bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of serum CCL2 with advanced stage, metastasis, and smoking history in non-small cell lung cancer patients.
Authors: Ferreira Ana Carolina , Cordeiro De Lima Vladmir Claudio , Chinen Ludmilla Thome , Haddad Fabio Jose
Published: March 2020

e21073

Background: Chronic exposition of respiratory tract epithelium to tobacco smoke triggers various inflammatory responses that participate in lung cancer initiation and promotion. CCL2, a CC chemokine, has been described to be involved in the lung inflammation associated with tobacco smoke exposure, and to play an important role in tumor progression and metastasis development in many solid malignancies. Methods: We prospectivelly collected blood from 165 individuals distributed in five groups: control/never smokers (64), former smokers (19), smokers (26), early stage NSCLC patients (9) and advanced stage (46). Former smokers must have stopped smoking for longer than 1 year. NSCLC diagnosis must have been confirmed histologically. Patients could not have been submitted to surgery, chemotherapy or radiotherapy, neither could have been taking corticoids, antibiotics or anticoagulants. 10ml of blood were drawn by peripheral vein puncture, using a dry Vacuntainer tube, which was kept at 37°C for 30' in a water bath. The serum was separated by centrifugation at 2000rpm, at 4°C, for 10 min., and frozen at 80°C. CCL2 was measured using a commercially available sandwich ELISA kit (Human CCL2 DuoSet kit, R&D Systems). Median concentration of CCL2 was compared among groups using Kruskal-Wallis test, followed by a Dunn’s test. Smoking burden and serum CCL2 concentration was correlated using Spearman’s test. Median CCL2 concentration in groups associated with each clinical-demographic variable was compared using Mann-Whitney or Kruskal-Wallis test. We assumed a p value <.05 to be statistically significant. Results: Serum CCL2 concentration was significantly higher in the advanced NSCLC group in comparison to the control group (p<.05) and the former smokers group (p<.05). Higher CCL2 levels were associated with having cancer (p=.002), metastasis (p=.025) and advanced stage disease (p=.029). No association was observed with smoking history and no correlation was observed between CCL2 level and smoking burden. Conclusions: Higher CCL2 level is associated with having NSCLC, advanced stage disease and metastasis. CCL2 concentration is not associated with smoking history or smoking burden.
Quantitative immunohistochemical (IHC) assessment of ataxia-telangiectasia mutated (ATM) in estrogen receptor (ER) negative early breast cancer (BC).
Authors: Tang Patricia , Klimowicz Alexander C. , Pond Gregory Russell , Heng Daniel Yick Chin , Webster Marc A. , Magliocco Anthony M. , Bebb D. Gwyn
Published: March 2020

e21083

Background: ATM plays a key role in the cellular response to DNA damage and germline mutations are associated with a predisposition to BC. We evaluated the impact of ATM expression on outcomes in Stage I-III ER negative BC patients (pts). Methods: A tissue microarray was constructed from formalin-fixed paraffin-embedded specimens of ER negative Stage I-III BC pts from the Tom Baker Cancer Centre. ATM expression was assessed by quantitative fluorescence IHC using a rabbit anti-ATM monoclonal antibody (Epitomics) and the HistoRx AQUA platform. ATM expression index (EI) was calculated by the tumor cell to stroma expression ratio. Prognostic ability of ATM EI was explored univariately, and multivariately after adjusting for clinicopathological factors selected using algorithmic methods, with Cox regression methods. Results: Of 126 eligible pts treated from 1999-2004, 44.4% were HER2-neu + and 52.4% were triple negative. ATM EI was normalized using a logarithmic transformation. Univariately, higher ATM EI was associated with worse outcomes (Table). Multivariately, higher ATM EI remained significantly prognostic for recurrence-free survival (RFS) (HR=5.46, p=0.046), local RFS (HR=5.56, p=0.052), distant RFS (HR=4.38, p=0.080), but not overall survival (p=0.48). Conclusions: High ATM EI is associated with worse RFS in ER negative BC in this hypothesis-generating study. Validation of this finding is currently ongoing. [Table: see text]
Dissecting the link between nanoparticle lung effects and tumor markers with CD24 measurements.
Authors: Saeed Anwaar Mohammed , Alkhazna Ammar Ali , Molteni Agostino , Quinn Tim , Herndon Betty
Published: March 2020

e21085

Background: It was postulated that carbon nanoparticles (CN) induced mesothelioma-like changes equal to asbestos in mice. We investigated CN added to human mesothelial cells in culture and reported that CN-induced cell damage to untransformed human mesothelial cells is rapidly followed by secretion of tumor markers like mesothelin and osteopontin. In vivo in animals, our group quantifies CN lung damage by HMGB1, an intranuclear protein released into alveolar lavage after CN exposure. Recent work suggests that the cell surface marker CD24 associates with HMGB1 to blunt lung responses to damage (like CN), but does not blunt cell response to pathogen-released HMGB1. Since CD24 is also a known cancer marker, elevated in many malignancies, we hypothesized that the cellular change elicited by CD24 when coupled with a damage marker would offer a mechanism through which CN could produce –repeated over time—malignant change in exposed human mesothelial cells. Such expression would support our previous research efforts. Methods: Untransformed human mesothelial cells were cultured and then stimulated or not with a CN dose giving 80% cell viability. At 24, 48 & 72 hr cells were fixed and stained with anti-CD 24. Presence of positive stain was photographed and counted. CN exposed and control rat lungs were harvested and frozen at 0.5 hr, 3 hr, 24 hr and 4 weeks. Western blot and immunostaining (with Anti-CD24 antibody and mucin chemical stain) was used to measure CD24 levels. Results: In CN-exposed animals, CD24 was highest at 24 hr. Mucin presence confirms the CD24 staining. Homogenates by Western blot also showed highest CD24 reactivity at 24 hr. In CN-exposed cultured cells, at 48 hr, some anti-CD24 staining was seen and at 72 hr in clusters of hyperproliferating cells, strong CD24 stain was seen. Conclusions: Our data suggest, as shown by a second cellular marker CD24, that the mesothelin upregulation seen in our previous studies indicated a cellular change beyond necrosis. Nanoparticles at a dose producing 20% cell death induce this change in healthy human mesothelial cells in culture.
Surrogate role of kinetic of perioperative circulating cancer cells (CTCs) in patients with liver metastases (M) of colorectal cancer (CRC).
Authors: Teijeira Lucia , Viudez Antonio , Antelo Maria L , Tarifa Antonio , Zazpe Cruz , Herrera Javier , Hernandez Irene , Vera Ruth
Published: March 2020

