bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic impact of body mass index upon cancer recurrence and survival in stage III colon cancer patients from adjuvant chemotherapy trials
Authors: Sinicrope F. , Foster N. R. , Sargent D. J. , Alberts S. R. , O'Connell M. J. 
Published: August 2020

11088 Background: Obesity is associated with an increased risk of colon cancer. However, the influence of body mass index (BMI) upon the prognosis of patients with established colon cancer remains unknown. Methods: We conducted a retrospective study of 1,803 patients with surgically resected stage III colon cancer who were enrolled in five randomized trials of 5-fluorouracil-based adjuvant chemotherapy conducted by the North Central Cancer Treatment Group. Patient height and weight were recorded at study entry and BMI (kg/m2) was calculated and categorized. Cancer recurrence or death were monitored during 5 years of follow-up. The score and likelihood ratio p-values were determined from univariate and multivariate Cox regression models respectively, after stratifying by study. Results: Among stage III colon cancer patients, 19% were obese (BMI 30 kg/m2), 37% were overweight (BMI, 25 to 29.9 kg/m2), 38% were of normal-weight (BMI, 20 to 24.9 kg/m2), and 6% were underweight (BMI < 20 kg/m2). Obese versus normal-weight patients showed higher rates of lymph node (LN) metastasis (>3 LNs; 38% vs. 29%, p <0.01) and tumor site was more likely to be distal versus proximal (52% vs. 45%, p= 0.03). No differences in age, gender, or histologic grade were found. In a univariate analysis, obese patients had significantly worse disease-free survival (DFS) compared with normal-weight patients (hazard ratio 1.25 (95% CI: 1.04 -1.51; p= 0.02). The 5 year DFS rates were 49% in obese patients versus 57% in normal weight subjects. Furthermore, poorer DFS was observed for obese patients after adjusting for age, sex, histologic grade, and tumor site (p= 0.03). Neither overweight nor underweight patients (vs. normal-weight) had significantly different DFS. Analysis of the predictive impact of BMI for 5-FU-based adjuvant therapy is in progress. Conclusions: Obesity (BMI 30 kg/m2) was associated with a greater number of metastatic lymph nodes and poorer disease-free survival in patients with stage III colon cancer, suggesting that obesity influences tumor progression. No significant financial relationships to disclose.
Validation of the web-based tool Adjuvant! in 5,381 Dutch breast cancer patients
Authors: Mook S. , Schmidt M. K. , van de Velde A. O. , Visser O. , Rutgers E. J. , van 't Veer L. J. , Ravdin P. M. 
Published: August 2020

11090 Background: Adjuvant! is a web-based tool that calculates individualized 10-year survival probability and estimates the benefit of adjuvant systemic therapy based on age, co-morbidity, tumor size, tumor grade, number of involved lymph nodes and estrogen-receptor status. The Adjuvant! model was constructed using observed overall survival (OS) for women diagnosed with breast cancer between 1988 and 1992 recorded in the US SEER registry (surveillance, epidemiology and end results) and has not yet been validated in any European series. It is of interest to see whether intrinsic characteristics of tumors and survival of Dutch patients may differ from those in the US. Methods: For this validation all patients who were treated at the Netherlands Cancer Institute for primary breast cancer between 1987 and 1998 were selected according to the following criteria: T1–3 tumor, N0–3, M0, definitive primary surgery, complete axillary staging, and no prior malignancies. Follow-up for OS was complete for >99% of the patients until at least February 2007 (median follow-up 11.7 years). Clinicopathological characteristics as mentioned above and adjuvant treatment data were entered into Adjuvant! version 8.0 for each individual, blinded to the clinical outcome, to calculate predicted 10-year outcomes. Results: In this hospital-based cohort of 5381 patients, all known prognostic factors were significant predictors of overall survival. Across all patients, the 10-year OS was excellently predicted by Adjuvant! (predicted OS - observed OS=0.2%; p=n.s.). Also, for most relevant clinicopathological subgroups the differences between predicted and observed OS were within 2%. Adjuvant underestimated the OS in patients with tubular type of breast cancer (predicted - observed = -6.8; p<0.01); presently, histology is not incorporated in Adjuvant!. Conclusions: Adjuvant! accurately predicts 10-year OS for common tumor types in this first large scale European validation study and is of use for adjuvant treatment-decision making. [Table: see text]
Loss of p27 expression and response to neoadjuvant chemotherapy: Results from the I-SPY Trial (CALGB150007/150012, ACRIN6657)
Authors: DeMichele A. , Dunn L. , Gimotty P. , Livasy C. , Perou C. , Carey L. , Esserman L. 
Published: August 2020

