bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of the colon cancer recurrence score with treatments received in patients with stage II colon cancer: The Clalit Health Services experience.
Authors: Brenner Baruch , Geva Ravit , Beny Alexander , Dror Ygael , Steiner Mariana , Hubert Ayala , Idelevich Efraim , Gluzman Alexander , Purim Ofer , Shacham-Shmueli Einat , Shulman Katerina , Soussan-Gutman Lior , Klang Shmuel , Merling Shahar , Liebermann Nicky 
Published: March 2020

e22111 Background: The Oncotype DX Colon Cancer Recurrence Score (RS) is a validated prognosticator in stage II colon cancer following surgery. However, the impact of the RS on daily practice is still unclear. Clalit Health Services(CHS) has reimbursed Oncotype DX colon testing since 1/2011. This prospective study examined the use of the RS and its association with treatment decisions in this setting in Israel. Methods: Eligible patients had stage II colon cancer and testing reimbursed by CHS from 1/2011 to 5/2012. Patient/tumor data and treatment information were gathered prospectively. Data were analyzed using the Chi-squared test. Results: The study included 341 patients of whom 314 had confirmed stage II, T3N0 disease, and were included in the analysis. Median age was 68 years (range: 29-89); 18.2%, 68.5%, and 9.9% had grade 1, 2, and 3 tumors, respectively; 15.3% had colonic obstruction and 5.7% had lymphovascular invasion. Thirty-nine patients (12.4%) had mismatch repair (MMR)-deficient tumors and their samples were not tested further. Of the 275 tested patients, 160 (58.2%), 87 (31.6%), and 27 (9.8%) had low (<30), intermediate (30-40), and high (>40) RS, respectively (1 patient [0.4%] had no RS due to technical failure of the assay). The grade 3 group had a higher proportion of MMR-deficient tumors than the grade 2 and grade 1 groups (35.5%, 7.9% and 10.5%, respectively, P<.0001). In the MMR-proficient tumors, the proportions of low RS tumors according to grade were 60.8%, 58.1% and 70.0% for grades 1, 2 and 3, respectively (P=0.57). Chemotherapy was administered to 86/314 (27.4%) patients, including 3/39 (7.7%) in the MMR-deficient, 27/160 (16.9%) in the low, 39/87 (44.8%) in the intermediate, and 17/27 (63.0%) in the high RS groups. The most commonly used regimen was capecitabine monotherapy (61/86 treated patients, 70.9%). The differences in the proportions of patients receiving chemotherapy between the MMR-deficient, low, intermediate, and high RS groups were significant (P<.0001). Conclusions: Our findings suggest that the RS results and MMR-deficient status are significantly associated with treatment decisions in stage II colon cancer patients in Israel.
Chemotherapy selection by gene expression profiling (MAGE) in resistant/refractory (R/R) patients with solid tumors: A feasibility study.
Authors: Rebollo Joseba , Gonzalez-Manzano Ramon , Fernandez-Morejon Francisco J. , Rey Severino , Farre Jose , Sureda Manuel , Brugarolas Antonio 
Published: March 2020

e22120 Background: Genomic-based profiling of tumors is a promising approach that allows the selection of the optimal chemotherapy regimen minimizing the possibility of futile therapies. Preliminary clinical results by our group showing a 23% response rate were presented at ASCO’12 (abstract 3,064). However, RNA isolation is a challenging technical step that requires a high quality specimen and takes 2-4 weeks interval to be finished. For this reason we analyzed the feasibility conditions in our series. Methods: Patients (pts) with R/R solid tumors had immediately frozen biopsies, underwent RNA isolation and quality validation after a pathologic confirmation of viable tumor in more than 30% of the sample. Results: From August 2010 to December 2012, 138 patients accepted the MAGE chemotherapy profiling. The median time from biopsy to MAGE analysis has been 4 weeks (ranging 2 to 6). In 17 (12%) pts the procedure was aborted for technical reasons. In these cases tumor samples were obtained from liver in 7 pts, local recurrence in 3 pts, soft tissues in 3 pts, peritoneum in 2 pts, and nodes in 2 pts. Reasons for canceling the assay were mainly a very low tumor cells rate (less than 30%) in 10 pts (fibrotic changes in 5 pts and predominance of necrosis in 5 pts), 2 pts with no tumor, 1 pt with a non-radiologically identifiable lesion, 1 pt with radiofrequency deterioration of the specimen and 3 pts with poor quality RNA. Among the remaining 121 pts who completed the procedure only 74 (61.2%) were treated according to the selected chemotherapy agents achieving a clinical benefit rate of 60%. The high attrition rate (38.8%) was due to poor clinical condition, refusal of recommendations and/or short life expectancy. Conclusions: MAGE-based chemotherapy profiling of tumors was feasible to guide antitumor therapy in selected patients. We recommend performing the study in untreated patients or earlier in the course of their disease (i.e. after failure to first line chemotherapy) in patients with a life expectancy of more than 3 months.
Integrin inhibition as a potential target for invasive meningiomas.
Authors: Mawrin Christian , Kirches Elmar , Wilisch-Neumann Anette 
Published: March 2020