e21086

Background: Kinetic behavior of perioperative CTCs in pts with liver CRC M has been little explored. The aim of this study was to quantified CTCs performance before/just performed and 3 months after radical liver surgery (LS) in pts with CRC M and analyzed the surrogate role of CTCs determinations in DFS and OS. Methods: 7.5 ml of blood were drawn in CellSave tubes. CTCs were isolated and enumerated before/just perfomed and 3 months after radical LS. CTCs were immunomagnetically separated and fluorescently labeled using the CellSearch System (Veridex®/Immunicon Corp.) Results: From February 2009 to December 2011, 35 pts were included. Median age was 61 (45-77); 53.7 % men. Kras status: 66.7% wild-type and 33.3% mutated; 48.6% with synchronous disease. Fong-Criteria (FC) distribution: 31.4% pts with 1 FC, 37.1% pts with 2 FC and 31.4% pts with 3 FC, of whom 60% received neoadjuvant (90% fluoropirimidines-based; 33.3% cetuximab-based; 38% bevacizumab-based) and 77.1% adjuvant treatment. PR and SD were observed in 60% and 40% of pts, respectively. In 70.7% of cases, limited LS were done (68.3% R0, median metastases resected:3) Of the 17 pts analysed, pCR were observed in 2 (12%) with 7 other pts (41%) with major pathological response. With a median of follow-up of 20 months (media 21.3; 95% CI:17.3-41.4) progression disease occurred in 13 pts (55.6% with liver progression), and 5 pts died. Median CTCs was 1 before (0-2: 76%; ≥3: 24%) and just performed surgery (0-2: 65%; ³3: 35%) and 0 in the 3 months determination (0-2: 94.1%; ³3: 5.9%). In the presurgery analysis, DFS was 15 months for the CTCs ≥3 group and 33 months for <3 CTCs (HR: 0.95; 95% CI:0.34-2.64) while in the postsurgery analysis, DFS was 13 months in CTCs ≥3 group and 33 months for <3 CTCs (HR: 1.11; 95% CI:0.37-3.29) CTCs ≥3 group after surgery, OS was 33 months, not having reached in the other groups. Conclusions: There is a marked difference in DFS in favor of pts with CTCs levels 0-2 before and just performed surgery. Our study shows a slight increase in CTCs quantification after LS, instead a significant CTCs decrease was observed after adjuvant therapy. Role of radical LS in kinetic of CTCs should continue to be analysed in future studies.
Development of a novel RT-PCR assay for the detection of EML4-ALK fusion products in FFPE speciments.
Authors: Papadopoulou Eirini , Murray Samuel , Nasioulas George
Published: March 2020

e21087

Background: EML4-ALK is a fusion-type protein tyrosine kinase identified recently in a subset of human lung carcinomas and seems to be a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC. To date, several EML4-ALK variants have been identified in lung cancer samples. Three methods have been used for the detection of these fusions, including IHC, FISH, and RT-PCR, which is the only method that can distinguish between different variants. Existing RT-PCR methods, are designed to amplify large cDNA fragments and are inadequate for the analysis of formalin-fixed paraffin-embedded (FFPE) tissues which produce cDNA fragments of limited size. Thus, we designed an RT-PCR assay that can detect all published EML4-ALK variants and is suitable for use with this commonly available material. Methods: Synthetic DNA fragments for each variant were cloned using the pCR2.1 cloning vector and used as positive controls. Specific primers that enhance specifically EML4-ALK transcripts 1, 2, 3a, 3b, 4, 5a, 5b, 6, 7, "4", and "5" were designed. Detection of all EML4-ALK fusions was achieved using RT-PCR. DNA sequencing analysis was performed to confirm the specificity of the obtained PCR products. The sensitivity of the method was calculated by adding to 1μg RNA serial dilutions of the synthetic DNA fragments. It was found that up to 22 copies of the translocation can be detected per μg of RNA. The study included FFPE specimens from NSCLC patients without EGFR and K-RAS mutations. Pathological review was obtained for all samples and macro-dissection was used to ensure a tumor cell content of >75%. We are currently increasing our sample size of Greek patients and are in collaboration with other centers to further understand the clinical impact of the variant spectrum. Results: Three control EML4-ALK FISH positive samples were positively subtyped using RT-PCR and sequencing. None of the 96 FFPE specimens tested so far was positive for the EML4-ALK fusion. Conclusions: We designed a robust multiplex RT-PCR assay that permits the sensitive detection of all published EML4-ALK variants. It’s suitable for use with commonly available materials such as FFPE specimens, cytological specimens and other aspirates.
Association of core needle biopsies with increase in metastatic dissemination of breast cancer.
Authors: Giacomantonio Carman A. , Dean Cheryl A. , Mathenge Edward G. , Black Amber A. , Schulte Wendy , Pink Desmond B. , Marcato Paola , Lee Patrick W. , Zijlstra Andries , Lewis John D.
Published: March 2020