11091 Background: Loss of expression of the cyclin-dependent kinase (cdk) inhibitor p27 has been associated with decreased survival among patients receiving adjuvant chemotherapy. The I-SPY Trial is a multicenter study of locally advanced breast cancer in which pretreatment tumor biopsies were obtained prior to the administration of anthracycline and taxane-based neoadjuvant therapy, and serial MRIs were performed to assess response to treatment. The aim of this study was to determine if loss of tumor p27 expression was associated with response to cytotoxic therapy. Methods: Eligible patients had biopsy-confirmed primary breast cancer measuring at least 3 cm. Immunohistochemistry for p27 was performed centrally on pretreatment core samples using rabbit anti-p27 (Upstate Cell Signaling #06–445). Nuclear p27 was classified as absent (no staining), low (1–50% staining) or normal (>50% staining). Following completion of chemotherapy, post-surgical excision/mastectomy cases were reviewed centrally to determine response to therapy including residual cancer burden (RCB) and pathologic complete response (pCR) rate. Exact Chi2 was used to compare proportions. Results: Pretreatment samples from 164 of 237 enrolled patients demonstrated that p27 expression was absent in 55 (33%), low in 96 (58%) and normal in 14 (8%). P27 loss was not associated with patient age. Compared to normal p27 expression, absent p27 was significantly associated with ER negativity (48% vs. 14%; p=0.03), PR negativity (59% vs. 21%; p=0.03), Her2 overexpression (28% vs. 14%; p=0.017) and basal molecular subtype (29% vs. 13%). The proportion of patients with p27 loss (absent or low) was higher for those with high Ki-67 expression compared to low/mod expression (98% compare to 88%) and lower for grade 1 (72% vs 92%) compared to grade 2/3 tumors (p=0.071 and p=0.090, respectively). Low or absent p27 was not associated with response to therapy as measured by pCR, RCB or change in tumor diameter by MRI. Conclusions: p27 loss in this neoadjuvant patient population was associated with aggressive tumor features, but not predictive of response to cytotoxic therapy. These findings suggest that the poor prognosis associated with loss of p27 is not due to relative chemotherapy resistance. No significant financial relationships to disclose.
Use of pretreatment serum CA9 (carbonic anhydrase 9) to predict PFS and survival in trastuzumab-treated metastatic breast cancer
Authors: Leitzel K. , Hou H. Y. , Shrivastava V. , Anyanwu U. , Ali S. M. , Koestler W. , Fuchs E. , Brown-Shimer S. , Carney W. , Lipton A. 
Published: August 2020

11092 Background: Approximately half of HER2-positive breast cancer patients will respond to first-line trastuzumab-containing therapy. However, in those patients with an initial trastuzumab response, most will progress within a year with acquired resistance. Since trastuzumab treatment is also now used in the HER2-positive adjuvant breast cancer setting, trastuzumab resistance will continue to be a vexing clinical problem, and better predictive and prognostic biomarkers are urgently needed. Methods: Serum HER2, tissue inhibitor of metalloproteinase-1 (TIMP-1), urokinase-type plasminogen activator (uPA), CA9, VEGF-165, and endoglin were measured using ELISA assays in 66 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. The HER2, TIMP-1, uPA, CA9, and VEGF-165 ELISAs were from Oncogene Science/Siemens Healthcare Diagnostics, Cambridge, MA; and the endoglin ELISA was from R&D Systems, Minneapolis, MN. Progression-free (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling with continuous pretreatment serum biomarker variables. Results: Pretreatment serum HER2 (p= 0.005), TIMP-1 (p< 0.0001), uPA (p= 0.006), endoglin (p= 0.008), and CA9 (p <0.0001) were all significant as univariate continuous biomarkers for predicting PFS to first-line trastuzumab-containing therapy, but VEGF was not. In multivariate analysis for PFS with all six biomarkers, only serum CA9 (p= 0.002) was a significant independent covariate. For OS, pretreatment serum HER2 (p= 0.018), TIMP-1 (p< 0.0001), uPA (p< 0.0001), endoglin (p= 0.002), and CA9 (p< 0.0001) were all significant as univariate continuous biomarkers for prognosis, but serum VEGF was not. In multivariate analysis for OS with all six biomarkers, only serum CA9 was a significant independent prognostic covariate (p= 0.001). Conclusions: Elevated pretreatment serum CA9 (a marker of hypoxia) predicts reduced progression-free survival and overall survival in metastatic breast cancer patients treated with first-line trastuzumab-containing therapy. These serum biomarkers deserve further study in larger trials of HER2-targeted breast cancer treatment. Supported by a grant from Komen for the Cure. [Table: see text]
Cytokeratin-19 (CK19) and mammaglobin (MGB1) gene expression in circulating tumor cells (CTCs) from metastatic breast cancer patients enrolled in the NCCTG trials, N0436 and N0437
Authors: Reinholz M. M. , Kitzmann K. A. , Hobday T. J. , Northfelt D. W. , LaPlant B. , Allred J. B. , Dueck A. C. , Stella P. J. , Lingle W. L. , Perez E. A. 
Published: August 2020

