bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards qualification of FDG PET as biomarker of response to neo-adjuvant therapy: A meta-analysis.
Authors: Vincent Andrew D. , Rizivi Saiyada N. F. , van Tinteren Harm , Riphagen Ingrid , Hoekstra Otto S. 
Published: March 2020

e22128 Background: For FDG PET to qualify as a biomarker of response to cancer therapy beyond proof of principle, the evidence should be aggregated. Methods: A systematic literature search (Jan 1995-May 2011) for studies in solid extracerebral tumors with distinct cohorts of n≥10 patients, PET before and after cytotoxic neoadjuvant systemic therapy (with or without radiotherapy), dichotomized histopathological (PA) response. For model development we selected studies reporting individual or dichotomous aggregated level data, and performed bivariate SROC meta-regression. Results: 52 studies were identified, comprising data from 1,710 patients: rectal (32%), esophageal (21%), sarcoma (20%), breast (13%) and other cancers (14%). Most PET measures were SUVmax (65%) and other SUV measures (32%). Treatment type ChT (38%) and ChRT (62%); 46% were PA responders. The meta-regression indicated a weak increase in specificity for chemotherapy studies over chemoradiotherapy studies (p=0.08), however this disappeared after adjusting for publication bias. High baseline uptake rates improved diagnostic sensitivity (p=0.01). The SROC-AUC after adjusting for publication bias was 0.77. Maximal sensitivity and specificity was achieved with a PET reduction of 60%. Conclusions: There is a moderate association between FDG-PET change and histopathological response. This relation appears to be a function of baseline uptake, which may (at least in part) relate to repeatability issues.
DNA repair gene promoter methylation in non-small cell lung cancer (NSCLC) patients treated with DNA damaging agents.
Authors: Buckingham Lela , Pelkey Gregory , Fidler Mary J. , Bonomi Philip D. 
Published: March 2020

e22130 Background: Approximately 75% of NSCLC patients are advanced at time of diagnosis. Treatments include regimens of DNA-damaging and alkylating agents. Previous in vitro studies have shown that loss of BRCA1 and BRCA2 function through promoter methylation increases sensitivity to sapacitabine, suggesting that tumor cells may be protected by repair systems including BRCA-RAD50 and MGMT pathways induced by DNA damage. The purpose of this study is to investigate the effect of DNA repair gene promoter methylation on outcome of NSCLC patients treated with DNA damaging agents. DNA repair gene promoter hypermethylation may sensitize tumor cells to DNA damaging agents. Methods: The patient group of 240 patients included 135 early stage and 105 late stage (III/IV) cases. Chemotherapy regimens of late stage patients included carboplatin, cisplatin and gemcitabine, as well as other non-DNA damaging agents. Mean overall survival (OS) was 43.7 months. DNA was extracted from micro-dissected primary tumor, bisulfite converted and assessed by pyrosequencing to quantify methylation of cytosine nucleotides along the MGMT, BRCA1 and BRCA2 promoters. Results: Overall average methylation values were 8.4%, 7.3% and 8.3% for MGMT, BRCA1, BRCA2 respectively (compared to 3.2%, 3.6% and 7.3%, respectively, in nonmalignant lung tissue). Percent promoter methylation levels were not significantly correlated with age, gender, smoking status nor histology, with the exception of higher MGMT promoter methylation in smokers. Hypermethylation (greater than 10%) of BRCA1 and BRCA2 promoter was not significantly associated with survival in late stage patients (6.6 mos vs 6.8 mos; p=0.533) in this patient group, however, superior survival was observed with BRCA2 promoter hypermethylation when early stage patients were included (29.3 mos vs median not reached; p=0.045). Promoter hypermethylation of MGMTwas significantly associated with lower five-year survival rate in early stage patients (p=0.022). Conclusions: These data suggest epigenetic control of DNA repair gene expression can affect response to therapy. Further studies on specific treatment regimens will be required to definitively assess these effects.
The key role of correlation between MR spectroscopy choline peak and calcium sensing receptor for breast cancer: Diagnosis by a 3T MR scanner.
Authors: Baio Gabriella , Valdora Francesca , Pace Daniele , Salvi Sandra , Villosio Nicolo , Truini Mauro , Calabrese Massimo , Neumaier Carlo Emanuele 
Published: March 2020