e21090

Background: Given the reported association between incisional procedures performed on cancer patients and subsequent increases in metastasis, as well as the established inverse relationship between metastasis and patient survival, this study establishes the extent to which incisional core needle biopsies (CNB) affects tumor growth and metastatic dissemination in two distinct breast cancer animal models. Methods: Using the chick embryo system (CES) and murine breast cancer model (MuBC)the impact of CNB on cancer metastases was evaluated. Human MDA-MB-231 and MDA-MB-435 cancer cells were used in the xenograft / CES, and murine 4T1 Breast cancer cells for the syngeneic MuBC . In each model, tumors were biopsied in half of the animals while the other half were left undisturbed (CES:n=40, MuBC:n=40). The impact of CNB on tumor growth, necrosis and metastases was assessed. Metastases levels in the CES was determined by quantitative PCR for human alu sequence DNA in chick tissue extracts. Metastatic burden in the MuBC model was evaluated by microscopic quantification of metastatic areas in sectioned and H-E stained mouse organs. Results: When biopsied and un-biopsied groups were compared, both models showed significant difference in pulmonary metastasis. MDA-MB-435 CES (p=0.025) and 4T1 MuBC (p=0.026). MDA-MB-231 CES showed no significant change in lung metastases in the CES but did however show increased Chorioallantoic Membrane (CAM) metastasis (p=0.018) and both cell lines showed statistically significant alteration in Liver metastasis, (MDA-MB-231 CES (p=0.006); MDA-MB-435 CES (p=0.004)). Interestingly only MDA-MB-435 (CES) tumor growth was significantly increased after CNB (p=0.002). Conclusions: These results offer the first experimental evidence that core needle biopsies result in an increased risk of metastatic dissemination and affect metastatic tropic behavior. They also reinforce the concept of a multi-step metastatic pathway and suggest involvement of extrinsic factors that influence the extravastion and intravasation steps. The clinical implications are considerable and follow-up studies examining potential mechanisms and countermeasures are urgently required
Frequency of Hsa-miR9 aberrant methylation in metastatic breast cancers.
Authors: Parrella Paola , Florescu Anca , Copetti Massimiliano , Murgo Roberto , Valori Vanna Maria , Castelvetere Marina , Latiano Tiziana Pia , D'Addetta Carmela , Fazio Vito Michele , Maiello Evaristo
Published: March 2020

e21092

Background: MicroRNAs (miRNAs) are a recently discovered class of very small non-coding RNAs involved in the regulation of gene expression by interfereing with mRNA translation. It has been shown that human miR-9 expression levels are reduced in breast cancer samples due to the aberrant methylation of its promoter region . Methods: We analyzed74breast cancer cases treated by surgery at the IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy. Pathological assessment included evaluation of histological type, grade and stage. Estrogen receptor (ER), progesterone receptor (PgR), Ki-67 labeling index and Her2 amplification were also evaluated. Six of the 74 patients showed metastases at the diagnosis, and 8 patients developed metastases during the follow up. The median follow up time for the patients cohort was 44 months (range 28-57+). All metastatic patients (n=14) died from the disease. Genomic DNA extracted from 6 normal breast tissues obtained by reductive mammoplasty, and tumour samples was subjected to bisulphite treatment and the converted DNA was used as a template for MSP using primers specific for the methylated hsa-miR9 sequence. Results: Methylation at the hsa-miR9 promoter region was detected in 33 of 74 (44%) breast tumours and none of the 6 normal breast tissues (p=0.02). Interestingly, hsa-miR9 methylation was significantly more frequent in patients with syncronous or metachronous distant metastases (8 of 14, 57%) as compared with patients free from metastases (11 of 33, 32%) (p=0.02 χ2 Test). In particular, methylation was detected in all 5 tumours showing only bone metastases (100%), whereas methylation was less frequent (33%) in the group characterized by the the presence of visceral metastases (P=0.03 χ2 Test). Conclusions: Our results suggest that hsa-miR9 methylation in breast cancer is associated with tumour metastatic behaviour and might represent a novel biomarker for monitoring breast cancer patients.
Systems biology in personalized medicine in oncology: A case study in non-small cell lung cancer.
Authors: Bianconi Fortunato , Perruccio Katia , Ludovini Vienna , Baldelli Elisa , Bellezza Guido , Flacco Antonella , Ragusa Mark , Valigi Paolo , Crinò Lucio
Published: March 2020

