bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential expression of biomarkers in gastrointestinal versus pulmonary carcinoid tumors.
Authors: Fong Erika , Peterson Gilbert , Basu Gargi D. , Blevins Richard , Ashfaq Raheela 
Published: March 2020

e13571 Background: Carcinoid tumors are endocrine neoplasms that commonly arise in the GI and pulmonary system. About 12,000 cases of carcinoid tumor are diagnosed a year with a 5-year survival rate of 67.2% .The majority of the cases present with advance disease with limited treatment options,therefore evaluation of predictive markers for chemotherapeutic agents is highly desirable. We studied the biomarker expression in carcinoid tumors and evaluated any differences based on site of origin. Methods: By computer search we retrospectively identified all cases submitted to Caris Life Sciences with the diagnosis of “carcinoid”. The cases were classified by primary site into three groups: Pulmonary, GI tract (including esophagus, stomach, small bowel, colon, rectum, appendix and pancreas) and miscellaneous. Biomarker expression performed by IHC and scored semi quantitatively by a pathologist for SPARC mono, SPARC poly, Her2, TOPO2, TOPO1, PGP, MRP1, PTEN, TS, ERCC1, RRM1,MGMT, C-KIT, ER, PR and AR and SSTR2 and SSTR5 analysis by DNA Microarray were compared between the groups. Results: 146 carcinoid tumors were interrogated for biomarkers, 33 pulmonary, 97 GI and 16 miscellaneous (mediastinum, thymus, cervix, breast and unknown primary site). Due to small number of tumors in the miscellaneous category, analysis was restricted to pulmonary and GI carcinoid tumors only. Based on our analysis the pulmonary carcinoids differentially express Topo2, PGP, MGMT, CKIT and PR, while the GI carcinoids differentially express Topo1, RRM1 and ER and SSTR2 and SSTR5. There is equivalent expression of SPARC, MRP1, PTEN, TS, ERCC1 at both sites . All pulmonary and GI carcinoid tumors were negative for Her2. Conclusions: Based on this study it appears that there are differences in biomarker expression in GI and Pulmonary Carcinoid tumors. Treatment with irinotecan, gemcitabine, anti-estrogens and Octreotide may be more relevant in GI carcinoids based on molecular markers present while targets associated with response to anthracyclines, temozolomide, imatinib may be more commonly expressed in pulmonary carcinoid tumors. Further studies are needed to understand the underlying biology and molecular drivers in this group of tumors.
Synergistic activity of vertical combinations of agents targeting multiple steps along the RAF/MEK/ERK cascade as a therapeutic strategy in human tumors.
Authors: Cesta Incani Ursula , Del Curatolo Anais , Di Sanza Cristina , Falcone Italia , Cognetti Francesco , Ciuffreda Ludovica , Milella Michele 
Published: March 2020

e13572 Background: BRAF-selective kinase inhibitors have potent antitumor effects in mutant BRAF(V600E) tumors; however, in BRAF-wt cells, they paradoxically activate MEK/ERK. In addition, MEK blockade may induce compensatory signaling through both upstream pathway elements (RAF) and parallel pathways (PI3K/AKT/mTOR). Methods: We set out to define molecular and functional effects of single and combined BRAF (GSK2118436A, BRAF-I) and MEK (GSK1120212B, MEK-I) inhibition, using WB analysis to dissect signaling and a fixed dose-ratio experimental design to assess functional synergism by conservative isobologram analysis. Results: In A549 lung adenocarcinoma (KRAS G12S), BRAF-I (10 μM) induces hyperphosphorylation of CRAF, MEK, ERK, and p90RSK, while MEK-I (10 nM), alone or in combination with BRAF-I, potently offsets MAPK activation. Combined BRAF-I and MEK-I suppress malignant growth and survival at 72 h with highly synergistic effects in the A549 (lung, KRAS G12S), H1299 (lung, NRAS), HCT116 (colon, KRAS G13D), and MIAPACA (pancreatic, KRAS G12V) models, with combination indexes (CI), ranging from 1.37 to 0.12. Conversely, in other lung cancer models (H460, Calu-1, Calu-3) the combination of BRAF-I and MEK-I produced modestly additive to highly antagonistic antitumor effects. In BRAF-mutant melanoma and colon carcinoma models (M14 and HT29), there was no paradoxical activation of the MEK/ERK module in response to BRAF-I and both BRAF-I and MEK-I had pronounced growth inhibitory effects as single agents, but were frankly antagonistic in combination. Similarly, the pan-RAF inhibitor RAF265 did not cause MAPK activation and did not result in synergistic growth inhibition when combined with the MEK-I in the A549 and MIAPACA cell lines. Conclusions: Overall, our data indicate that combined inhibition of multiple signaling elements along the RAF/MEK/ERK pathway results in strongly synergistic growth inhibition, particularly in tumors with RAS mutations. Additional studies to better define genetic determinants of sensitivity/resistance and molecular mechanisms of therapeutic synergism of combined BRAF-I and MEK-I are currently ongoing.
Dual endothelin-1/VEGFsp receptor (DEspR): Common target on tumor vascular endothelial cells (TVECs), tumor cells (TCs), and cancer stem cells (CSCs) in glioblastoma and pancreatic cancer.
Authors: Herrera Victoria L.M. , Tan Glaiza L.A. , Moran Ann Marie , Pasion Kristine A. , Decano Julius L , Ruiz-Opazo Nelson 
Published: March 2020

