bluuebunny/crossref_metadata_2025 huggingface dataset:
Comorbidity and survival in veterans with non-Hodgkin's lymphoma (NHL).
Authors: Floyd Leroy Cordero , Srinivas Shanthi , Gonzalez Melanie L. , Chang Victor Tsu-Shih , Cogswell Janet , Einhorn Jan , Sullivan Maryann , Duque Lourdes , Paz-Querubin, Emma , McPherson Monica , Crump Barbara , Kasimis Basil
Published: March 2020

e19638

Background: Predictors of survival in patients with NHL remain an area of intense interest. Our aim was to determine whether comorbidity indices can be used to predict survival in veterans with NHL. Methods: In an IRB-approved protocol, we reviewed the records of 152 veterans diagnosed with NHL from January 1997 to December 2011 at VANJHCS. Records were reviewed for demographic, clinical and pathology data including HIV, Hep B/C, ECOG PS (PS) and Veteran status- Vietnam (V), Non-Vietnam era(non-V). PS, International Prognosis Index (IPI) and Follicular Lymphoma International Prognostic Index (FLIPI) were tabulated. Comorbidity was assessed using the Charlson Comorbidity Index (CCI), the Kaplan-Feinstein Index (KFI) and the Cumulative Illness Rating Scale (CIRS). Cox regression analysis was used to determine predictors of survival using SAS v9.2. Results: A total of 152 Veterans data were analyzed; 78 V and 74 non-V; the groups did not differ by PS, stage, beta 2 microglobulin (b2m), and HIV status, IPI/FLIPI. In univariate analysis, Grade, PS, Hgb, LDH, Alb and comorbidity indices were predictors of survival. In a multivariate analysis Grade, PS, LDH were predictors of survival in both groups. Comorbidity indices were predictors of survival only in the V group. Conclusions: Grade, PS, and LDH are predictors of survival in both groups. Comorbidity indices were able to predict survival only in the V group probably because the groups differed in age and tumor grade. Supported by New Jersey Commission Cancer Research 09-1133-CCR-EO. [Table: see text]
Prevalence of recurrent thrombosis in cancer patients with isolated gonadal vein thrombosis: A retrospective study.
Authors: Tanasanvimon Suebpong , Garg Naveen , Viswanathan Chitra , Javle Milind M. , Truong Mylene , Kaur Harmeet , Garrett Chris R.
Published: March 2020

e19645

Background: The natural history of isolated gonadal vein thrombosis (GVT) occurring in cancer patients (pts) is not well described in the medical literature. GVT in cancer pts it is of uncertain clinical significance. Methods: Utilizing a software program allowing a searchable database of radiology reports, the computerized tomographic scan (CT) reports of pts at a single cancer center from January 1, 2004 to June 30, 2011, were searched for the term “gonadal vein thrombus”. Pts included in this analysis had a diagnosis of cancer, isolated GVT (i.e. no evidence of thrombosis at another site), and at least six months of follow-up information. Results: 162 cancer pts with GVT were identified for analysis [median age 57.8 ± 12 years, right GVT 89 pts (54.9%), left GVT 59 pts (36.4%), bilateral 14 pts (8.6%)]; the majority of the pts (96, 59.3%) had a non-gynecologic malignancy. At the time of diagnosis of GVT the majority of pts were receiving chemotherapy (84, 51.9%); 70 pts (43.2%) had surgery within the prior six months (the most common being hysterectomy, 127 pts, 78.6%). The majority of pts in this study had metastatic disease (93, 57.4%) as well as active cancer (138, 85.1%, defined as GVT occurring at the time of cancer diagnosis, disease recurrence, metastatic disease, or treatment for cancer within the prior six months); median follow-up time was 22 months. A minority of pts received anticoagulation (28pts, 17.2%). Twenty-two pts (13.6%) developed a recurrent venous thromboembolic event (VTE); these events were pulmonary embolism (12 pts, 7.4%), deep venous thrombosis (5 pts, 3.1%), inferior vena cava thrombosis (4 pts, 2.5%). Median time to development of re-thrombosis was 7 months (range 2-13.5 months). Active cancer was the only risk factor significantly associated with recurrent VTE (p = 0.047); pts with prior hysterectomy had a significantly reduced risk of recurrent VTE (p = 0.036). Conclusions: Incidental isolated GVT identified in cancer pts has a high risk of recurrent VTE (13.6%). Based upon specific pts risk factors for VTE, treatment of an incidentally detected GVT in cancer pts with anticoagulation, as per guidelines for other VTE sites, may be indicated.
Vitamin D levels in patients with childhood cancer.
Authors: Tacyildiz Nurdan , oktay Tanyildiz Gulsah , Tekin Deniz , Ates Can , Dincaslan Handan , Yavuz Gulsan , Unal Emel , Kose Kenan , Ozyoruk Derya , Suskan Emine , Kucuk Omer
Published: March 2020