e21096

Background: Systems biology together with translational oncology is a new approach to discover sensitive pathways in specific cancers. In this study, we propose a computational modeling technique to investigate the possible effects various alterations, such as protein overexpression, gene amplification or mutations, may have on signaling, through of the EGFR and IGF1R pathways, in non-small cell lung cancer (NSCLC). Methods: EGFR and IGF1R pathways and the downstream MAPK and PIK3 networks have been reproduced through a mathematical model. One hundred-twenty five tumors from surgical NSCLC patients were evaluated for EGFR and IGF1R protein expression, by immunohistochemistry (IHC) and gene amplification, by fluorescence in situ hybridization (FISH). KRAS mutations (exons 2 and 3) were evaluated by direct sequencing Results: To correlate EGFR and IGF1R expression levels, and KRAS mutations to tumor cell proliferation, we focused on the ERK signaling pathway, which plays a central role in several steps of cancer development including proliferation and cancer cell migration. The mathematical model predicts a relationship between a simultaneous high expression level of both receptors and a modification on ERK time behavior, implying a stronger attitude for cell proliferation. Furthermore KRAS activating mutations predict high level of active ERK and high probability to have cell proliferation. Cell growth can be closely related to disease progression and act, in survival analysis, as DFS estimator. Patients with concomitant IGF1R/EGFR FISH/IHC positivity had a worse DFS ( p=0.005). KRAS mutations have a statistically significant shorter DFS (p<0.001) as well Conclusions: We propose a Systems Biology approach, combined with Translational Oncology methodologies, to understand the interaction between EGFR, IGF1R and KRAS pathways in NSCLC. Computational model predictions confirm clinical evidences of survival analysis. Future work will validate our model with experiments on various NSCLC cell cultures and further investigate the response to drug administration. We thank AIRC and Fondazione Cassa di Risparmio for supporting the study.
Importance of the biologic effective dose in achieving local control of adrenal tumors treated with stereotactic radiosurgery.
Authors: Rai Hema , Desai Amishi , Witten Matthew R. , Haas Jonathan A. , Schneider Jeffrey Gary
Published: March 2020

e21114

Background: Adrenalectomy achieves long term survival in ~ 25% of patients with solitary adrenal metastasis (SAM). Stereotactic radiosurgery (SRS) represents a potential non-surgical alternative to this same endpoint, but reported local control rates vary from 45% to 96%. SRS delivers a range of biologic effective doses (BED) dependent upon fraction size, number and schedule. We herein review our experience with SRS for adrenal metastasis to evaluate the interaction between BED and local adrenal tumor control. Methods: The Winthrop SRS data base was queried to identify 14 patients undergoing SRS for malignant adrenal tumors from 2006 to 2011. Patients were characterized by their primary tumor site, stage at diagnosis and the time to adrenal involvement. BED was calculated for each patient. Local adrenal tumor control and durability of response were also recorded. Results: Calculated BEDs ranged from 4,667 cGy to13,000 cGy. Of the factors examined, BED was the single most important predictor of local adrenal tumor control. According to best adrenal tumor response, mean BEDs were: 10,053 cGy for radiographic regression of disease; 8,115 cGy for stable disease, and 6,667 cGy for progression of disease (p = 0.0465, by one-tail test). No solid tumor patient responded to SRS with BED < 8,800 cGy and no patient immediately progressed through SRS with BED > 6,667 cGy. Duration of adrenal tumor control also correlated with calculated mean BED which was: 9,676 cGy for never locally failing (n=6) and 7,600 cGy for ever locally failing tumors (n=5). However, eventual local treatment failure was seen in one of three patients receiving even the highest calculated BED (13,000 cGy). Conclusions: Because eventual local failures are observed with SRS even at the highest examined BED, adrenalectomy rather than SRS should remain the standard of care for patients with potentially curable SAM. SRS remains an acceptable alternative to adrenalectomy for palliation of symptomatic adrenal tumors or for the definitive treatment of SAM in non-surgical candidates. When given for these purposes, our data support the use of SRS regimens delivering a minimum BED of 8,800 cGy.
Role of FDG-PET as predictive biomarker of pathologic complete response (pCR) in locally advanced rectal cancer (LARC) treated with capecitabine-based neoadjuvant chemoradiation (NACR).
Authors: Pietrantonio Filippo , Di Bartolomeo Maria , Bampo Chiara , Valvo Francesca , Alessi Alessandra , Crippa Flavio , Biondani Pamela , Leo Ermanno , Milione Massimo , Dotti Katia F , Fantini Simona , Avuzzi Barbara , Formisano Barbara , Battaglia Luigi , Chiruzzi Chiara , De Braud Filippo G.
Published: March 2020

e21118

Background: A favourable outcome is associated with pCR in LARC treated with NACR; pCR prediction through functional imaging may help the prospective evaluation of management strategies alternative to standard surgery. The aim of this prospective study was to identify whether FDG-PET activity and early/late response predicted independently pCR. Methods: Patients with histologically diagnosed cT3-4 and/or N+ primary rectal cancer were treated homogeneously with NACR (simultaneous boost technique radiotherapy 54 Gy on GTV/24 fractions plus capecitabine 1650 mg/mq/day) and total mesorectal excision 7-8 weeks later. FDG-PET uptake, expressed as maximum standardized uptake value, was obtained at baseline (SUV-1), at interim (2 weeks after treatment start: SUV-2) and 6 weeks after NARC completion (SUV-3) and was calculated as percentage difference (Δ-SUV). The role of SUV-1, SUV-2, SUV-3, Δ-SUV(1-2) and Δ-SUV(1-3) for pCR prediction was assessed using logistic regression analysis; ROC analysis was performed to identify the optimal thresholds. Results: The study enrolled 30 pts (median age 59 yrs; 12M:18F) treated from January 2009 to November 2011 at Istituto Nazionale Tumori of Milan. All underwent FDG-PET at baseline and post-NACR and 80% consented to an interim assessment; one patient was excluded due to surgery refusal. pCR rate was 28%. Among all parameters, only post-NACR SUV (mean 4 +/- 1.7 for pCR vs 8.7 +/-5.8 for non-pCR; P=0.001 by Mann-Whitney test) showed significant association with pCR at univariate analysis (P=0.03). At multivariate analysis including baseline SUV, post-NACR SUV, Δ-SUV, age (≤ or >65 yrs), sex (F or M) and pre-treatment stage (N- or N+/cT3 or cT4), only female sex and post-NACR SUV predicted independently pCR (both P=0.01). With ROC analysis, a post-NACR SUV threshold <5.5 had 88% sensitivity and 81% specificity, with 83% overall accuracy. Conclusions: The SUV cut-off of 5.5, explained by inflammatory modifications, could limit the applicability in clinical practice assuming values ≤2.5 for negativity. However, FDG-PET SUV post-NACR may serve as useful predictive biomarker in LARC.
A review of clinicopathologic characteristics, therapy, and outcomes of 22 patients with aggressive B-cell lymphoma.
Authors: Jaglal Michael , Peker Deniz , Bello Celeste M. , Shah Bijal D. , Sokol Lubomir , Zhang Ling , Sotomayor Eduardo M. , Tao Jianguo , Cultrera Jennifer L.
Published: March 2020