e13574 Background: New therapies are needed for glioblastoma (GBM) and pancreatic adenocarcinoma (PCa), given their low survival rates. To address this mandate, we tested the hypothesis that inhibition of DEspR, as a common target on TVECs, TCs, and CSCs, can affect multiple key steps in metastasis: angiogenesis, invasiveness, anoikis resistance. Methods: Various analyses were performed: co-immunostaining of tumor tissue and cancer cell lines from PCa and GBM using anti-CD133 and anti-DEspR mAbs; in vitro anti-DEspR mAb inhibition of angiogenesis and TC invasiveness; isolation, functional validation, and DEspR immunostaining of CSCs from PCa (Panc1) and GBM (U87) cell lines; DEspR inhibition of Panc1- and U87-derived CSC tumorsphere formation and CSC-enriched xenograft tumor growth in nude rats respectively; and phosphoproteome analysis of DEspR signaling. Results: In PCa and GBM, we detected DEspR+ TVECs, TCs, and CD133+ putative CSCs in contrast to respective normal tissues. DEspR expression on TCs and TVECs were confirmed in PCa (Panc1) and GBM (U87) cell lines, and HUVECs undergoing angiogenesis, respectively. Dose-dependent anti-DEspR mAb inhibition decreased HUVEC angiogenesis and Panc1 invasiveness compared to isotype controls. DEspR+ expression was detected in functionally validated Panc1 and U87 CSCs exhibiting tumorsphere formation, increased tumorigenicity in nude rat xenograft models, and self-renewal from xenograft tumors. DEspR inhibition decreased tumorsphere formation and increased dead cell numbers, suggesting decreased anoikis resistance for both U87 and Panc1 CSCs. Phosphoproteome analysis detected DEspR signaling through phosphoproteins implicated in TVEC-TC crosstalk, angiogenesis, and anoikis resistance. DEspR inhibition decreased tumor growth of Panc1 and U87 CSC-enriched subcutaneous xenograft tumors in nude rat models. Conclusions: Data demonstrate DEspR as a common target on TVECs, TCs, and CSCs in PCa and GBM, whose inhibition provides a potential therapeutic strategy for simultaneous inhibition of multiple pro-malignancy steps: angiogenesis, invasiveness, and anoikis resistance.
Evaluation of the PI3K inhibitor BAY 80-6946 in hematologic malignancies.
Authors: Jeffers Michael , Dubowy Ronald L. , Lathia Chetan D. , Mallon Robert , Appleman Leonard Joseph , Ramanathan Ramesh K. , Patnaik Amita 
Published: March 2020