e22140 Background: Meningiomas are frequent intracranial tumors, which may show high rates of tumor recurrence after surgery. Additionally, a number of meningiomas show aggressive clinical behaviour with significant reduction of patient´s survival. In the present study, the impact of cilengitide, an integrin inhibitor, on migration, proliferation and radiosensitization of meningioma cells was evaluated. Methods: We analyzed integrin expression in tissue microarray samples and the anti-meningioma properties of cilengitide in vitro using different meningioma cell lines including pairs with knockdown of NF2, and tested the substance in subcutaneous and intracranial orthotopic nude mice models. Results: The predominantly expressed integrin in the tumor cells was αvβ5, while αvβ3 was mainly restricted to tumor blood vessels. One µM cilengitide was sufficient to significantly inhibit meningioma cell migration and invasion in vitro. On the other hand, even high doses of the drug resulted in only mildly reduced proliferation/survival of the cells, although the effects on cell survival were improved by irradiation. A daily dosage of up to 75 mg/kg did not affect tumor volumes in both mouse models. However, a combination of 75 mg/kg cilengitide daily and irradiation (2 x 5 Gy) led to a stronger reduction of MRI estimated tumor volumes in the intracranial model (67%, p<0.01), as compared to the corresponding reduction reached by irradiation alone (55%, p<0.05). Conclusions: These data show that the integrin inhibitor has mild cytostatic properties in meningioma cells, but strongly inhibits cell migration/invasion. In combination with radiotherapy it may help to further reduce meningioma tumor recurrence.
The cytotoxicity of select neutrophils in breast cancer patients and the role of chemokines in neutrophil cytotoxicity.
Authors: Comen Elizabeth Anne , Granot Zvika , Blum Brian , Coker Courtney , Shah Riddhi , Koh Eileen , Norton Larry , Benezra Robert 
Published: March 2020

e22148 Background: Recent research in murine breast cancer models demonstrates that primary breast tumors can mobilize select neutrophils, which have the unique capacity to inhibit metastatic seeding in the lung through cell-kill mechanisms. (Granot Z et al. Cancer Cell. 2010). In both breast cancer patients and healthy women, we investigated whether neutrophils were cytotoxic to breast cancer cell lines. We also assessed whether serum chemokines were associated with neutrophil cytotoxicity. Methods: Neutrophils were purified from the blood of 59 randomly selected newly diagnosed pre-operative breast cancer patients without evidence of metastatic disease, 50 metastatic breast cancer patients, 15 DCIS patients, and 45 healthy female volunteers with no history of cancer. Cytotoxicity was evaluated by incubating neutrophils with luciferase labeled MDA-MB-231 cells. Luciferase activity was measured as a reflection of % cytotoxicity. Serum was also isolated from breast cancer patients and healthy volunteers. Millipore Milliplex Human Cytokine Plex Kit was used to assess the concentration of 42 different chemokines in each of the serum samples. Results: In comparison to healthy volunteers whose mean neutrophil cytotoxicity to MDA-MB-231 cells was 6.5%, pre-operative breast cancer patients demonstrated a mean neutrophil cytotoxicity of 13.4%, p<0.0001, metastatic patients mean neutrophil cytotoxicity was 19.4%, p <0.003 and DCIS patients had a mean neutrophil cytotoxicity of 11.7%. p <0.01. By Kruskal-Wallist test, the relative concentrations of three chemokines, Il.1a, MCP.1 and TNF-a, were found to have a statistically significant association with neutrophil cytotoxicity (p-value: 0.005, 0.002, 0.0005 respectively). Conclusions: Our work demonstrates the cytotoxic role of select neutrophils in the peripheral blood of breast cancer patients as contrasted with neutrophils from healthy women. We further demonstrate that select chemokines appear to be correlated with neutrophil cytotoxicity, in varying concentrations. Further studies are needed to evaluate the prognostic and therapeutic role of cytotoxic neutrophils as well as the role of chemokines in neutrophil cytotoxicity.
Imaging biomarker in phase I trials: DCE-US and early evaluation of antiangiogenic treatments.
Authors: Cohen Romain , Koscielny Serge , Soria Jean-Charles , Armand Jean-Pierre , Benatsou Baya , Lassau Nathalie 
Published: March 2020