e21123

Background: B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL) or Burkitt like lymphoma is a high grade lymphoma that is associated with a high proliferation index and a complex karyotype mostly involving MYC and BCL-2 genes, so called “double hit” as well as BCL-6 or CYCLIND1 genes, so called “triple hit”. This high grade lymphoma shows an aggressive behavior for which the most appropriate therapeutic approach is yet to be established. Methods: This was a single center retrospective review of pts with a confirmed diagnosis of B cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL from 2006 to 2011. The definitive diagnosis in all cases was based on morphological and phenotypic features, and genetic abnormalities involving MYC, BCL-2, BCL-6, and or CYCLIND1. Clinicopathological data was extracted including age, gender, primary disease location, phenotypic subtype, genetic abnormalities by FISH, IPI scores, treatment regimens and survival data . Descriptive statistical analyses were utilized. Kaplan-Meier method was used to estimate OS and log rank test was used to compare the groups. All data were analyzed using SPSS version 20.0 statistical software. Results: 22 pts with "Double or Triple Hit" lymphomas were identified between 2006 and 2011. The age range at diagnosis was 33-87 years with median age of 66. 16 of 22 pts (73%) were ≥ 60 years old. Male to female ratio was 1.75 :1 (14:8). The median ECOG PS was 1. No pts had HIV. A majority of pts presented with extranodal disease 17 with only 5 pts presenting with nodal disease. The median survival of the entire cohort was 9 months with ranges 32 to 2 months. 16 of 22 pts (73%) are currently alive. In the cohort of pts that are currently alive, 10 was treated with RCHOP and 6 with RHyperCVAD. Pts who presented with CNS disease had a worse prognosis when compared to the entire cohort with a median overall survival of 6.5 months (p=0.016). Conclusions: RCHOP was the most utilized treatment regimen in the cohort of  alive patients. CNS disease is associated with worse prognosis in patients with "Double or Triple Hit" lymphomas.
Prognostic significance of MAGE-A10 and NY-ESO-1 cancer-testis antigen in breast cancer.
Authors: Badovinac Crnjevic Tanja , Jakic Razumovic Jasminka , Spagnoli Giulio C , Podolski Paula , Saric Nera , Basic Koretic Martina , Juretic Antonio
Published: March 2020

e21126

Background: Cancer testis antigens (CTAs) are expressed in a variety of malignant tumors. In normal adult tissues CTA expression is restricted predominantly to germs cells of the adult testis and placenta. Based on their tumor-restricted expression pattern, CTAs are regarded as valuable targets for cancer immunotherapy. The prognostic significance of CTAs in breast cancer has not been analyzed previously. Methods: To evaluate the potential prognostic significance of two member of this family, MAGE-A10 and NY-ESO-1 antigens, we examined their expression in breast cancer patients who underwent curative surgery at our hospital between 2002 and 2003. Paraffin embedded tumor sections were collected retrospectively from 165 breast cancer patients and immunohistochemical staining for MAGE-A10 and NY-ESO-1 was performed. Impact of MAGE-A10 and NY-ESO-1 expression on disease free survival (DFS) and overall survival (OS) was analyzed by the Kaplan-Meier method using 8-year follow up data. Results: MAGE-A10 expression (score ≥2+) was detected in 105/164 (64%) and NY-ESO-1 expression (score ≥2+) was observed in 14/164 (8.5%) patients. 8-year DFS for MAGE-A10 positive patients was 69% and 73% for MAGE-A10 negative (p=0.452). 8-year OS for MAGE-A10 positive patients was 80% and 90% for MAGE-A10 negative (p=0.134). For NY-ESO-1 positive patients 8-year DFS was 67% and 70% for NY-ESO-1 negative patients (p=0.837). 8-year OS for NY-ESO-1 positive patients was 83% and 84% for NY-ESO-1 negative patients. (p=0.991) Conclusions: To our knowledge this is the first study analyzing prognostic significance CTAs in breast cancer. In this retrospective study we did not show statistically significant correlation between MAGE-A10 and NY-ESO-1 expression and clinical outcome. Additional studies are warranted to determine weather this antigens might have prognostic value in breast cancer patients.
Study evaluating possible causes of the normal variant 18F-FDG uptake in the thoracic spinal cord in patients without CNS malignancy.
Authors: Bhatt Geetika , Li Xiao-Feng , Sharma Vivek R. , Bhatt Aashish D. , Cambon Alex , Rai Shesh , Civelek Ali Cahid
Published: March 2020