e22132 Background: The Ca2+-sensing receptor (CaSR) regulates the Ca2+ signaling and its expression is present in both normal and malignant breast tissues. Recently, we demonstrated in a pre-clinical setting the CaSR expression in breast cancer mouse model by manganese enhanced MRI (Baio G et al. Eur Rad 2011). Alteration in choline phospholipid metabolism as detected by MRI, is a common feature of breast and many other cancer cells or tumors. Since CaSR-ChoK signaling plays an important role in breast cancer, we compared the MRS (MR spectroscopy) choline peak by a 3T MR scanner between calcium sensing receptor positive and negative breast cancers. Methods: Breast MRI of 16 consecutive patients with breast lesions were performed by a 3T MR and MRS findings were defined as positive by the visual inspection for the presence or the absence of choline peak. MRS imaging were compared with histologic findings and the pattern of CaSR by immunohistochemistry. The immunohistochemical results were qualitatively classified according to intensity and pattern of the staining, using a 6-point scale to score the intensity of the CaSR expression (0, absent; 5, intense, widespread expression). Results: A choline peak was present in 10 of 15 malignant lesions and the CaSR expression was between 3 to 5 score at immunohistochemestry analysis (p<.0006). In 4 of 15 malignant lesions the choline peak was absent or not consistent at the visual analysis with a CaSR patterns of 1-2. In one benign lesion (papillary hyperplasia), the choline peak was consistent and the CaSR pattern was with score 3. Conclusions: In this study we evaluated if MRS presence or absence of choline peak well correlated with CaSR positive and negative breast cancers. We observed a choline peak with an high level expression of CaSR (score 3-5) in 67% of the breast lesions, while in 27% of the lesions the choline peak was absent with a low CaSR expression (score 1-2). These preliminary results support the hypothesis that CaSR represents an important role in the production of choline in breast cancer, determining an increase of his production when CaSR is expressed at high level and implicating and absence of choline peak when CaSR is not expressed.
A single-center experience with CELLSEARCH system circulating tumor cell test on patients with metastatic breast cancer.
Authors: Montero Alberto J. , Eapen Sara , Andrews Ryan M. , Gorin Brian 
Published: March 2020

e22135 Background: Clinical studies have shown that circulating tumor cell (CTC) detection via the CELLSEARCH assay is a validated prognostic marker that is a predictor of overall survival (OS) in metastatic breast cancer (mBC) patients. By analyzing real-world observational data in one center, we evaluated the impact of CTC testing on predicting OS. Methods: Electronic medical records (EMR) were used to identify patients who were: (i) women > 18 years diagnosed with mBC on or after their date of registration, (ii) registered to the EMR system on or after 4/1/2010, and (iii) followed for at least 2 months from the time of metastases. Patients who had CTC testing were required, on average, to have at least 1 valid CTC test result every 3 months. OS from the date of initial diagnosis of metastases among mBC patients with CTC testing was compared to a cohort of patients without CTC testing (non-CTC) using a Cox model controlling for covariates such as age, race, hormone receptor status, and scanning frequency. Results: Mean (SD) ages of CTC (N=79) and non-CTC (N=1,146) patients were 65 (13) and 64 (14) years, respectively. ER or PR+ patients comprised 67% of the CTC population, and 64% of the non-CTC population. The majority of patients in both cohorts were Caucasian (89% - CTC, 57% - non-CTC). The Cox model showed that the group where CTC testing occurred had a statistically significant 40% reduction in risk of death (HR=0.60, p-value=0.03); this reduction was even greater among ER or PR+ patients who received CTC testing compared to those who did not (51%, HR=0.49, p-value=0.03). Conclusions: This retrospective analysis shows that the CTC population had a better prognosis than the non-CTC population. Thus, the assessment of CTCs could be associated with improved monitoring and prediction of cancer progression, and improved evaluation of response to therapy in mBC patients, possibly guiding more informed care decisions. The reliance on a single center and the relatively small number of CTC patients limits the ability to rule out other potential confounders in the analysis. Further studies using larger CTC samples and data from other centers with CTC testing are needed to verify and better understand this result.
Correlation between biopsy type and insufficient tissue availability for biomarker testing in five solid cancer types.
Authors: De Richter Pieter , Ilacqua Jackie 
Published: March 2020