e20000

Background: There is increasing interest in the possible association between cancer incidence and vitamin D through its role as a regulator of cell growth and differentiation. Although there are several studies related cancer risk and prognosis of cancer, related vit D levels in adult patients there are only few recent studies in pediatric patients. Methods: Between 2010 and 2011, D Vit levels of 45 patients (25 boys, 20 girls; age range: 6 months-17 years, median: 11 years) have been compared to D Vit levels of 22 healthy children with similar age group. Patient groups were leukemias, lymphomas, bone tumors, retinoblastoma (RB), and other tumors. Kruskal-Wallis and Spearman nonparametric correlations test of SPSS has been used for statistics. Results: Although there was no statistically significant difference for vit D levels between control group (range: 7.2-22.8; median: 14.75 ng/ml) and patients (range: 5.5-40.2; median: 16.0 ng/ml),difference between patients groups were significant (Table). Patients with RB have statistically lower level of Vit D than leukemia (p:0.016) and lymphoma groups ( p: 0.047). “Other tumors group” has lower vit D levels than leukemia group (p: 0.024). Since RB and other tumors group have younger age than other patients, Spearsman’s nonparametric correlation has been performed to exclude age effect on the results and no statistically significant correlation between D vit levels and age (p: 0.779) was found, although there was an inverse correlation between age and vit D levels in patient group (p: 0.03). Conclusions: According to our preliminary results, most of the patients and healthy children have low level of Vit D. Especially patients with RB have statistically significant lower level of Vit D than other malignancies which can be subject to future studies for confirmation of our results. In addition, etiologic studies related RB may have a new area. [Table: see text]
Differences in response to imatinib between gastrointestinal stromal tumors involving the liver and tumors that do not: Experience from Nairobi.
Authors: Othieno-Abinya Nicolas Anthony , Singh Riyat Malkit , Omollo Raymond , Gichuru Gladwell Wantiru
Published: March 2020

e20504

Background: More than 60% of gastrointestinal stromal tumours (GISTs) arise from the stomach and about 20% from the small intestines. About 95% of GISTs express kit receptor tyrosine kinase (CD117) which is used for purposes of diagnosis and targeted treatment. However, kit expression alone is not specific for GIST, nor does it necessarily imply kinase activation. Poor prognostic features include involvement of the liver, and other bulky sites of disease. Methods: Patients with CD117-positive leiomyosarcomas arising in the abdomen and treated through the Glivec International Patient Assistance Program (GIPAP) clinics in Nairobi were studied. Details taken included sites involved by disease at diagnosis, stage, sites of metastases, whether the tumour had been resected or not, and outcome of treatment with imatinib. Data were summarized using proportions where the variables were categorical while mean (SD) or median (range) was used for continuous variables. Comparisons for categorical variables were done using chi square tests (or Fishers exact test for cell counts less than 5). The statistical level of significance was set to 5%. Results: In total 54 patients were included. Males were 36 (66.7%) and females 18 (33.3%). Age range was 25-86 years, median 50. Stomach was involved primarily in 22 of 47 cases evaluable (46.8%). The liver was primarily involved in 3 (6.4%) and liver metastases in 7 (15%). None of 8 patients (0%) with evaluable liver involvement regressed or stabilized on treatment for at least 6 months compared with 10 of 14 (71.4%) from the stomach, 7 of 7 (100%) from small bowel, and 7 of 13 (53.8%) with mesenteric/omental involvement. These differences were statistically significant (p = 0.001). Conclusions: Apparent lack of response by tumours involving the liver could suggest that the kit expression here may not be the factor activating the kit target in this subset of patients, or they could be of exon 9 mutation predominantly. Mutational analysis studies may shed more light in this issue.
Theranostic profiling of Ewing sarcoma (ES) and desmoplastic small round cell tumors (DSRCT).
Authors: Wen Wenhsiang , Chen Sting , Ghazalpour Anatole , Rhees Brian , McGinniss Matthew Jerome , Gatalica Zoran
Published: March 2020

e20507

Background: Ewing Sarcoma (ES)/PNET and Desmoplastic Small Round Cell Tumor (DSRCT) are sarcomas with distinct chromosomal translocations involving the EWS gene (predominately EWS-FLI1 and EWS-WT1; respectively). Their diagnosis and treatment has been difficult due to the rarity, diverse clinical presentation, overlapping histologic features and genetic complexity (Taylor BS et al, 2011). Therefore, novel approaches in clinical management are warranted. Methods: Seventeen cases (9 ES and 8 DSRCT) were analyzed using a commercial molecular profiling service (CarisTargetNow, Caris Life Sciences, Phoenix, AZ). The whole genome transcriptome analysis (29285 transcripts) was performed using HumanHT-12 beadChip (Illuminia Inc, San Diego, CA) and comparison to pooled soft tissue reference sample. Additionally, a select number of chemotherapy-predictive (theranostic) biomarkers were evaluated using immunohistochemistry, FISH, and DNA sequencing. Results: We observed 160 commonly up and 357 commonly down regulated genes between ES and DSRCT in transcriptome analysis. Cell cycle signaling, DNA replication and E2F mediated pathway genes were most commonly up regulated. In addition, higher expression of SOX-2, a recently identified cancer stem cell marker (Riggi et al, 2010), were observed in DSRCT than in ES, suggesting EWS-WT1 translocation might result in reprogramming of DSRCT to express cancer stem cells. Above threshold expression of TOP2A and TOPO1was observed in approximately 50% of all cases. Additional theranostic biomarkers (ERCC1, TS, SPARC and MGMT) showed significant inter-individual variations. No KRAS mutations or EGFR gene amplification were observed in any case. Conclusions: 1. Our transcriptome analyses might provide future therapeutic targets in cell cycle regulation, DNA replication, receptor TKI pathways and stem cell reprogramming. 2. Using multimodality test approaches, we confirmed and refined the benefits in both tumor types of individualized therapeutic assessment including predicted susceptibilities to anthracycline, irinotecan, platinum analogs, fluorouracil, and temozolomide.
Treatment practice patterns and survival among patients with metastatic soft tissue sarcoma (mSTS) in a community setting in the United States.
Authors: Chen Clara , Borker Rohit , Dhanda Rahul , Nadler Eric
Published: March 2020