11095 Background: Biologic characterization of CTCs is increasingly important in determining metastatic breast cancer (MBC) patient (pt) prognosis and treatment prediction. Combined preliminary results from two earlier metastatic BC NCCTG trials, N0234 & N0336, suggested that the change in CTC mammaglobin (MGB1) gene expression between baseline and two cycles of chemotherapy predicted tumor response (p=0.04). The objectives of this study were to 1) determine CTC gene expression of CK19 and MGB1 before, during, and after treatment in N0436 & N0437 and 2) determine associations between baseline and post-treatment gene expression and treatment response. Methods: CTCs were enriched using CD45-depletion from ∼10ml EDTA blood obtained from metastatic BC pts before, after two cycles, and at end of treatment with either first/second-line irinotecan plus cetuximab (N0436) or first-line paclitaxel poliglumex and capecitabine (N0437). CK19 and MGB1 mRNA levels were determined using quantitative RT-PCR in baseline and serial CTC samples of up to 19 pts from N0436 and 40 pts from N0437. The relative gene expressions were normalized to β2-microglobulin and calibrated to healthy blood using the 2-ΔΔCt algorithm; a value of 2 was defined as positive for the respective marker. Results: CK19+ mRNA was detected in 58% of baseline samples from N0436 (11/19) and N0437 (23/40). MGB1+ mRNA was detected in 32% (6/19) and 38% (15/40) of N0436 and N0437 baseline samples, respectively. CK19+ mRNA was detected in 50% (7/14) and 56% (29/52) of N0436 and N0437 serial CTC samples, respectively. MGB1+ mRNA was detected in 29% (4/14) and 27% (14/52) of N0436 and N0437 serial CTC samples, respectively. Of the 66 serial samples, 27% of samples (18/66) had turned positive from baseline for CK19 or MGB1. CK19 mRNA was detected in 85% (33/39) of MGB1+ mRNA samples but their baseline mRNA levels were not correlated. Conclusions: CK19 mRNA was detected in MBC pts with similar frequencies to the CellSearch imaging system. CK19 was detected at a higher frequency than MGB1. In the majority of cases, MGB1 was co-expressed with CK19. Associations between gene expression and treatment response using Chi-Squared analyses and Cox regression models will be presented. No significant financial relationships to disclose.
XPG D1104 single-nucleotide polymorphisms and the prognosis of melanoma
Authors: Becker J. C. , Schneider M. , Scherer D. , Ugurel S. , Zapatka M. , Schadendorf D. , Kumar R. , Schrama D. 
Published: August 2020

11096 Background: Sunlight is a major risk factor for melanoma. Since UV radiation causes DNA damage, it is not surprisingly, that genetic variants in DNA repair enzymes contribute to the susceptibility to cutaneous melanoma. Methods: Presence of common non-synonymous single-nucleotide polymorphism in different DNA repair enzymes were established and correlated with overall survival of melanoma patients. To this end, the SNPs of 6 different DNA repair enzymes were evaluated in a cohort of 742 melanoma patients. The impact of these polymorphisms on overall survival was subsequently calculated by the cox hazard model. Results: This analysis demonstrated that after adjustment to gender and primary tumor T classification XPG 1104 His/His as well as XPD 751 Lys/Lys genotypes were significantly associated with improved survival. Cox hazard coefficients were 0.744 for XPG 1104 His/His (p = 0.0059) and 0.651 for XPD 751 Lys/Lys (p = 0.017). Importantly, bootstrapping confirmed theses results for subpopulations. Furthermore, multivariate analysis demonstrated that XPG 1104 His/His is an independent factor affecting overall survival (cox coefficient 0.95788; p = 0.0011). Conclusions: XPG codon 1104 polymorphism may be predictive of survival outcome in patients with cutaneous melanoma. No significant financial relationships to disclose.
Measurement of gene expression biomarkers by qNPA from archived NSCLC FFPE: Prognosis of 5-year survival
Authors: Joshi M. M. , Seligmann B. , Sabalos C. , Harpole D. H. 
Published: August 2020