e21144

Background: Focal increased lower thoracic spinal cord 18F-FDG uptake is not infrequently observed and may be confused for spinal cord metastases. The cause of this physiological uptake is indeterminate though various theories have been postulated. We hypothesized that there may be a correlation between the thoracic (T11-T12) spinal uptake and lower limb movements or to bowel FDG activity. In the absence of paired FDG PET studies in same patients with and without leg movements we correlated the FDG uptake of the lower thoracic cord in ambulatory to that in bedridden patients. Methods: Sixty-three consecutive patients (12 bedridden) with 18F- FDG PET-CT with no known evidence of spinal cord or bony spine metastases were included. The SUV max/avg values of the liver, Thoracic: T11-T12 and Cervical: C3-C5 spinal cord segments and the bowel FDG activities of the ambulatory and bedridden patients were determined and compared. Statistical analysis was performed to evaluate various factors predictive of increased spinal cord FDG uptake. Results: Median age was 54 years (18- 93). Primary tumor histology was lung (21.8%), breast (9.3%), melanoma (15.6 %) and lymphomas (21.8%). The mean SUV max/avg values were liver (2.89/2.43); Thoracic cord (2.46/1.89); Cervical cord (2.25/1.82) and Bowel (4.4/2.9). Visible 18F-FDG thoracic spinal uptake was seen in 28%. Our analysis showed no significant correlation between the ambulatory status (p=0.219) or bowel FDG activity (p=0.210) and T11-T12 cord uptake. Conclusions: Although of no significance in this study, there might be a correlation between limb movements (amongst other factors) and physiological FDG uptake in the lower T-spine which warrants further dual studies in the same patient with and without leg motion. This may also help in differentiating normal variant spinal cord uptake from spinal cord metastatic lesions. [Table: see text]
Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: A GCIG and EORTC-GCG study.
Authors: Vergote Ignace B. , Joly Florence , Katsaros Dionyssios , Coens Corneel , Reinthaller Alexander , Hall Marcia , Steer Christopher B. , Colombo Nicoletta , Lesoin Anne , Casado Antonio , Petru Edgar , Green John , Buck Martin , Ray-Coquard Isabelle Laure , Ferrero Annamaria , Favier Laure , Reed Nicholas , Curve Herve , Jimeno Antonio , Pujade-Lauraine Eric
Published: March 2020

LBA5000

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
A phase Ib/II study evaluating the efficacy of doxorubicin (D) with or without a human anti-PDGFRα monoclonal antibody olaratumab (IMC-3G3) in the treatment of advanced soft tissue sarcoma (STS).
Authors: Tap William D. , Van Tine Brian Andrew , Elias Anthony D. , Livingston Michael B. , Agulnik Mark , Cooney Matthew M. , Chmielowski Bartosz , Brenner Andrew Jacob , Pennock Gregory K. , Somaiah Neeta , Dang Long H. , Tian Gary G. , Jones Robin Lewis , Okuno Scott H. , Loizos Nick , Nippgen Johannes , Schwartz Gary K.
Published: March 2020

TPS10099

Background: PDGFRα is a receptor commonly overexpressed in STS. Olaratumab is a fully human IgG1 MAb which specifically binds to human PDGFRα and blocks PDGFR-mediated signaling pathways. Olaratumab demonstrated significant tumor inhibition as a monotherapy and in combination with standard chemotherapy in preclinical human sarcoma xenograft models. A Phase 1b/2 clinical trial for patients with advanced or metastatic STS is currently enrolling patients in 9 sites across the United States; approximately 45 patients have been randomized. Methods: In Phase 1b, patients received olaratumab (15 mg/kg) via intravenous infusion on Days 1 and 8 of each 21-day cycle and D (75 mg/m²) 1 hour after olaratumab on Day 1. Phase 1b was completed without encountering dose-limiting toxicities; enrollment into Phase 2 has begun. The primary endpoint of the Phase 2 portion is to compare progression-free survival in patients with advanced STS when treated with D plus olaratumab versus D alone. Planned enrollment goal for Phase 2 is 130 patients. Patients are required to be ≥ 18 years old with ECOG 0-2, have appropriate organ function and histologically confirmed, measurable, and advanced STS. There is no restriction on the number of prior therapies. Patients are randomized 1:1 to either D plus olaratumab (Arm A) at same dose/schedule as in Phase 1b or D alone (Arm B). All patients can receive dexrazoxane. Upon completion of 8 cycles, patients in Arm A continue with olaratumab monotherapy. Patients in Arm B who develop disease progression during or after treatment can subsequently receive olaratumab monotherapy. Patients are stratified to treatment arms according to PDGFRα expression (positive vs. negative), number of previous lines of treatment, sarcoma subtype, and ECOG performance status. Response assessment occurs every 6 weeks. Exploratory analyses include biomarkers of olaratumab pharmacodynamic activity including PDGF ligands, PDGFR downstream molecules, VEGF, and changes in vascularity of tumor specimens.
NSABP B-47: A phase III trial of adjuvant therapy comparing chemotherapy alone (six cycles of docetaxel plus cyclophosphamide or four cycles of doxorubicin plus cyclophosphamide followed by weekly paclitaxel) to chemotherapy plus trastuzumab in women with node-positive or high-risk, node-negative, HER2-low invasive breast cancer.
Authors: Fehrenbacher Louis , Jeong Jong-Hyeon , Rastogi Priya , Geyer Charles E. , Paik Soonmyung , Ganz Patricia A. , Land Stephanie R. , Costantino Joseph P. , Swain Sandra M. , Mamounas Eleftherios P , Wolmark Norman
Published: March 2020