e22136 Background: Limited tissue availability is a known barrier to conducting biomarker testing on cancer tissue specimens. It has been assumed that the frequency of insufficient tissue being available is correlated with type of tissue biopsy performed, but this has not previously been quantified across multiple cancer types. Methods: A panel of pathologists in the US (N=90) were asked to report on recent cancer tissues they prepared/handled for biomarker testing. The physicians were asked to report on the cancer type, biopsy method, molecular diagnostics tests conducted, and whether sufficient tissue was available for all requested tests. If insufficient tissue was available, they were asked to report on which tests they were unable to perform as a result. All data was collected through an online survey between August and November 2012. Results: In total, 99 breast cancer samples, 85 NSCLC samples, 60 CRC samples, 30 gastric cancer samples and 40 melanoma samples were reported on. Insufficient tissue was available in 5 (6%) of all NSCLC samples, 2 of which were obtained through fine needle aspirations (14% of all FNAs), a further 2 through core biopsies (5%), and a further 1 through a bronchoscopy (8%). Insufficient tissue was available in 1 (1%) of all breast cancer samples (core biopsy, 1% of all core biopsies), 1 (3%) of all melanoma samples (core biopsy, 13% of all core biopsies) and 1 (2%) of all CRC samples (core biopsy, 11% of all core biopsies). Conclusions: Insufficient cancer tissue for biomarker testing occurred across 4 out of 5 cancer types reported on, though was rare (<5%) in cancers other than NSCLC. The majority of tissue samples in which insufficient tissue was present were acquired through core biopsies (67% of all cases) or FNAs (22% of all cases).
Effect of tumor-treating fields on DNA repair in cancer cell lines.
Authors: Kirson Eilon David , Giladi Moshe , Schneiderman Rosa S. , Porat Yaara , Munster Mijal , Weinberg Uri , Palti Yoram 
Published: March 2020

e22138 Background: TTFields Therapy is an antimitotic treatment modality approved by FDA for the treatment of patients with recurrent glioblastoma (GBM). TTFields act by disruption of spindle microtubule arrangement during metaphase and interference with cytokinesis during anaphase and telophase. These effects are the result of rotation of charged and/or polar macromolecules in the direction of the applied antimitotic fields. We hypothesized that the negatively charged, double stranded DNA fragments induced by ionizing radiation (RT) or ultraviolet light (UV) undergo similar rotation. Double strand break repair relies on proper alignment of the strands during the process of homologous recombination. Thus application of TTFields during the DNA repair process holds the potential of interfering with normal DNA repair. Methods: Cancer cells (786-O renal cell carcinoma) were exposed to TTFields for various durations up to 4 hours after UV or RT treatment. The extent of DNA repair over time was evaluated using the alkaline comet assay (Trevigen, USA). This assay allows the computation of the relative proportion of intact DNA strands and DNA fragments in individual cells after inducing DNA breaks. Results: Exposure of UV treated cells to TTFields for 4 hours led to a significant increase in the content of DNA fragments per cell compared to the content without TTFields exposure (45 + 14%; p=0.012). This increase was accompanied by a significant decrease in the intact DNA content per cell compared to the content of cells not exposed to TTFields (47 + 14%; p=0.005). Inhibition of DNA repair was apparent 1-4 hours after irradiation depending on the extent of DNA damage. Similar results were seen after exposure of the cultures to 2Gy RT (17% increase in DNA fragment content and 14% decrease in intact DNA content at 4 hours). Interestingly, while TTFields did not lead to any DNA damage when applied alone, the application of TTFields for one hour after UV exposure led to a 27 + 29% (p=0.02) increase in the extent of the DNA damage (fragment content). Conclusions: This is the first demonstration that, in addition to its known anti-mitotic effect, TTFields Therapy also inhibits DNA repair and may thus lead to an increase in the cytotoxic effects of therapeutic irradiation.
Demonstration of the efficacy of compound CFAK-C4 targeting FAK-VEGFR3 protein-protein interaction in gastric cancer.
Authors: Kurenova Elena V. , Sanghera Sartaj Singh , Liao Jianqun , Yemma Michael , Cance William G. 
Published: March 2020