e20510

Background: Although guidelines exist for use of chemotherapy in mSTS, a disease associated with extremely poor survival, data on real world treatment practice patterns and disease prognosis are lacking, especially in community settings. This study describes the treatment patterns and survival among patients with mSTS in a community setting. Methods: A retrospective cohort study using an oncology electronic medical record (EMR) database from 7/2008 to 12/2010 was conducted. Study subjects were aged ≥18 years, had mSTS, and received 1st and/or 2nd line chemotherapy during the study period. Treatment patterns were documented based on descriptive analysis of the EMR data. Kaplan-Meier estimates were calculated for reporting overall survival (OS) across lines of therapy. Results: The study sample consisted of 368 mSTS patients (mean age [SD]: 61 years [16 years]). Among those who received chemotherapy (179 patients), 178 patients (99%) received 1st line treatment while 43 patients (24%) received 2nd line treatment. Doxorubicin + ifosfamide (29%), docetaxel + gemcitabine (25%) and doxorubicin (13%) were more frequently used in 1st line treatments, while docetaxel + gemcitabine (58%) and doxorubicin liposomal (16%) were more frequently used in 2nd line treatments. The table reports the data on OS. Conclusions: There is a lack of standard of care in treatment of mSTS in the community setting in the US. The prognosis of metastatic disease, especially in the advanced lines of treatment, remains poor. [Table: see text]
Phase II study of adjuvant imatinib mesylate (IM) in patients after resection of primary gastrointestinal stromal tumor (GIST): Efficacy and safety at one year.
Authors: Yalcin Suayib , Buyukberber Suleyman , Yilmaz Ugur , Lee Po-Huang , Srimuninnimit Vichien , Lin Pin-Wen , Elserafy Mostafa M. , Manieh Moustafa , Sunpaweravong Patrapim , Istomin Yuriy , Sriuranpong Virote , Hwang Tsann-Long
Published: March 2020

e20514

Background: The mainstay treatment of primary GIST is surgery, but GIST often recurs even after complete resection. This study assessed the safety and efficacy of adjuvant IM in patients (pts) with resected GIST at intermediate/high risk of tumor recurrence. Methods: This open-label, single arm, prospective Ph II study (NCT01172548) was conducted in Asia Pacific/Africa/Russia/Middle East/Europe in eligible pts: aged ≥18 years (yrs), having had complete gross resection of primary GIST within 70 days of enrollment, with CD117 +ve, WHO PS ≤1, and no other adjuvant therapy. The planned sample size was 150 pts. Pts were to receive IM (400 mg/day, po) for 2 yrs post surgery. Dose modifications were allowed for toxicity. The primary endpoint was recurrence-free survival (RFS) rate at 2 yrs (based on CT/MRI and survival) in ITT pts (all pts who received ≥1 dose of study drug); null hypothesis based on historic data controls treated with surgery alone: RFS rate at 2 yrs of 0.7 (1 yr rate 0.98) (NCT00041197). A protocol-planned analysis at 1 yr in all enrolled pts (mITT) included safety, RFS, and overall survival. The study was approved by IRB/IEC/REB; all pts provided written informed consent. Results: Pt accrual was complete with 127 pts in the mITT population. Most pts (n=94, 74%) were <65 yrs (median 56 [19–81] yrs); female (53%). Most common primary tumor sites: stomach (n=68, 54%), small intestine (n=48, 38%), colon/rectum (n=7, 6%). Main discontinuations (n=24, 18%): disease progression (n=8, 6%); withdrawal of consent (n=7, 5%); adverse events (AEs) and lost to follow-up (each n=3, 2%). Mean RFS rate at 1 yr was 0.95 (95% CI 0.907–0.993). Most AEs were mild or moderate (Table); no deaths occurred by 1 yr. Conclusions: Adjuvant IM 400 mg/day was efficacious and had a promising safety profile at 1 yr in pts after complete resection of primary GIST. [Table: see text]
Soluble HER2 (sHER2) as a prognostic serum biomarker of non-small cell lung cancer.
Authors: Wilson Bethany Cox , Cardenas Andres , Kimbler Kimberly D. , Gal Tamas , Witt Lisa A , Arnold Susanne M. , Branscum Adam J. , Baron Andre T.
Published: March 2020

e21000

Background: The human epidermal growth factor receptor (EGFR/HER) gene family encodes four homologous tyrosine kinases that regulate cell growth and proliferation, survival, motility, and adhesion. HER2 gene amplification and receptor overexpression have been observed in < 20% of non-small cell lung cancers (NSCLC). Serum concentrations of soluble HER2 (sHER2), a proteolytic fragment of the receptor’s extracellular domain, have been associated with tumor HER2 overexpression, advanced stage, and high grade. This study evaluated serum sHER2 as a prognostic biomarker of NSCLC. Methods: Patients with primary NSCLC (n=149) were recruited at the University of Kentucky prospectively between 2002 and 2008 by the Markey Cancer Center Biospecimen Core Program and linked to the Kentucky Cancer Registry - a population-based cancer registry of the NCI Surveillance, Epidemiology and End Results (SEER) Program - to obtain clinicopathological data. Serum samples were collected prior to surgery and quantified to determine sHER2 concentrations by sp185HER-2 ELISA (Bender MedSystems Diagnostics GmbH). Non-parametric tests were performed to assess whether sHER2 concentrations differed between NSCLC patients stratified by gender, stage, histology, and grade. Cox regression analyses were performed to assess whether sHER2 concentrations, age, gender, stage, histology, and grade are associated with progression free and overall survival. Results: Mean patient age in this case series is 62 years (SD = 10.84 years) and median overall survival is 30 months. Over 97% of patients are smokers. Although serum concentrations do not differ between males and females (p = 0.12), high sHER2 concentrations portend a 72% lower relative risk of death (H.R. = 0.283, p = 0.009) and longer overall survival among men, but not among women (H.R. = 1.012, p = 0.965) adjusted for stage. Conclusions: The results show that low serum sHER2 concentration is an adverse prognosticator of overall survival in males, but not females, and suggest that low serum sHER2 could be useful for stratifying male NSCLC patients for HER2-targeted therapy. Further investigation is warranted to assess sHER2 as a gender dependent prognostic (and potential theragnostic) biomarker of NSCLC.
Modulation of regulatory dendritic cell polarization in cancer by paclitaxel.
Authors: Zhong Hua , Zhong Runbo , Han Baohui , Shurin Galina , Shurin Michael
Published: March 2020