TPS1142

Background: Adjuvant studies utilizing trastuzumab in early HER2+ breast cancer demonstrated a large reduction in recurrence and death. Post-enrollment central testing showed HER2 non-amplified participants derived similar benefit. Methods: Selection of one of the two chemotherapy regimens is by physician choice: The non-anthracycline regimen is TC (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2) administered IV every 3 weeks for 6 cycles; the anthracycline regimen is AC followed by WP (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 administered IV either every 3 weeks or every 2 weeks [per investigator discretion] for 4 cycles followed by paclitaxel 80 mg/m2 IV weekly for 12 doses). Patients are randomly assigned to receive chemotherapy with or without trastuzumab therapy. For patients receiving the TC chemotherapy regimen, trastuzumab is given every 3 weeks during and following chemotherapy until 1 year after the first trastuzumab dose (8 mg/kg loading dose; 6 mg/kg for the remaining doses). For patients receiving the AC followed by WP chemotherapy regimen, trastuzumab begins with the first dose of weekly paclitaxel and will be given weekly for 12 doses (4 mg/kg loading dose; 2 mg/kg for the remaining weekly doses). Following completion of WP, trastuzumab therapy continues with 6 mg/kg doses given every 3 weeks for a total of 1 year. Eligibility: Eligibility includes: node positive or high risk node negative female breast cancer patients; HER2 IHC 1+ or 2+ scores, but non amplified by FISH Statistical Design: The primary aim is to determine whether the addition of trastuzumab to chemotherapy improves invasive disease-free survival (IDFS). 3260 patients will be enrolled to provide statistical power of 0.9 to detect a 33% reduction in the hazard rate of IDFS using a one-sided alpha level of 0.025. Progress: Protocol was activated in January 2011. As of January 27, 2012, 486 of 3260 patients have been enrolled. Supported by NCI U10-12027, -37377, 69651, 69974, and Genentech, Inc.
ARTemis: Randomized trial with neoadjuvant chemotherapy for patients with early breast cancer.
Authors: Earl Helena Margaret , Blenkinsop C , Grybowicz L , Vallier A-L , Cameron David A. , Bartlett John M.S. , Murray Nicholas , Caldas Carlos , Thomas J , Dunn Janet A , Higgins Helen B , Hiller Louise , Hayward Larry
Published: March 2020

TPS1144

Background: Bevacizumab is a new humanised monoclonal antibody which targets vascular endothelial growth factor (VEGF) and thereby the neoangiogenic process in cancer. Bevacizumab has shown promising anti-tumour effect when given concurrently with taxane-based chemotherapy in breast cancer. However two neoadjuvant breast cancer trials have produced conflicting results. The NSABP-B40 study showed significant benefit for bevacizumab only in the ER+ve patients (pathological complete response (pCR) in ER+ve population 15.2% vs 23.3%, p=0.008). Whereas the GEPARQUINTO trial reported significant benefit only in the triple negative patients (pCR 27.8% vs 36.4% p=0.021). Methods: ARTemis is a phase III randomised trial to determine whether the addition to neo-adjuvant chemotherapy of bevacizumab is more effective than standard chemotherapy alone in patients with HER2-negative early breast cancer. A total of 400 patients will be randomised into each of the two treatment arms which will allow an absolute difference in the pCR rates in excess of 10% to be detected at the 5% (2-sided) level of significance with an 85% power. Primary outcome is pathological complete response rates after neo-adjuvant chemotherapy, i.e. no residual invasive carcinoma in the breast, and no evidence of metastatic disease within the lymph nodes. Secondary outcomes are disease free survival, overall survival, complete pathological response rates in breast alone, radiological response after 3 and 6 cycles of chemotherapy and rate of breast conservation and toxicities. Results: Recruitment into ARTemis began in April 2009 and as of January 2012 had recruited 469 (59%). ARTemis is due to complete recruitment by Dec 2012 and the first planned interim analysis of the primary outcome will be Dec 2013. Conclusion: The IDSMC reviewed the trial in June 2011 and recommended continuation of recruitment to this important trial given there were no safety concerns, and results from the other neoadjuvant studies (NSABP-B40 and GEPARQUINTO) are conflicting.
Trial of exercise in ovarian cancer survivors.
Authors: Irwin Melinda , Gottlieb Linda , Cartmel Brenda , Ercolano Elizabeth , Rothbard Marianna , Zhou Yang , Schwartz Peter E. , Ligibel Jennifer A. , Von Gruenigen Vivian E. , Risch Harvey
Published: March 2020

TPS1614

Background: Physical activity (PA) has been associated with improved QOL and survival in breast and colorectal cancer survivors, yet no study has examined the effect of exercise on ovarian cancer outcomes. The purpose of our NCI-funded trial is to examine, in 230 women diagnosed with Stage I-IV ovarian cancer, the impact of exercise vs. attention control on: QOL, body composition, and serum markers associated with ovarian cancer. This abstract presents preliminary recruitment and adherence results. Methods: Women are being recruited via Connecticut Tumor Registry and Yale Cancer Center into the Women’s Activity and Lifestyle Study in Connecticut (WALC). We are also recruiting patients nationally via self-referral and collaboration with medical oncologists at DFCI and Summa Akron City Hospital. Women are randomly assigned to exercise (n = 115) or attention control (n = 115). Both groups receive weekly telephone calls for six months from a certified health educator to discuss ovarian cancer health topics. In addition, the exercise group receives PA counseling to participate in 150 min/wk of aerobic exercise (primarily brisk walking) for six months. Results: Study recruitment began in March, 2010 and will be ongoing through December, 2013. As of December 31, 2011, we have identified 556 potentially eligible women. Of these, 145 are recently diagnosed and are awaiting screening, 115 were unable to be contacted, and 296 have completed the telephone screening. Of the 270, 46% were ineligible (e.g., already exercising, physical limitations); 30% were not interested, 24% (n = 66) have been randomized, and 9% (n = 24) are undergoing baseline visits. On average, women are 62 years old, diagnosed 1.8 years in the past, with primarily stage III disease. Thirty-three patients have completed the trial, with high adherence among women randomized to exercise (average 141 min/wk of exercise reported and 75% of exercisers participating in at least 150 min/wk of exercise). Conclusions: Women are interested in and able to participate in exercise after an ovarian cancer diagnosis. Our trial could suggest a unique and important role for exercise in ovarian cancer care given that physical and functional aspects of QOL are often the most compromised in ovarian cancer patients.
A phase Ib/II study testing the safety and efficacy of combined inhibition of the AKT/PI3K and AR signaling pathways in castration-resistant prostate cancer: GDC-0068 or GDC-0980 with abiraterone acetate versus abiraterone acetate.
Authors: Funke Roel Peter , Zhu Jin , Meng Raymond D. , Yan Yibing , Musib Luna C. , Talluto Craig Charles , Patel Premal H.
Published: March 2020