11098 Background: There are vast archives of formalin fixed paraffin-embedded (FFPE) tissue samples that are clinically annotated offering great research potential. However, the technology currently available to assess gene expression is limited to fresh, frozen, tissue. Recently, a method for measuring gene expression from FFPE using the quantitative Nuclease Protection Assay (qNPA) has been published in a model of diffuse large B-cell lymphoma. It was demonstrated that identical results were obtained from small amounts of FFPE as from matched frozen tissue, or from freshly fixed versus 18 year archived FFPE. Methods: This study used the qNPA assay to measure gene expression in archived FFPE primary tumor samples of patients with stage 1 NSCLC for whom the survival outcomes are known (n=86). HTG lysis buffer is added to the sample; nuclease protection probes that are complementary to the mRNA of interest are then added to the solution. The probes hybridize to all RNA, soluble and cross-linked. After hybridization, S1 nuclease was added and destroys all nonspecific, single strand nucleic acid, producing a stoichiometric amount of target-mRNA to probe duplexes. Base hydrolysis releases the probe from these duplexes. Probes were transferred to a programmed ArrayPlate, detection linker added, and both probes and detection linkers were captured onto the array. The ArrayPlate was washed, HRP-labeled detection probe added, incubated, washed, and chemiluminescent substrate was added. Finally, the ArrayPlate was imaged, to measure the expression of each gene in all the wells. Results: Mantel-Cox analysis indicates that the detection of increased expression of G-CSF (p = 0.07; H.R. =1.904; 95% CI=0.9003–4.028) and Leptin (p=0.09; H.R. =1.910; 95% CI=0.9299–3.924) individually suggest an improved survival. Age, gender and T size were found to not be significant in this data set. Conclusions: These results suggest an improved survival advantage in patients with an elevated native GCSF level in stage 1 NSCLC that is consistent with the survival benefits associated with the prophylactic treatment of GCSF for chemosensitivity in stage III or IV NSCLC patients. These results are currently being assessed using a larger cohort. [Table: see text]
[11C]Choline-PET imaging of breast cancer
Authors: Kenny L. M. , Coombes R. C. , Contractor K. , Stebbing J. , Al-Nahhas A. , Palmieri C. , Shousha S. , Lowdell C. , Aboagye E. 
Published: August 2020

1110 Background: Molecular imaging techniques are increasingly being used in cancer diagnosis, staging, and assessment of response to treatment. This study sought to evaluate, for the first time, [11C]choline-PET in patients with breast cancer. The potential of [11C]choline-PET for differentiating tumours from normal tissue, correlation with molecular markers, determine its normal variability range, and finally the effect of trastuzumab on [11C]choline uptake in patients with breast cancer was investigated. Methods: 21 patients with newly diagnosed and recurrent breast cancer AJCC stage II-IV were enrolled in the study, all of whom had a baseline dynamic [11C]choline-PET scan with arterial sampling. 14 patients had 2 [11C]choline-PET scans to examine reproducibility, and 7 had a scan after trastuzumab. Analysis of [11C]choline uptake was measured using SUV, Ki (irreversible retention), and IRF@60min (retention using spectral analysis). Results: Breast tumour lesions were visualised by [11C]choline PET in all patients. The difference in tumour and non-tumour uptake were significant for SUV, Ki, and IRF@60 min (Wilcoxon p < 0.0001 for all parameters). [11C]choline uptake was reproducible in breast tumour lesions (r2 = 0.945 for SUV, 0.894 for Ki, and 0.799 for IRF60). The metabolism analysis of arterial plasma samples in 19 patients showed that [11C]choline decreased rapidly post-injection such that at 60 mins the mean radioactivity in arterial plasma due to choline was 15.15 ± 2.16%.Early responses to trastuzumab were determined to be significant in 5 lesions which corresponded with 3 clinical responses. Conclusions: [11C]choline-PET is a promising imaging modality in breast cancer, and could play an important role for determining response to novel treatment strategies in vivo. No significant financial relationships to disclose.
Mechanisms of Plk4 haploinsufficiency in hepatocellular carcinogenesis
Authors: Wu P. , Rosario C. , Paderova J. , Gladdy R. , Ko M. , Squire J. , Dennis J. , Swallow C. 
Published: August 2020