e21001

Background: Tumors are dynamic organs, in which active processes of cell differentiation affect disease course by regulating the composition of cells at the tumor site. we hypothesize that regDC form the premalignant niche in the lung to support lung cancer development and sustain lung cancer growth and progression. Furthermore, we evaluated if paclitaxel affected regDC and paclitaxel in noncytotoxic concentrations prevents polarization of cDC into regDC.Methods: Bone marrow-derived cDC were treated with tumor conditioned media from 3LL lung cancer cell lines for 48 h, washed, depleted of GR1+ cells and added to ConA-stimulated syngeneic T cells. 3LL-induced regDC were isolated by cell sorting from the in vitro generated cultures or from lungs harvested from 3LL-bearing mice. Analysis of immunosuppressive DC revealed them as CD11clowCD11bhigh CD80lowCD86lowMHC-IIlowPDCA1negGR1neg cells. For the in vivo evaluation of the potential protumorigenic properties of regDC, sorted CD11clowCD11bhigh (regDC) and CD11chighCD11blow/neg (cDC) subsets were injected (5x105cells i.p.) into mice together with 1/15 of the minimum tumorigenic dose of 3LL tumor cells (2x104cells, i.v.). As expected, no tumor nodules were detected in lungs in mice treated with saline or cDC (0/6 mice).However, >30% of mice injected with regDC developed lung tumors, suggesting that regDC exhibit a potent protumorigenic activity in vivo. Next, we asked if paclitaxel could alter regDC formation in vivo. Paclitaxel was administered in 3LL lung metastasis bearing mice. Lymphoid and non-lymphoid tissues were harvested 3 weeks later and analyzed for regDC subsets by flow cytometry.Results: The addition of tumor conditioned converts immunostimulatory cDC into regDC that can suppress proliferation of T cells. Paclitaxel in ultra low noncytotoxic concentrations in vitro could prevent tumor-induced polarization of conventional cDC into regDC. Furthermore, administration of paclitaxel prevented formation of regDC in the lung and significantly inhibited formation of metastases .Conclusions: These data suggest that paclitaxel in ultra low nontoxic doses is able to module the tumor immunoenvironment and support the anti-cancer efficacy of cancer vaccine.
Prognostic value of post-induction PET/CT in untreated multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT).
Authors: Kostakoglu Lale , Dingli David , Beksac Meral , Zamagni Elena , Mark Tomer Martin , Chari Ajai , Elliott Brian M , Lowe Val J. , Ozkan Elgin , Nanni Cristina , Kucuk Ozlem , Fanti Stefano , Coleman Morton , Jagannath Sundar
Published: March 2020

e21006

Background: Induction with novel biological agents has significantly improved progression free survival (PFS) of MM pts. However, role and timing of ASCT is unclear and there remains a need for a practical means to predict post-ASCT outcome. Our goal was to determine the prognostic value of FDG PET/CT (PET) after induction therapy (IT) in comparison with other prognostic factors and International Myeloma Working Group (IMWG) response criteria. Methods: Prospective, multicenter study of 113 newly diagnosed MM pts undergoing IT+ASCT. IT was not controlled and consisted of 2 or 3 novel agent combinations. The tested variables to predict PFS are shown in table. Two PET scoring systems were used: Score1, positive>marrow uptake; Score2, positive>liver uptake. ROC analysis determined the SUV cut-off. Results: With a median follow-up of 29.5 mo 56 (49.6%) pts relapsed (median PFS: 24.3 mo). Results are displayed in table. Post-IT, when a "+" PET (Score2) was associated with less than a VGPR response, relapses occurred in 83% of pts vs. in only 30% when PET was "-" and pts were in CR or VGPR. Multivariate analysis revealed only ISS to be an independent predictor of PFS (p=0.014). Conclusions: Post-IT a "-" PET associated with CR+VGPR suggests a durable response. Qualitative PET evaluation using a more liberal threshold (liver) to define positivity can be used to accurately assess response in MM. These data failed to prove the post-IT IMWG and PET response to be independent prognosticators while ISS was a superior predictor. This may be attributed to inadequate sample size, nonuniform pre- and post-ASCT treatments, varying follow-up times. Further analyses with stratifying various prognostic indicators and therapy schemes in a larger population are underway to determine a definitive role for PET as a predictor of post-ASCT outcome. [Table: see text]
Sensitivity of microcavity array system for circulating tumor cells in lung cancer patients.
Authors: Kenmotsu Hirotsugu , Hosokawa Masahito , Koh Yasuhiro , Yoshino Tomoko , Yoshikawa Takayuki , Naito Tateaki , Takahashi Toshiaki , Murakami Haruyasu , Nakamura Yukiko , Tsuya Asuka , Shukuya Takehito , Ono Akira , Akamatsu Hiroaki , Watanabe Reiko , Ono Sachiyo , Endo Masahiro , Kikuhara Yoshihito , Kanbara Hisashige , Matsunaga Tadashi , Yamamoto Nobuyuki
Published: March 2020