e22153 Background: The French prospective STIC study (Support for Innovative and Expensive Techniques) of dynamic contrast enhanced-ultrasonography (DCE-US) with quantification for evaluation of anti-angiogenic treatments showed that a decrease of 40% of AUC is predictive of response in 539 patients treated with approval drugs. The objective was to evaluate the decrease of AUC DCE-US at one month as a predictive imaging biomarker for time to progression (TTP) in phase I trials using anti-angiogenic agents. Methods: Patients included in phase I in our institution from 2007 and evaluated with DCE-US were retrospectively reviewed. Patients were evaluated at baseline and 1 month with the same standardized methodology: a bolus injection of contrast medium, 3 minutes of recorded raw linear data with 4 frames per second and the quantification using ESFUMB guidelines. All data were prospectively stored in a centralized database. TTP was calculated according to RECIST criteria and clinic. A decrease of more than 40% of AUC at one month was challenged to be predictive of TTP. Results: In the preliminary results concerning 26 patients, 6 had a decrease of more than 40% of AUC at one month with a median TTP of 5.5 months. The 20 others without a strong decrease of AUC had a TTP less than 2 months. The decrease of AUC was correlated to TTP (p=0.004). Eighty one supplementary phase I patients are under radiological blind review and will be included for presentation at ASCO. Conclusions: The decrease of more than 40% of AUC at one month could be a predictive biomarker of response to anti-angiogenic treatments in phase I. The final results will be presented with 107 patients. Considering the toxicity risk for the patients and the cost of anti-angiogenic drugs, such a simple and cheap imaging biomarker should be considered to maintain or not the treatment after US evaluation of the first cycle.
Challenges with the ODAC-proposed independent audit of site investigator assessments.
Authors: Bohnsack Oliver , Schmid Annette Maria , Chen Liddy , Chandler Barbara 
Published: March 2020

e22161 Background: The ODAC (Oncologic Drug Advisory Committee) Meeting, July 24th, 2012, on “Evaluation of Radiologic Review of Progression-free Survival in Non-hematologic Malignancies” discussed the merits of implementing an audit process of the investigator assessments in certain oncology trials with PFS endpoint instead of a full Blinded Independent Central Review (BICR) of all cases. The discussion centered around two potential methods (Dodd et al., 2008, 2011 and Amit et al., 2011) – their methods aimed to reduce the risk of informative censoring based on site central discordance, streamline trial conduct and provide cost savings. Both methods provide novel and interesting approaches. However, based on logistical and especially statistical challenges we found that both proposed methods in their current form can not achieve either goal of reducing cost, complexity, time and data censoring challenges inherent in the BICR process. Methods: This paper criticially evaluate the proposed methods and challenge the proposed processes and provide detailed explanations to obstacles inherent logistically, timewise, statistically, operationally. Results: Both of the proposed methods increase the complexity of conducting Oncology trials. As such the study duration will not be shortened but rather extended in certain scenarios. The statistical consequences of a discrepancy rate between Local Evaluations (LE) and BICR are not fully foreseeable and not defined. Operationally, both sponsor and imaging CRO need to implement new and forego well established processes, increasing risk, complexity and the chance for errors. Conclusions: This paper gives examples why the proposed methods are not suitable in their current form to be implemented in Oncology trials and rather put sponsors and study data at risk.
Peripheral blood microRNAs expression profile: A fingerprint for metastatic prostate cancer.
Authors: Medina Villaamil Vanessa , Aparicio Guadalupe , Santamarina Cainzos Isabel , Gomez-Veiga Francisco , Valladares Ayerbes Manuel , Quindós Varela Maria , Antón Aparicio Luis M. 
Published: March 2020