e22143 Background: While the emerging data strongly suggest that FAK is an excellent target for developmental therapeutics of cancer, kinase inhibitors of FAK have shown crossreactivity with other protein kinases and toxicity in preclinical and clinical studies. It is known that FAK acts pleiotropically, as a kinase and as a scaffolding protein, and our goal is to explore targeting the scaffolding function of FAK to inhibit protein-protein interactions important for tumor progression. Previously, we have shown that FAK physically interacts with VEGFR3 and we identified small molecule inhibitor CFAK-C4 that targets this site of interaction. Both of these kinases are overexpressed in gastric cancers and were found to be independent poor prognostic factors. The prognosis of patients with gastric cancer remains unfavorable and molecular based treatments are necessary for a potential breakthrough in the therapy of this disease. We hypothesize that FAK-VEGFR3 interaction provides essential survival signals for gastric tumor growth and that simultaneous inhibition of these signals will inhibit tumor progression. Methods: Effects of CFAK-C4 on gastric cancer cell lines AGS and NCI-N87 were examined by MTT assay (viability), colony formation assay and Western blotting (phosphorylation, apoptosis). Subcutaneous mouse model was used to demonstrate effect of CFAK-C4 in vivo. Results: CFAK-C4 specifically blocked phosphorylation of VEGFR3 and FAK, directly inhibited cell viability (p<0.05), increased cell detachment and inhibited colony formation in a dose-dependent manner (range 1-100µM). CFAK-C4 (50mg/kg, IP) effectively caused tumor regression in vivo, when administered alone and its effects were synergistic (p<0.05) with chemotherapy. In vivo effects of C4 were confirmed by a decrease in tumor FAK and VEGFR3 phosphorylation, and disruption of their complexes. Conclusions: In this study we have shown that CFAK-C4 inhibits FAK-VEGFR3 signaling in gastric cancer cells and affects tumor growth. This result demonstrates that targeting the scaffolding function of FAK is a unique approach of highly-specific molecular-targeted therapy and can be used to develop oral-based cancer therapeutics.
Changes in shedding of soluble tumor necrosis factor receptors (sR1/R2) and in dynamic MRI as early predictors of outcome with NGR-hTNF.
Authors: Zucali Paolo A. , Simonelli Matteo , De Vincenzo Fabio , Santoro Armando , Lambiase Antonio , Bordignon Claudio 
Published: March 2020

e22145 Background: Dose-response curve of NGR-hTNF, a selective antivascular agent, is typically biphasic with activity shown either at low dose (LD) or high dose (HD). Receptor shedding may block drug activity. Vascular effects at LD are characterized by early vessel stabilization and late vessel damage, while at HD by rapid vessel disruption. Methods: 60 pts (median age: 61; M/F: 44/16; PS 0/≥1: 25/35; median prior lines: 3) received in 2 ph I trials NGR-hTNF at LD (0.2-1.6 µg/m2; n=14) or HD (60-325 µg/m2; n=46) every 3 weeks. We tested the impact of early changes (post 1st dose) in baseline-normalized plasma receptor levels (n=60) and in DCE-MRI-assessed Ktrans (n=49) on treatment effect, including disease control (DC, rate of pts progression free at 6 weeks by RECIST criteria) and progression free survival (PFS). Results: Baseline receptor levels were not related to outcome. Post-dosing levels of sR1 (median, 4.6 ng/mL; interquartile range, 2.8-5.7) and sR2 (8.6; 4.5-10.7) increased with dose (p<.0001 for both), with median values of sR1 (0.3) and sR2 (0.5) at LD being significantly lower than those of sR1 (4.9) and sR2 (9.6) at HD (p<.0001 for both). Using as cutoff the 1st quartile, low sR1 levels (≤2.8 ng/mL) correlated with improved DC (OR=4.9; p=0.01) and PFS (HR=0.30; p=.003). In low vs high groups, median DC duration was 7.4 vs 2.9 months and 6-month PFS was 29% vs 0%, respectively. By adjusting for baseline covariates (age, sex, PS and prior lines), low sR1 levels remained independently associated with better DC (p=.02) and PFS (p=.008). Similar effects were noted for sR2. Levels of sR1 (r=-0.35; p=.01) and sR2 (r=-0.27; p=.07) inversely correlated with early fractional decreases in Ktrans, which resulted in median values unchanged after LD (4%; p=.73) and reduced after HD (-32%; p=.009). However, Ktrans significantly declined over time after both LD (-24%; p=.04) and HD (-44%; p=.001). Early changes in Ktrans did not relate with DC as defined by RECIST, but smaller decreases in Ktrans were associated with longer PFS (HR=0.56; p=.04). Conclusions: NGR-hTNF at LD is associated with better outcome than at HD likely due to early effects that involve minimal receptor shedding and vessel stabilization. Clinical trial information: NCT00878111-NCT00914628.
Secreted alkaline phosphatase defined by ms17-57 mab and ectopically expressed on the surface of GI cancer cells as a potential therapeutic target.
Authors: Feng Runhua , Li Ming , Gao Jianpeng , Chen Xuehua , Sun Jianyu , Wang Yuling , Zhang Dongqing , Feng Zhenqing , Liu Binya , Zhu Zhenggang , Lu Mason , Lee Jeffrey Edwin 
Published: March 2020