e21007

Background: Epithelial Cell Adhesion Molecule (EpCAM)-based enumeration of circulating tumor cells (CTCs) has prognostic value in solid tumors such as advanced breast, colon and prostate cancers. However, poor sensitivity has been reported in non-small cell lung cancer (NSCLC). We have developed a microcavity array (MCA) system integrated with a microfluidic device for recovery and enumeration of CTsC, regardless of EpCAM expression level. This system can isolate tumor cells on the basis of differences in size and deformability between tumor and hematologic cells. Methods: Paired peripheral blood samples were collected from metastatic lung cancer patients. CTCs were enumerated by EpCAM-based immunomagnetic capture (CellSearch, Veridex) and by the MCA system. In the MCA system, trapped cells were stained with Hoechst 33342, FITC-labeled anti-pan cytokeratin antibodies and PE-labeled anti-CD45 antibodies for subsequent imaging analysis. CTCs were defined as cells with round to oval morphology, a visible nucleus, positive staining for pan-cytokeratin and negative staining for CD45. We evaluated the sensitivity of the MCA system for detecting CTCs in lung cancer patients compared with the CellSearch system. Results: Twenty-two metastatic NSCLC patients and 13 small-cell lung cancer (SCLC) patients were enrolled into this study between April 2011 and January 2012. CTCs were detected using the MCA system in 17 of 22 NSCLC patients (count ≥1 per 7.5 ml) compared with 9 of 22 patients using CellSearch (p=0.013). On the other hand, CTCs were detected using MCA in all 13 SCLC patients compared with just 9 of 13 patients using CellSearch (p=0.012). More CTCs from NSCLC patients were detected by the MCA system (median 13, range 0-313 cells/7.5ml) than by the CellSearch system (median 0, range 0-37 cells/7.5ml) demonstrating statistical superiority (p=0.002, Wilcoxon test). Conclusions: Our results suggest that the MCA system is potentially superior to the CellSearch system for detecting CTCs in lung cancer patients and further clinical development should be considered.
Exposing the criminal record of every blood sample: Use of SOMAmer technology and sample mapping vectors to mitigate false biomarker discoveries in lung cancer.
Authors: Gill Rosalynn D , Williams Steve , Ostroff Rachel , Brody Ed , Stewart Alex , Pass Harvey , Rom William , Weissfeld Joel L. , Siegfried Jill , Mehan Mike
Published: March 2020

e21012

Background: Biomarker discovery studies may fail to translate to the clinic because the study population does not match the intended clinical use or because hidden preanalytic variability in the discovery samples contaminates the apparent disease specific information in the biomarkers. This can arise from differences in blood sample processing between study sites or in samples collected differently at the same study site. Methods: To better understand the effect of different blood sample processing procedures, we evaluated protein measurement bias in a large multi-center lung cancer study using the >1000 protein SOMAscan™ assay. These analyses revealed that perturbations in serum collection and processing result in changes to families of proteins from known biological pathways. We subsequently developed protein biomarker signatures of cell lysis, platelet activation and complement activation and assembled these preanalytic signatures into quantitative multi-dimensional Sample Mapping Vector (SMV) scores. Results: The SMV score provides critical evaluation of the quality of every blood-based sample used in discovery and also enables the evaluation of candidate protein biomarkers for resistance to preanalytic variability. Despite uniform processing protocols for each clinic, the SMV analysis revealed unexpected case/control bias arising from collecting case and control serum from different clinics at the same academic centers, an effect that created false or bias-contaminated disease markers. We therefore used the SMV score to remove bias-susceptible analytes and to define a well-collected, unbiased training set. An improved classifier was developed, resistant to common artifacts in serum processing. Conclusions: . The performance of this classifier to detect lung cancer in a high-risk population is more likely to represent real-world diagnostic results. We believe this approach is generally applicable to clinical investigations in all fields of biomarker discovery and translational medicine.
Correlation of markers of oxidative damage and circulating IL6 levels with survival following treatment with bevacizumab in metastatic colorectal cancer patients.
Authors: Noonan Sinead , Martin Petra , Maguire Aoife , Biniecka Monika , Tosetto Miriam , Hyland John , Sheahan Kieran , O'Donoghue Diarmuid , Mulcahy Hugh , Fennelly David , O'Sullivan Jacintha
Published: March 2020

e21024

Background: Angiogenesis drives cancer growth, tumour progression and metastases. Hypoxic tumours initiate recruitment of their own blood supply and enhance expression of vascular endothelial growth factor (VEGF). Bevacizumab is a recombinant humanised monoclonal anti-VEGF antibody which prevents VEGF binding to its receptors and improves overall survival in metastatic colorectal cancer patients when combined with cytotoxic chemotherapy. Currently, Bevacizumab is indicated as a first line treatment in all metastatic colorectal cancer patients, however only 38-44% of these patients will have a response to treatment. There is no good marker to predict treatment response. The role of inflammation and oxidative damage in driving angiogenesis and clinical response to bevacizumab is poorly understood. The aim of this study was to investigate the levels of oxidative damage and inflammation in the tissue and in the circulation of patients receiving Bevacizumab. Methods: Tissue from 80 patients was constructed into tissue microarrays (TMAs) and screened by immunohistochemistry for the levels of a DNA adduct marker 8oxodG and a lipid peroxidation marker 4HNE in addition to Ki67 status. Serum was screened for 8oxodG, 4HNE and the inflammatory cytokines; IL1β, IL6, IL8, TNFα and pro-angiogenic factors; Ang 2, TGFβ, VEGF using ELISA. Data was correlated with patient survival following Bevacizumab treatment. Results: 8oxodG stromal nuclear positivity significantly correlated with survival following bevacizumab (p=0.035) and this was independent of cell proliferation status. Following multivariate analysis, circulating IL6 levels also significantly correlated with survival following bevacizumab treatment (p=0.01). Using linear regression, circulating levels of 8oxodG correlated with IL6 levels (p=0.016). Circulating Ang 2 levels correlated with IL6 (p=0.006). Conclusions: We have shown for the first time that levels of a DNA adduct marker 8oxodG and circulating levels of IL6 correlate with survival in metastatic patients receiving Bevacizumab.
Concordance of histology type between synchronous and metachronous contralateral breast carcinoma: Is there susceptibility for breast cancer of particular histology?
Authors: Tomasevic Zorica , Gavrilovic Dusica , Tomasevic Zoran , Kolarevic Daniela
Published: March 2020