e22171 Background: We previously have studied differentially microRNA expression levels related to hormone refractory and sensitive prostate cancer cell lines (VCap and LNCap respectively). Now, we investigated circulating miRNAs differentially expressed between metastatic prostate adenocarcinomas (mPA) and healthy controls (HC) that may serve as novel diagnostic and/or prognosis markers. Methods: Using SYBR-green-based custom microRNA RT-qPCR arrays technology (Exiqon), we compared the expression levels of miRNAs in blood samples from 18 HC and 48 mPA. Results: Among a panel of 92 candidates we found 41 underexpressed (UE) and 8 overexpressed (OE) miRNAs. The level of significance was p<0.05. Conclusions: Among the UE miRNAs are miR-203 and 129 which regulate a cohort of metastatic genes. Among the OE is miR-200a, a member of miR-200 family which directly targeted β-catenin mRNA and miR-135b which induce invasion and distant metastasis. The knowledge of miRNAs involved in mPA progression could provide us a profile that could identify patients for adjuvant therapy or even propose new target drugs to avoid disease progression or treat mPA. Our group is actively involved in the study of selected OE miRNAs for their potential as circulating markers for mPA. [Table: see text]
A prospective registry study assessing decision impact and patient outcomes following gene-expression profiling for tumor-site origin.
Authors: Degtiar Irina , Pillai Raji , Colvin Gerald , Shtivelband Mikhail , Li Qianyi , Henner William David , Becker Shawn , Hornberger John C. 
Published: March 2020

e22172 Background: A retrospective registry study has shown that gene-expression profiling (GEP) of the tissue of origin (Pathwork Tissue of Origin Test) of metastatic or poorly differentiated cancer changes the working diagnosis and management for the majority of patients. The FDA-cleared GEP test determines similarity of tumors of uncertain origin to gene expression patterns representing 60 morphologies in 15 cancer types. Inability to identify cancer primary sites presents challenges for patient treatment, outcomes, and prognosis. This study aims to prospectively assess impact of GEP on physician decisions and patient outcomes. Methods: A prospective, observational study is examining GEP’s impact on treatment changes and outcomes in adult patients with difficult-to-diagnose cancers. The study is assessing changes in diagnosis, management, oncologist confidence and perception of the test’s clinical utility, survival, therapy response, and other outcomes over 2 years of follow-up. Results before and after GEP are presented here for 18 patients. The study is designed to enroll 300 patients overall. Results: The primary working diagnosis changed for 37% of patients: 4 whose physicians obtained a working diagnosis while previously not having a tissue-specific diagnosis, and 3 for whom the primary diagnosis changed. After GEP, all patients had a working diagnosis. At least one aspect of management plans changed for 65% patients after GEP. Chemotherapy was ordered for 2 more patients and the regimen changed for 3 others; surgery was performed for 4 fewer, radiation for 1 fewer, and hospice for 2 more patients. After obtaining results from GEP, 58% of the treating oncologists “agreed” or “strongly agreed” that they were confident in both their diagnosis and treatment. Seventy-two percent believed that their changes in management would lead to improvement in at least one outcome (survival, response rate, time to relapse, quality of life, or patient anxiety). Conclusions: Current results of this prospective study are consistent with results of the prior retrospective study: GEP significantly changed and improved physician confidence in their diagnosis and treatment. Clinical trial information: NCT01649453.
Accuracy and clinical utility of in vitro cytometric profiling to personalize chemotherapy: Preliminary findings of a systematic review and meta-analysis.
Authors: Apfel Christian , Souza Kimberly , Hornuss Cyrill , Weisenthal Larry , Nagourney Robert Alan 
Published: March 2020

e22188 Background: Cytometric analysis, or in-vitro functional profiling, has been developed as a method to predict tumor response to different drugs with the premise to personalize chemotherapy and improve patient outcomes. Methods: We performed a systematic review and a meta-analysis a) of correlative studies using cytometric profiling that reported diagnostic accuracy (sensitivity and specificity) and b) of effectiveness studies comparing patient outcomes when allocated to treatment guided by a cytometric assay versus population-based standard of care. We used Meta-DiSc software to find pooled sensitivity and specificity and analyze the summary receiver operating characteristic (sROC) curve and used Review Manager 5.1 to generate forest plots on overall tumor response (50% or greater decrease in tumor diameter) and on 1-year overall survival. Results: We included 28 mostly retrospective trials (n=664) reporting accuracy data and 15 prospective trials (n=1917) reporting therapeutic efficacy data. The accuracy of correlative study revealed an overall sensitivity of 0.922 (95% confidence interval 0.888 to 0.948), specificity of 0.724 (95% CI 0.669 to 0.774) and an area under the sROC curve of 0.893 (SE=0.023, p<0.001). Studies comparing the clinical utility revealed a two-fold overall tumor response for an assay-guided therapy versus standard of care therapy (odds ratio 2.04, 95% CI 1.62 to 2.57, p<0.001). Similarly, patients who received assay-guided therapy compared to those who received standard of care or physician’s choice had a significantly higher 1-year survival rate (OR 1.44, 95% CI 1.06 to 1.95, p=0.02). Conclusions: Despite various limitations of individual studies, the aggregate and fairly consistent evidence of these data suggests cytometric profiling to be accurate, to improve overall tumor response, and to increase 1-year patient survival. Given the enormous potential for our society, a well-designed and sufficiently-powered randomized controlled trial is urgently needed to validate these results.
Inhibition of the receptor tyrosine kinase ROR1 by anti-ROR1 monoclonal antibodies and siRNA induced apoptosis of melanoma cells.
Authors: Hojat Farsangi Mohammad , Ghaemimanesh Fatemeh , Daneshmanesh Amir Hossein , Bayat Ali-Ahmad , Mahmoudian Jafar , Jeddi-Tehrani Mahmood , Mellstedt Hakan 
Published: March 2020