e13576 Background: BAY 80-6946 is a new investigational compound that potently inhibits all PI3K Class I isoforms. BAY 80-6946 is under phase 1 clinical evaluation and PRs have been observed in solid tumors (ST) and follicular lymphoma (FL). The present analysis was performed to gain mechanistic insights into the activity of this compound in FL and potentially other hematological malignancies. Methods: Preclinical: The growth-inhibitory activity of BAY 80-6946 on hematological cancer cell lines (n= 32) was determined by the CellTiterGlo assay. GS-1101 (formerly called CAL-101) and cisplatin (CP) were also tested. Clinical: Specimens from subjects enrolled in a BAY 80-6946 Phase 1 trial MTD expansion were used. Levels of various cytokines and chemokines were determined by ELISA or multiplex immunoassay in plasma samples (n= 27) obtained prior to and during BAY 80-6946 treatment of 6 subjects (3 FL + 3 ST). Proteins examined included CXCL13 (involved in B-cell homing) and BAFF (involved in B-cell survival). Tumor tissue was used to determine PTEN expression via IHC and the mutational status of PTEN via sequencing. PIK3CA mutational status was evaluated in tumor tissue and plasma via BEAMing. Results: Preclinical: BAY 80-6946 was more potent on B-cell lymphomas and other hematological cancer cell lines than GS-1101 or CP (median IC50 in μM: BAY 80-6946= 0.49; GS-1101= 37; CP= 2.9). Clinical: Plasma levels of CXCL13 decreased and BAFF increased following BAY 80-6946 administration in all subjects examined (CXCL13 mean change: -58%; p= 0.004; BAFF mean change: +67%; p= 0.042). PTEN expression was lower in FL compared to ST. No mutations in PTEN or PIK3CA were identified in FL. Mutations in PIK3CA were identified in some ST. Conclusions: These preclinical results indicate that the observed early clinical activity of BAY 80-6946 in FL may be due to a direct anti-proliferative effect on malignant B-cells. The plasma chemokine/cytokine results support the possibility that the modulation of factors involved in B-cell homing and survival may play a mechanistic role in mediating this activity. Overall these results support the continued clinical evaluation of BAY 80-6946 in FL and other hematological malignancies.
Pharmacodynamic monitoring of DNA damage biomarkers in circulating tumor cells (CTCs) to assess the mechanism of action of the topoisomerase-1 (Topo1) inhibitor, NKTR-102.
Authors: Sukumaran Sujita , Neal Christopher , Woo Jacky , Melnikova Vladislava O. , Anderes Kenna Lynn , Brew Christine Taylor , Davis Darren W. , Hoch Ute 
Published: March 2020

e13577 Background: Inhibitors of Topo1 abrogate DNA replication and induce apoptosis in tumor cells. Topo1 inhibitors are effective cancer therapeutics however improved pharmacokinetic profiles have been sought. NKTR-102 is a next generation topoisomerase I-inhibitor with a unique pharmacokinetic profile that provides continuous exposure of the active metabolite, SN38. NKTR-102 is in phase III clinical development for patients with metastatic breast cancer. Monitoring DNA damage response markers in CTCs may be an informative, minimally invasive approach to detect drug activity in patients. Objectives of this study are to: 1) develop a multiplex immunofluorescent assay for measuring DNA damage effects of SN38 in CTCs; 2) obtain data to determine whether measuring DNA damage biomarkers in CTCs isolated from blood of cancer patients treated with SN38 ex vivo could be applied clinically to identify the best responders to NKTR-102. Methods: Solid tumor cell lines were treated with SN38 for 24 hr. Expression levels of gH2AX, survivin, BRCA1, BRCA2, RAD51, ATM and TUNEL were measured by quantitative laser scanning cytometry (LSC).Cytotoxcity was confirmed by MTT assay. Blood samples from 3 cancer patients were treated ex vivo with SN38 and CTCs were recovered and analyzed for expression of DNA damage biomarkers by LSC. Results: Treatment of H460 and HCT116 cells with SN38 led to a dose-dependent increase in the level of protein expression and/or frequency of positive cells for all DNA damage markers. Ex vivo treatment of breast cancer patients' blood with SN38 for 24 hr induced a dose-dependent increase in the expression of ATM (7.8-fold) and RAD51(188-fold) in one patients’ blood sample. An increase in the percent TUNEL-positive cells (0-20% in untreated to 44-54% in drug-treated samples) was observed in 2 patients’ samples without affecting the total number of isolated CTCs. Conclusions: Quantitative multiplex immunofluorescent assays for monitoring changes in gH2AX, ATM, RAD51 protein expression and percent TUNEL positive CTCs have been developed using LSC. These assays have been incorporated into an ongoing phase III clinical study of NKTR-102.
Circulating VEGF levels as a biomarker to clinical benefit to PTC299, the first inhibitor of VEGF synthesis.
Authors: George Claude Paul , Luke Jason John , Winkelman J. , Cao Yen Thi Kim Hong , Shakes LaShaina , Donnelly Kerri , Darby Charles Harris , Davis Thomas W. , Elfring Gary L. , Schwartz Gary K. 
Published: March 2020