e21030

Background: Contra-lateral breast cancer (CBC) is considered to be the most frequent new malignancy after primary breast cancer (PBC) However, there are few reports whether the histology and other major molecular characteristics differs between PBC and CBC. The aim of this paper is toevaluate and compare PBC/CBC histology according to the time to CBC development. Also, age at CBC and major molecular characteristics (tumor grade, estrogen/progesterone receptors, HER2) have been analyzed. Methods: A cohort of 113 patients with CBC, without distant metastases, has been prospectively registered during 28 months. Patients are divided in 2 groups according to the time of CBC diagnose: 1. Synchronous, if the CBC (S-CBC) was diagnosed either simultaneously or within 6 months after PBC; 2. Metachronous (M-CBC) if CBC was diagnosed > 6 months after PBC. Results: Results are presented in Table 1. Median age was calculated at the time of CBC diagnose. Patient with S-CBC are median 7 years older than patients with M- CBC that is statistically significant difference (p-0.007) S-CBC is more likely to be of the same histological type (76%) than M-CBC (56%) (p 0.006) In the whole analyzed group, and each subgroup separately, lobular carcinoma is registered in higher percentage (41%) than expected (~20%) For all other analyzed BC characteristics, statistical difference was not confirmed, however ~ 25% of specimens were not available for testing. Conclusions: Although it is still unclear what could be the clinical significance of these findings, genetic susceptibility to particular histology type of BC might be reasonably speculated. [Table: see text]
Plasma TS mRNA expression as a potential predictive biomarker for pemetrexed and raltitrexed in gastric cancer.
Authors: Liu Baorui , Shen Jie , Wang Hao , Wei Jia , Yu Lixia , Xie Li , Qian Xiaoping , Zou Zhengyun , Guan Wen xian
Published: March 2020

e21034

Background: Plasma mRNA opens up new investigational opportunities and has great potential for use in disease and treatment assessment. Pemetrexed and raltitrexed are novel water-soluble quinazoline folate analogues and act as direct and specific TS inhibitors. Although TS expression levels detected in tumor have shown potential in predicting sensitivity to those two chemotherapeutic agents, current knowledge is limited on the role of plasma TS mRNA as a predictive biomarker. The aim of this study was to investigate the association between plasma TS mRNA expression and in vitro chemosensitivity to pemetrexed and raltitrexed in gastric cancer. Methods: 150 freshly-removed gastric tumor specimens and corresponding blood samples before surgery were collected. Pemetrexed and raltitrexed sensitivity was determined by histoculture drug response assay (HDRA) procedures. Plasma and tumor TS mRNA expression level were determined by quantitative RT-PCR. Results: A significant correlation was observed between plasma and tumor TS mRNA expression levels (rho=0.665, P<0.001). Plasma TS expression level was negatively correlated with in vitro sensitivity to pemetrexed and raltitrexed in gastric cancer (pemetrexed-sensitive sub-group: 0.90, 95% CI: 0.66-1.16; pemetrexed-resistant sub-group: 1.82, 95% CI: 1.38-2.26, P<0.001; raltitrexed-sensitive sub-group: 0.91, 95% CI: 0.64-1.22; raltitrexed-resistant sub-group: 1.62, 95% CI: 1.06-2.17, P=0.013). There was no significant association between clinical characteristics and plasma TS mRNA levels or in vitro chemosensitivity. Conclusions: Our results indicated that plasma TS mRNA expression could be a prominent predictive biomarker for raltitrexed in gastric cancer, enabling the development of ‘‘real-time’’ individualized chemotherapy while tumor progression.
Importance of serum VEGF and basic FGF levels in determining response to treatment and survival in patients with metastatic colorectal cancer.
Authors: Keskin Muge , Ustuner Zeki , Dincer Murat , Etiz Durmus , Celik H.Eray , Gulbas Zafer
Published: March 2020