e22198 Background: The receptor tyrosine kinase ROR1 has important functions during normal embryogenesis. It is overexpressed and of importance for the survival of different malignancies, including lung adenocarcinoma, breast cancer and chronic lymphocytic leukemia (CLL). ROR1 inhibition in CLL cells and cell lines with high expression of ROR1 induced specific apoptosis of the cells. There is however little information on the expression and function of ROR1 in melanoma. Here, we investigated ROR1 expression, phosphorylation and the effects of anti-ROR1 monoclonal antibodies (mAbs) and ROR1 suppressing siRNA on seven melanoma cell lines. Methods: ROR1 expression and phosphorylation was analysed in a series of malignant melanoma cell lines using RT-PCR, immunocytochemistry, flow cytometry and western blot. Annexin V/PI staining, MTT assay, PARP and caspase 8 and 9 cleavage as well as MCL-1 protein were used for detection of apoptosis induced by anti-ROR1 mAbs. The cytotoxic effects of anti-ROR1 mAbs were evaluated in the absence or presence of complement (CDC) or immune effector cells (ADCC). Transfection of melanoma cell lines using ROR1 siRNA was used for gene silencing. Results: ROR1 was shown to be overexpressed to a varying degree at protein level. ROR1 was phosphorylated at tyrosine and serine residues. Three out of four anti-ROR1 mAbs (clones 3H9, 5F1 and 1A8) induced a significant direct apoptosis of the ESTDAB049, ESTDAB112, DFW and A375 cell lines as well as cell death in the presence of complement or immune effector cells. ESTDAB081 and 094 cell lines were resistant to direct apoptosis of the four anti-ROR1 mAbs alone compared to the other melanoma cell lines, but not to complement dependent cytotoxicity (CDC) and antibody dependent cell mediated cytotoxicity (ADCC). ROR1 siRNA transfection induced down-regulation of the ROR1 expression both at the mRNA and protein levels proceeded by a significant apoptosis of the melanoma cells. Conclusions: The results indicate that ROR1 may play an important role in the survival of melanoma cells. The surface expression of ROR1 on melanoma cells may support the notion that ROR1 might be a suitable targeted for mAb therapy.
Evaluation of dickkopf-1 (Dkk-1) expression in non-small cell lung, esophageal, and gastric cancer.
Authors: Park Haeseong , Poklepovic Andrew Stewart , Almenara Jorge , Sirard Cynthia , Qian Junqi , Powers Celeste N. , Grossman Steven R. 
Published: March 2020

e22203 Background: Dkk-1 is an inhibitor of the canonical Wnt/β-catenin signaling pathway. Inhibition of Wnt pathway results in the stabilization of β-catenin, leading to target gene expression such as cyclin D1, c-myc, VEGF and other factors associated with cell growth. Elevated levels of serum Dkk-1 in a variety of tumor types are well established, and are hypothesized to have a negative prognostic value. Tumor tissue expression of Dkk-1 has not been systematically examined. We evaluated Dkk-1 expression in various tumors. Methods: Utilizing an anonymous banked tumor repository, we identified 119 patient samples (NSCLC (squamous, n=19; adenocarcinoma, n=47), esophageal (squamous, n=15; adenocarcinoma, n=17) and gastric (n=20)). Immunohistochemical (IHC) staining was performed using commercially available antibodies. One pathologist evaluated all slides using IHC staining quantification on a 4-point scale (0, 1+, 2+, 3+). Results: Dkk-1 expression is more pronounced in tumor tissues than peritumoral normal tissues of lung and esophagus. Unexpectedly, Dkk-1 expression is seen in two staining patterns, perinuclear and cytoplasmic that varied by primary location and histology. Conclusions: Elevated Dkk-1 expression is demonstrated in lung, esophageal and gastric cancer regardless of histology. All except squamous cell lung express perinuclear Dkk-1 more frequently than cytoplasmic pattern. Additional studies are needed to understand significance of these patterns and potentially define Dkk-1 as a novel therapeutic target in these malignancies. [Table: see text]