e13588 Background: Solid tumor growth is dependent on angiogenesis, a process mediated primarily by vascular endothelial growth factor (VEGF). Currently approved anti-angiogenic agents sequester VEGF or block activation of VEGF receptors. Despite extensive investigations, no reliable biomarkers have been identified for these agents. PTC299 is an investigational oral small molecule that differs from existing therapies by inhibiting VEGF synthesis at the translational level while conserving physiologic VEGF expression. Methods: A phase 1b clinical trial is evaluating PTC299 monotherapy (36 pts) or in combination with docetaxel (10 pts) from 0.3 mg/kg to 600 mg bid in patients with advanced incurable cancer. Serum VEGF was assessed at baseline and during therapy. The maximum on‑treatment reduction in VEGF at any post-baseline visit was used for a stratified analysis. Decreases in VEGF, defined as <10% (low) and ≥10% (high), identified the strata. Duration of therapy was used as a surrogate for stable disease in a Kaplan‑Meier analysis. Results: The study enrolled 46 patients (20 males; 26 females; median age: 62 years). Patients with lower VEGF reductions while on therapy (<10%, n=12) had a median duration of stable disease of 5.3 weeks while patients with greater maximal VEGF reductions (≥10%, n=31) had significantly longer stable disease (median 12.0 weeks, log-rank p<0.001). VEGF decreases were greater in patients with higher baseline values. No Grade 3 or 4 hypertension, bleeding, or proteinuria occurred. One patient had an acute liver injury. Conclusions: Reductions in circulating VEGF are associated with prolonged duration of anti-angiogenic therapy and stable disease. Results are consistent with preclinical experiments and support the hypothesis that PTC299 does not affect physiologic VEGF but inhibits pathologic VEGF. In this study, oral administration of PTC299 as monotherapy or in combination with docetaxel therapy has been generally well tolerated at all doses tested.
Expression of type I insulin-like growth factor receptor (IGF1R) in tamoxifen-resistant cells: Implications for cotargeting of IGF1R and estrogen receptor (ER) in breast cancer.
Authors: Fagan Dedra H. , Uselman Ryan R. , Sachdev Deepali , Yee Douglas 
Published: March 2020

e13590 Background: Crosstalk between the insulin-like growth factor (IGF) and estrogen receptor (ER) systems has been well defined in breast cancer. The majority of anti-IGF1R clinical trials are in estrogen receptor-positive patients who have progressed on prior endocrine therapy; early reports show no benefit for addition of IGF1R inhibitors to endocrine therapy in this setting. Methods: To examine the effectiveness of IGF1R inhibitors, tamoxifen-resistant (TamR) cells were generated in MCF-7L and T47D cells. IGF1R was inhibited by monoclonal antibody (dalotuzumab) or IGF1R/insulin receptor (IR) tyrosine kinase inhibitor (AEW541). Results: TamR cells had diminished levels of IGF1R with unchanged levels of IR. Further, TamR cells failed to respond to IGF-I-induced Akt activation, proliferation, and anchorage-independent growth while retaining responsiveness to both insulin and IGF-II. Dalotuzumab inhibited IGF-I-mediated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells, but had no effect on TamR cells. AEW541 with equal potency for the IGF1R and IR, inhibited IGF-I-, IGF-II-, and insulin-stimulated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells. Interestingly, AEW541 also inhibited insulin- and IGF-II-stimulated effects in TamR cells. MCF-7L xenografts from estrogen replete mice were inhibited by dalotuzumab. However, dalotuzumab add no additional benefit to tamoxifen in estrogen depleted mice. Xenograft tumors from tamoxifen treated mice had reduced levels of IGF1R mRNA. Conclusions: Because ER regulates IGF1R mRNA expression, inhibition of IGF1R does not add to tamoxifen growth inhibition of breast cancer cells. Furthermore, inhibition of IR may be necessary to manage tamoxifen resistant breast cancer. The failure of clinical trials of IGF1R inhibitors in endocrine resistant breast cancer could be explained by this crosstalk between the two growth regulatory receptors.
Serious adverse events among a population-based cohort of patients receiving first-line chemotherapy for metastatic colorectal cancer (mCRC).
Authors: Jang Raymond Woo-Jun , Enright Katherine , Booth Christopher M. , Chan Kelvin K. , Yun Lingsong , Krzyzanowska Monika K. 
Published: March 2020

e14003 Background: Little is known about the toxicity of first line chemotherapy for mCRC in the general population. We sought to determine the proportion of patients who experienced at least one of the following: a serious toxicity (defined as an emergency department visit or hospitalization) or death within 30 days of receiving chemotherapy. Methods: All patients, age 18 or older, diagnosed with CRC from January 1 2007 to December 31 2009 in Ontario, Canada were identified using the Ontario Cancer Registry. Patient records were linked deterministically to multiple provincial healthcare databases to identify receipt of first-line chemotherapy for metastatic disease and to evaluate Emergency Department (ED) visits, hospitalizations, and deaths. An event was determined to be potentially treatment related if it occurred within 30 days of any cycle of chemotherapy. Results: The cohort contained 2359 patients. Mean age was 62 (range 19-89) and 59% were men. See table below. Conclusions: A significant proportion of patients visit the ED at some point during first line chemotherapy and many are hospitalized. A quarter of all patients had a hospital admission whereby an infectious complication was at least a contributing diagnosis. A significant minority of patients died within 30 days of receiving chemotherapy, raising concerns of either poor patient selection or severe treatment toxicity. [Table: see text]
Colorectal peritoneal carcinomatosis treated by completed surgery and systemic chemotherapy without HIPEC.
Authors: Becouarn Yves , Maziere Camille , Brouste Veronique , Desolneux Gregoire , Fonck Marianne , Bechade Dominique , Evrard Serge 
Published: March 2020