e21050

Background: Colorectal cancer has an important place in worldwide death from cancer causes. Angiogenesis, in which angiogenic factors such as VEGF and basic FGF have a key role, is an important factor in patient survival with respect to progression and metastatic spreading in colorectal cancer. In this study, we aimed to determine that whether serum VEGF and bFGF pre- and post-treatment serum levels are decisive in evaluating response to treatment and progression in metastatic colorectal cancer (mCRC) patients treated with FOLFIRI-bevacizumab. Methods: In 33 mCRC patients treated in our department serum VEGF and bFGF levels were monitored in the beginning of treatment and until progression during FOLFIRI-bevacizumab treatment before 4.-, 8.- and 12.-regimens. Serum levels of VEGF and bFGF were assssed using the quantitative sandwich enzyme immunoassay technique. Results: In our study serumVEGF and bFGF levels were significantly higher than the healthy controls (p<0.001). We found that the patients with pre-treatment high serum bFGF levels have significantly short PFS and with pre-treatment high serum LDH levels have significantly short overall survival (OS). In patients with pre-treatment low serum VEGF value (< 147.79 pg/ml) had significantly longer OS (27.93 vs 23.27 mounts, P:0.026) in metastatic rectum cancer. In multivariate analysis were found to be prognostic factors VEGF levels and side of tumor for PFS and VEGF levels and whether to be operated of tumor for OS. Conclusions: Serum VEGF level was detected to be one of the factors that determine PFS and OS in mCRC. Pretreatment serum bFGF levels were determined PFS and monitorization of serum bFGF during treatment was found to be releated to response to treatment. Pretreatment serum LDH level was detected to determine OS in metastatic CRC. Although there was no statistical significance, in mCRC patients, whose pretreatment serum VEGF were high, PSK was longer with bevacizumab treatment. The important of pretreatment high serum VEGF level to select for treatment of bevacizumab will be planed in metastatic CRC requires to be confirmed in comprehensive, prospective studies.
The influence of mammaplasty on axillary lymphatic drainage patterns and sentinel lymph node detection: A 40-patient prospective study including the 20 first patients of the preliminary study.
Authors: Gremillet Eric , Soler Claude , Bouteille Catherine , Steiner Aline , Geissler Benjamin
Published: March 2020

e21056

Background: In the field of sentinel lymph node (SLN) for patients with previously breast surgery, opinions are not definitive. On the first hand, the ASCO in 2005 recommended that SLN biopsy should not be performed in patients with previous mammaplasty or axillary surgery, but, on the other hand, the same panelists of the ASCO guideline suggested that a preliminary lymphoscintigraphy (LSG) could be done when considering a SLN biopsy in patients with previous mammaplasty, with the objective of verifying the integrity of axillary nodes. We started a prospective study in January 2009, to evaluate the location of sentinel lymph node (SLN) before and after mammaplasty. The preliminary results of the first 20 patients were presented in June 2010 (Chicago, ASCO), however it was to be necessary to have more patients to validate these encouraging results. The results of additional study is presented here. Methods: 40 patients who underwent mammaplasty were evaluated by LSG acquired with a SPECT-CT immediately after intradermal periareolar injections of 99mTc -labelled sulphur colloid at two time points: before mammaplasty (Pre-LSG) and between 40 to 60 days after mammaplasty (Post- LSG). Results: The localisation of hot SN was evaluated as in the first study, using the SPECT-CT images : - antero-posterior distance was estimated in centimeter from SLN region to dorsal vertebrae spine center. - SLN’s coronal position was compared to rib cage. The average value of 40 antero-posterior distance before and after surgery was 14.2 vs 14.4 centimeters, in the preliminary study it was 13.6 vs 13.8 centimeters, the difference keeps the same between 2 studies (2 millimeters). As in the first study, SN was in the same position in relation to grill rib. The binomial test did not show statistical difference in lymphatic drainage patterns between Pre-LSG and Post-LSG. Conclusions: after evaluating the impact of the previous mammaplasty surgery on the SLN position, we observed that surgery did not modify lymphatic mapping and thus that it may be possible to propose SLN biopsy even after mammaplasty. This study confirms the results of our preliminary study.
Differential frequency of breast cancer molecular profiling by socioeconomic status in San Diego, California.
Authors: Vosganian Gregory Sumpao , Rosenberg Joshua Daniel , Verman Radha , Waalen Jill , Mason James R.
Published: March 2020

e21061

Background: Previous reports demonstrate inferior outcomes for cancer patients of low socioeconomic status (SES). The development of breast tumor molecular profiling has optimized anticancer therapy but its effect on outcome for those with barriers to care is unknown. Methods: Breast cancer patients appropriate for OncotypeDX testing (Genomic Health, Inc) were identified from The Scripps Health Tumor Registry. High SES was defined as patients residing in zip codes with a median household income in the top quartile for the county according to the San Diego Association of Governments. Low SES was defined as patients residing in zip codes with median income in the bottom quartile or with Medical as primary insurance. The frequency of OncotypeDX testing, result, therapy prescribed, relapse and cancer specific death rates are reported. Statistical analysis was performed by unpaired t-test; p values≤0.05 were considered significant. Results: 2,192 early-stage breast cancer patients were identified; 167 met criteria. Patients were younger (p<0.0001) and a lower rate of OncotypeDX testing was noted in the low SES group (p=0.028); no difference in stage was observed. All patients were prescribed anti hormone therapy but the low SES group received chemotherapy more frequently (p=0.0075). No difference in relapse rate and no deaths attributable to cancer were noted. Conclusions: We observed a lower rate of OncotypeDX use in the low SES cohort. While the cause is unclear, the higher rate of chemotherapy use in this group may represent overtreatment. Determining a survival impact attributable to this difference requires longer follow-up. Our data demonstrate the need for prospective analysis of tumor profiling use in low SES individuals to ensure early stage breast cancer patients receive optimal therapy. [Table: see text]
Differential gene expression associated with the tropism between hepatic and pulmonary metastases in colorectal cancers.
Authors: Kim Sung-Hyun , Choi So-Jung , Lee Jinseon , Kim Jhingook
Published: March 2020