11100 Background: The pathogenesis of hepatocellular carcinoma (HCC) is multifactorial and includes genetic predisposition, though the precise nature of the latter is as yet poorly understood. Mice heterozygous for the polo like kinase Plk4 develop spontaneous HCC and human HCC cases show a high rate of LOH (loss of heterozygosity) at the Plk4 locus. We hypothesize that Plk4 is a haploinsufficient tumor suppressor in man. The purpose of this study was to investigate the mechanisms by which a 50% reduction of Plk4 leads to carcinogenesis. Methods: We established Plk4± and Plk4+/+ murine embryonic fibroblast cell lines (MEFs) in vitro. 5 of 5 Plk4+/+ MEF lines senesced at passage 7–8 as expected, while 9 of 9 Plk4±MEF lines immortalized in culture under NIH 3T3 protocol. The latter were used at passage 15–20 for in vivo tumorigenesis studies. Results: Plk4± MEFs demonstrated increased ploidy with increased passage number. By passage 4, Plk4± MEFs showed a near tetraploid karyotype as well as multiple chromosomal rearrangements and deletions, as assessed by Spectral Karyotype (SKY) Analysis. 5 out of 9 late passage Plk4± MEF lines injected into NOD-SCID mice grew tumors, with a latency of 3 to 12 weeks. By contrast, injection of Plk4+/+ MEFs yielded no tumors. Tumors generated from injection of Plk4± MEFs were harvested, cultured and submitted to SKY analysis; this showed increased clonal rearrangements and deletions compared to the parent cell lines. Conclusion: A 50% reduction in Plk4 expression results in immortalization, aneuploidy and chromosomal instability in vitro, and tumorigenicity in vivo. These results demonstrate that insufficient levels of Plk4, whether due to mutation or LOH, can contribute to the pathogenesis of HCC. No significant financial relationships to disclose.
Role of selectins in the pathogenesis of multiple myeloma
Authors: Azab A. , Azab F. , Runnels J. , Roccaro A. M. , Magnani J. L. , Sarkar A. , Anderson K. C. , Lin C. P. , Ghobrial I. M. 
Published: August 2020

11103 Background: Multiple myeloma (MM) is characterized by the disseminated involvement of the bone-marrow (BM), and its progression involves a continuous circulation of the MM cells (MMCs) in the peripheral blood and homing back to the BM. Selectins are adhesion molecules involved in the primary interaction of lymphocytes with the endothelial cells (ECs) of blood vessels. In this study we studied the role selectins in the pathogenesis of MM. Methods: We have characterized the expression of E, L and P-selectins and their ligands on MM cell lines, patient sample and plasma cells from normal subjects (NPCs). We have tested the effect of blockade of each of the selectins and selectin-ligands on the interaction of MMCs with ECs. Moreover, we tested the effect of a pan selectin inhibitor on MMCs adhesion to ECs, and trans-well (through filter) and trans-endothelial SDF1-induced migration in vitro, and characterized its effect on cytoskeletal signaling induced by the interaction of MMCs and ECs. Moreover, we have tested the effect of the inhibitor on homing of MMCs to the BM in mice using in vivo flow cytometry to detect the number of circulating cells, and in vivo confocal microscopy to directly visualize the homing. Results: All MM cell lines and patient samples had low expression of all selectins and high expression of L and P, but not E, selectin ligands. While NPCs showed low expression of all selectins and ligands. Blockade of L and P-selectin ligands reduced the interaction of MMCs with ECs in vitro, while blockade of E-selectin ligand or any of selectins did not show any effect. The pan-selectin inhibitor reduced the interaction of MMCs with ECs in vitro, did not alter their SDF1-induced migration through filter, but reduced significantly the migration through ECs. The inhibitor inhibited the activation of FAK and ERK induced by interaction of MMCs and ECs. Moreover, the selectin inhibitor extending the circulation time of MM cells in mice, and reduced the homing of MMCs. Conclusions: We found that L and P selectin ligands are highly expressed in MMCs compared to NPCs, and that those play a major role in homing of MMCs to the BM. Moreover, the pan-selectin inhibitor prevented the homing of MMCs to the BM. This provides a basis for testing the effect of the inhibitor on MM tumor progression and initiation. No significant financial relationships to disclose.