e14017 Background: Cytoreductive peritoneal surgery (CPS) associated with hyperthermic peritoneal chemotherapy (HIPEC) has become the standard treatment for peritoneal carcinomatosis (PC) of colorectal origins. Nevertheless, if CPS efficacy is demonstrated, evidence supporting HIPEC role is lacking. Methods: Overall survival (OS), progression-free survival (PFS) and outcomes were analysed retrospectively for thirty consecutively included patients treated for colorectal PC with CPS and systemic chemotherapy only. Outcomes and morbidity of the treatment were compared to outcomes and morbidity in the literature following CPS + HIPEC treatments. Results: PCI indices ranged from 1-21 with a mean of 9. Median hospitalization duration was 15 days (range 5-51), and median intensive care unit stay was 1 day (range 0-7). There was no post-operative mortality. Seventeen complications were Grade 1 or 2 (Dindo & Clavien), and remaining 13 were Grade 3. Median follow up was 40.7 [95%CI: 15.1 – 66.3] months. Median OS was 30.7 months [95%CI: 12.65-48.66}]. OS estimates were 83% [95CI%: 63.9- 92.5] and 45% [95%CI: 23.7-64.4] at 1 year and 3 years respectively. Median PFS was 11.1 months [95%CI: 7.98-14.25]. PFS at one year was 43.2% [95%CI: 24.7-60.4]. Patients without any other metastases (n=17) had a median OS of 73.3 months [95%CI: 25.7-120.9], compared with median OS of 18.7 months [95%CI, 16.9-20.6] for patients with at least one liver or lung metastases (p=0.011). Conclusions: The results obtained for patients with colorectal PC treated by CPS and systemic chemotherapy compare favourably with series including HIPEC in the treatment. No mortality, shorter operation duration and hospitalization, less blood loss and transfusions, and no hematologic toxicity were observed.
Lack of a chemobrain effect for adjuvant FOLFOX chemotherapy in colon cancer patients: A pilot study.
Authors: Zaniboni Alberto , Andreis Federica , Ferri Marco , Mazzocchi Maria , Meriggi Fausto , Rizzi Anna , Rota Luigina , Di Biasi Brunella , Abeni Chiara , Codignola Claudio , Rozzini Renzo 
Published: March 2020

e14018 Background: Chemotherapy improves the survival rate of stage III colon cancer patients. The combination of oxaliplatin, 5-fluorouracil and leucovorin (the FOLFOX4 regimen) has emerged as the standard of care. Cognitive changes and disfunction after cancer chemotherapy are increasingly reported as a disturbing side-effect in cancer survivors. This prospective study evaluates potential alterations in cognitive function in Folfox4-treated patients. Methods: We evaluated 57 consecutive colorectal cancer patients who received adjuvant chemotherapy with FOLFOX4. Patients underwent a complete battery of neuropsychological tests at three different times: before (T0), at the end (T1) and six months after treatment (T2). Changes in neuropsychological test scores at T0, T1 and T2 were compared with a two tail t-test (T1-T0, T2-T1, T2-T0), using the repeated measure ANOVA model. Results: We have analyzed cognitive impairment (Mini Mental State Examination, MMSE), visuo-spatial memory, information processing speed (Trial Making Test-A and Trial Making Test-B), verbal memory (Rey Auditory Verbal Learning Test), emotional distress (Psychological Distress Inventory), anxiety (State and Trait Anxiety Inventory) and depression (Beck Depression Inventory). We found no cognitive impairment in time considered, as we found a median MMSE score of 27,51 ± 1,21 at T0, 27,63 ± 0,65 at T1 and 27,26 ± 1,17 at T2. We noticed some transient variations in tests evaluating verbal memory and in information processing speed performances. The only significative scores modifications were those related to anxiety and depression. Conclusions: We found no significant effect on cognitive function related to chemotherapy, the only little modification is about some emotional performance during chemotherapy. These findings may be explained by the central role of the psychological adaptation process, which occurs during the period from diagnosis to completion of treatment and is characterized by anxiety and adjustment depression. Our results seem to rule out any significant cognitive impairment due to adjuvant Folfox4 chemotherapy in colon cancer patients.