e21062

Background: In metastatic colorectal cancers tumor cells were already disseminated, prior to surgical resection of the primary tumors, but micrometastases remain dormant until proper colonization mechanisms are activated. Specific aims of this study are, 1) to examine the colonization pathways and genes newly activated in metastatic tumors by longitudinal pair-wise comparisons between primary-to-metastatic tumors and 2) to understand tropism between colon-to-liver and colon-to-lung metastases at gene expression level. Methods: Total 24 tumor samples were prepared as longitudinal pairs from 6 hepatic, and 6 pulmonary cases. In these samples mRNA levels were quantitatively determined for 215 genes that were previously reported to play roles in metastasis, cytokines signaling, or angiogenesis, as provided as RT2 Profiler TM PCR arrays (PAHS-022, 024, 028). Unsupervised hierarchical clustering of Ct values and heat map analyses of DCt values were carried out using web based data analysis program, and 17-gene tropism signature was selected for stratification of the hepatic and the pulmonary metastases. Results: Ct values of 23 duplicated genes and 5 house-keeping genes showed plate-to-plate correlation of 0.92. Unsupervised hierarchical clustering of the Ct values from the Metastasis Arrays revealed that the hepatic metastases were indistinguishable from the primary colorectal cancers (n=5/6), but the lung metastases were highly diversified (n=6/6). Cytokine Array data also showed the divergence of pulmonary metastases from the primary colorectal cancers (n=6/6). Heat map analyses of DCt values from the Metastasis Arrays identified 17-gene tropism signature that was sufficient not only to distinguish the liver and the lung metastases, but also reconstitute the clustering of primary tumors with the hepatic metastases. Conclusions: Intrinsic difference existed between the pulmonary and hepatic metastases of colorectal origins among the tested samples. 17-gene tropism signature was identified, and further genomic and clinical studies are in process to validate their potentials as therapeutic targets to treat pulmonary metastases of colorectal cancers.
Plasma DNA and DNA integrity in breast cancer patients undergoing neoadjuvant chemotherapy.
Authors: Stoetzer Oliver J. , Stefan Holdenrieder , Lehner Julia , Fersching Deborah , Salat Christoph
Published: March 2020

e21067

Background: In breast cancer patients undergoing neoadjuvant chemotherapy before surgery, biomarkers for predicting the response to the therapy are highly needed. Methods: Concentrations of ALU115, ALU247 and DNA integrity were analyzed in prospectively collected plasma of 68 patients with localized breast cancer (UICC II and III), of 47 patients with metastatic breast cancer and 28 healthy women as controls. In all 68 patients with breast cancer who had completed the course of chemotherapy until surgery, DNA and tumor biomarkers CEA and CA 15-3 were evaluated concerning response to therapy (no change, NC: N=18; partial remission, PR: N=35; complete remission, CR: 15). Results: Plasma levels of ALU 115 and ALU 247 were significantly higher in patients with localized (medians 16.3 and 16.8 ng/mL) and metastasized breast cancer (22.2 and 29.8 ng/mL) than in healthy controls (1.8 and 1.9 ng/mL). However, plasma DNA integrity showed no significant differences between the diagnostic groups. AUCs in ROC curves for discrimination of localized breast cancer from healthy controls were 96% for ALU 115 and ALU 247, respectively, and 60% for DNA integrity. Concerning therapy response, pretherapeutic ALU 115, 247, and DNA integrity and also CEA and CA 15-3 were not significantly different when patients with and without remission (CR vs PR+NC and CR+PR vs NC) were compared. Conclusions: While plasma DNA levels are valuable for discrimination of breast cancer patients from controls, pretherapeutic DNA integrity provides no additive diagnostic information nor indicates response to neoadjuvant therapy.
Effect of cancer patients’ oxygen breathing during uptake phase of the study on tumor F18-FDG uptake.
Authors: Li Xiao-Feng , Kloecker Goetz H. , Sharma Vivek R. , Bhatt Geetika , Bhatt Aashish D. , Civelek Ali Cahid
Published: March 2020

e21072

Background: We previously reported that in mice, 18F-FDG uptake is higher in hypoxic cancer cells than well-oxygenated xenografts of human cancer cells. This enhanced uptake was abrogated by carbogen (95% O2 +5% CO2) breathing. We hypothesized that in clinical applications, oxygen breathing of the patients’ during the uptake phase may blunt the 18F-FDG uptake of the tumor and the liver. Methods: Overnight fasted patients with blood glucose level < 200 mg/dl were injected with < 14.0 mCi of 18F-FDG, and PET/CT scans were performed at 60 -80 minutes later with a Siemens PET/CT scanner. Group-1 is consisted of 11 patients who were breathing room air only, without any additional oxygen during the procedure. Group-II consisted of 12 patients who were breathing oxygen during the uptake phase. Group-III consisted of 10 patients who were breathing oxygen only at the time of scanning and not during uptake phase. Tumor FDG activities of the groups were not compared since no paired data (with and without oxygen in same patient) was available. Thus, Liver FDG activity of the patients in each group were measured as surrogate to the oxygen effect on tumor, and expressed as Liver SUV max and Liver SUV average values, and they were compared to each other to determine the statistical significance. Results: Both liver SUV max and SUV average values were significantly lower in Group-II patients who were breathing oxygen during the uptake phase compared to Group–I and Group-III (P< 0.05 for both). Liver SUV max and SUV average values were not significantly different between Group–I and Group–III. In one patient who had a paired scans with and without O2 during the uptake phase showed a significant FDG activity of the tumor when he was breathing O2 during uptake phase. Conclusions: In cancer patients, O2 breathing during FDG uptake phase may significantly blunt 18F-FDG uptake, thus, in cancer patients this may decrease the accuracy of the FDG PET/CT for the detection, staging of the disease and the assessment of the therapy effect. [Table: see text]