e22169 Background: There remains considerable interest in generating monoclonal antibody (mAb) directed against specific tumor targets for antigen (Ag) discovery, diagnosis and therapy. In this investigation, mAbs were generated against potentially novel Ags on the cancer cell surface using a flow cytometry-high throughput screening (FACS-HTS) strategy. Methods: Mixed live cells from four human gastric cancer (GC) cell lines were used as the immunogen in A/J mice; Sixteen highly positive hybridoma colonies were selected via FACS-HTS using a total of 20,000 colonies in sixty-seven 96-well plates against live cells (mixed human GC cells versus normal human PBMC). The purified ms17-57 and control commercial ALP mAbs were used to confirm the target Ags, which were identified as alkaline phosphatases (ALPs) expressed on the GC cell surface through a combination of western blot, immunoprecipitation and mass spectrometry (MS). Results: MS identified the Ags recognized by ms17-57 to be two variants of a secreted ALP, PALP and IALP (Placental and Intestinal ALP). These proteins belong to a hydrolase enzyme family responsible for removing phosphate groups from many types of molecules (i.e. dephosphorylation). Immunohistochemical staining using ms17-57 demonstrated significantly higher staining of gastrointestinal (GI; gastric and colorectal) cancer tissues than normal (non-cancer) GI control tissues (P<0.01), and confirmed binding of ms17-57 to be restricted to a functional epitope expressed on the cancer cell surface. Proliferation assay using the PALP/IALP-expressing GC cell lines demonstrated that ms17-57 inhibited cell growth by 32±8%. Transwell cell migration assay documented that ms17-57 can inhibit PALP/IALP-expressing GI cancer cell migration. Conclusions: Our findings indicate that PALP and IALP can be ectopically expressed in the extracellular matrix of GI cancers, and that ms17-57 directed against PALP/IALP identified through HTS can inhibit GI cancer cell growth and migration. This investigation provides an example of identification of cancer biomarkers representing promising therapeutic targets using mAb generated through a novel HTS technology.
Relationship of Ki-67 proliferative index and metastatic tumor of breast cancer.
Authors: Kobayashi Kokoro , Ito Yoshinori , Ogiya Akiko , Gomi Naoya , Horii Rie , Takahashi Shunji , Hatake Kiyohiko , Akiyama Futoshi , Iwase Takuji 
Published: March 2020

e22190 Background: The metastatic breast tumor tends to be more aggressive with high proliferation, but this has not been proven in clinical sampling of metastatic tumors. Methods: Forty-eight patients who had histological specimens of both primary and metastatic sites of luminal breast cancer (ER and/or PgR positive and HER2 negative) were examined. We classified them as luminal A (LA) with Ki-67 labeling index of less than 14% and as luminal B (LB) with Ki-67 labeling index of more than 14%. We analyzed their overall survival (OS) and progression free survival (PFS) of 1st line treatment of each subtype of primary and metastatic tumors. Results: Subtypes of primary tumors and metastatic tumors were as follows; the primary tumor: LA; 34 patients (70.8%), LB; 14 (29.2%), metastatic tumors: LA; 21 (43.8%), LB; 27 (56.2%). Patients with LA of the primary tumor demonstrated statistically longer OS (LA; 72.5 months, LB 39.6 months, p=0.009). OS depended on the subtype of the primary tumor. In contrast, patients with LB of a metastatic tumor showed a statistically worse PFS (LA; 20.5 months, LB; 11.5 months, p=0.040). PFS of the 1st line treatment for MBC depended on the subtype of the metastatic tumor. Conclusions: The frequency of LB was increased on metastatic tumors and tended to acquire a higher proliferation index. This suggests that characterization of metastatic tumors could be better as an indicator of subsequent treatment for MBC. [Table: see text]