TPS2616

Background: Loss of PTEN, leading to activation of the AKT/PI3K pathway is frequent and associated with poor prognosis in prostate cancer. In addition, AR and AKT/PI3K cross-regulate by reciprocal feedback and combined inhibition of both pathways resulted in improved preclinical efficacy. This study is designed to evaluate the effect of combined inhibition of AR pathway (with abiraterone) and AKT/PI3K pathway (with either GDC-0068 or GDC-0980). GDC-0068 is a potent, selective ATP-competitive inhibitor of AKT1, 2, and 3. Preclinical studies showed that cell and tumor models with PTEN loss are more likely to be sensitive to GDC-0068. GDC-0068 was generally well tolerated in phase I and a MTD of 600 mg daily was identified. GDC-0980 is a potent pan-inhibitor of Class I PI3K and inhibits wild-type and mutated p110α isoforms, as well as mTOR kinase. The recommended phase II dose (RP2D) for single-agent GDC-0980 is 40 mg daily. Methods: This study will enroll CRPC patients previously treated with docetaxel. In phase Ib, the RP2D will be determined separately for GDC-0068 and GDC-0980 in combination with abiraterone 1000 mg qd and prednisone 5mg bid. In phase II, patients will be randomized 1:1:1 to receive GDC-0068 + abiraterone, GDC-0980 + abiraterone, or placebo + abiraterone. The primary endpoint of phase II is PFS measured by PCWG2 in all patients and in patients with PTEN loss. Secondary endpoints include OS, PSA response rate, ORR, safety, Pharmacokinetics and biomarker analyses. The effect of each treatment on the number of circulating tumor cells will be assessed. Primary and secondary analyses will include all randomized patients and will be conducted according to assigned treatment arm. Kaplan-Meier methodology will be used to estimate median PFS for each arm. Up to 24 patients are planned to be enrolled in phase Ib; 240 patients (80 per arm) are planned for phase II. This study is open for accrual; to date 2 patients have been enrolled in phase Ib.
A phase I study of 1-methyl-D-tryptophan in combination with docetaxel in metastatic solid tumors.
Authors: Jackson Erica , Minton Susan E. , Ismail-Khan Roohi , Han Heather , Neuger Anthony , Antonia Scott , Sullivan Daniel , Soliman Hatem Hussein
Published: March 2020

TPS2620

Background: The indoleamine 2, 3 dioxygenase pathway (IDO) can create immune suppression and unresponsiveness to tumor antigens in tumor-bearing hosts. 1-methyl-D-tryptophan (1-MT), an oral inhibitor of the IDO pathway, showed favorable toxicity profile and biologic activity in prior studies. Remarkably, in prior animal models (MMTV-neu mice), 1-MT in combination with chemotherapy produced 30% greater tumor regressions. Based on this data, a phase I trial was initiated to study the synergism of 1-MT with docetaxel. The primary goal of this trial is to determine the MTD and toxicity for the combination of docetaxel and oral 1-MT. A secondary endpoint will be to determine the PK data and the overall response rate. Methods: This phase I study utilizes a 3+3 design comprised of five dose levels. Dose levels 1-4 will evaluate docetaxel 60mg/m2 IV d1 q3wks plus 1-MT at 300mg, 600mg, 1000mg, and 2000mg PO BID d1-21 respectively. Dose level 5 is docetaxel 75mg/m2 IV d1 q3wks + 1-MT 2000mg PO BID d1-21. Eligibility for this study includes patients with measurable metastatic solid malignancy, no prior docetaxel for metastatic disease, age ≥18, life expectancy >4 months, and adequate organ/marrow function. Patients will be excluded if they meet any of the following criteria: chemotherapy within the past 3 weeks, untreated brain metastases, active autoimmune disease, or GI disease causing malabsorption. In addition, any patients who have received prior immunotherapy such as ipilimumab are excluded. Treatment will continue until disease progression, unacceptable toxicity, or patient/physician discretion. Accrual to dose level 3 is complete and dose level 4 accrual is underway. The PK of 1-MT and docetaxel will also be characterized, using an HPLC assay. PK measurements for 1-MT are drawn on C1D1 after a single dose of 1-MT is given and then on C1D8 after the morning dose of 1-MT is given. (Drawn at 0,1,2,4,8,12,24, and 48 hours) Because IDO is hypothesized to cause regulatory T cell expansion, circulating Tregs will be quantified utilizing flow cytometry for CD4+CD25+ FoxP3+ cells. (NCT01191216)