. In 5-FU–resistant cells, proline and glutamate levels were less affected than in non-resistant cells, and PRODH mRNA expression and superoxide generation were not increased following treatment. Conclusions: The authors identified a candidate biomarker, PRODH, for drug effects using the metabolomic approach, a result that was confirmed by conventional methods. In the future, metabolomics will play an important role in the field of cancer research.