bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three dimensional organotypic ex vivo culture of tissues from post-operated tumor samples: Strengths and limitations.
Authors: Dey Nandini , Sun Yuliang , Krie Amy K. , Rojas Luis , Starks David , Lin Xiaoqian , Williams Kirstin Anne , Megan Quast Megan , Carlson Jennifer , Jepperson Shelby Hintze , Lazar Vladimir , De Pradip , Williams Casey B. , Leyland-Jones Brian 
Published: September 2018

e23151 Background: Evolution of tumor occurs in two phases, pretreatment phase, and posttreatment phase.Tumorigenic history and path of tumorigenic evolution determine the response of tumor cells to antitumor drug and thus the outcome of treatment. Carcinomas from the same organ-site with similar genomic alterations in different patients may vary in their tumorigenic history and their diverse paths of tumorigenic evolution which cause them respond differently to the same antitumor drugs. Uniqueness of tumorigenic history and paths of tumorigenic evolution in individual patient makes it ideal to test drugs, N-of-1. Here we present our experience with 3D organotypic ex vivo culture of tumor tissue from post-operated tumor samples. Methods: Informed consent was obtained from patients ( NCT02470715). The investigation was approved by IRB of the Avera Cancer Institute and the Western IRB. Surgically resected tissue was obtained from patients with different tumors of different organ sites including ovarian, breast, lung, endometrium, and cervix at the Avera Cancer Institute, SF, SD. Tissues from patients were collected in two formats, paired samples (tumor and tumor-adjacent normal) and unpaired samples. Results: As extracellular matrix lost in cell cultures, provide important signals for cell survival, differentiation and drug resistance we have established a protocol to culture slices in the 3D format. We have established 3D slice cultures (3x3 mm) of tumor-derived tissues which can be maintained ex vivo for at least three days. Tumor cells / normal cells from different tumors/tumor-adjacent normal tissues from day zero (non-cultured) were used to compare day1, day2, and day3 cultures. At the end of the culture period, slices were embedded in paraffin for histological analysis following H&E staining as well as IHC-staining for proliferation index (Ki-67), cellular proliferation signals (pS6RP), apoptosis (activated caspase 3), or tumor angiogenesis (CD31). Ki67 staining was characteristically different in cultured normal and cultured tumor tissues. Conclusions: Here, we show that tumor-derived tissues survive in 3D Matrigel culture for a minimum of 6 hours and maximum up to 3 days. Clinical trial information: NCT02470715.
CT20p as a therapeutic for lung cancer with elevated chaperonin containing TCP1 (CCT) expression levels.
Authors: Vishnubhotla Priya , Carr Ana C , Khaled Amr , Bassiouni Rania , Khaled Annette R. 
Published: September 2018

e23163 Background: We previously reported, in breast cancer, the effectiveness of a novel therapeutic peptide called CT20p that displays cancer-selective cytotoxicity. CT20p targets for inhibition a macromolecular complex called Chaperonin-Containing TCP-1 (CCT) that is responsible for folding actin and tubulin and other proteins, like STAT3, into their active forms. CCT is composed of 8 subunits (CCT1-8) that are highly conserved among species. In breast cancer cases, we found that the genes for CCT were frequently amplified (CCT2), upregulating the chaperonin’s activity, which correlated with decreased patient survival. Methods: To determine whether CCT is active in other cancers and thereby a broad therapeutic target, we examined the protein levels of CCT2 in colon, liver, prostate and lung cancer by immunohistochemistry (IHC), using human tissue microarrays (TMAs). Genomic data from The Cancer Genome Atlas (TCGA) was used to support IHC findings. Immunoblot probing of three CCT subunits (CCT2, CCT4, CCT5) was performed to determine their relative expression level in five small cell lung cancer (SCLC) cell lines compared to normal lung cells and these cells tested for susceptibility to killing by CT20p. Results: Results of IHC staining for CCT2 were interpreted on a scale of 1 to 4 (with 4 being the strongest staining). We found that with the exception of colon cancer, all cancers expressed high levels of CCT2 with advancing stage. We identified a significant correlation with cancer progression in both small cell lung carcinoma (SCLC) and squamous cell lung carcinoma (SqCLC). While individual levels of the three probed CCT subunits varied amongst the SCLC cell lines, overall CCT expression was higher in the SCLC cells when compared to normal lung cells and correlated with susceptibility to killing by CT20p. Using the TCGA database, CCT gene alterations were detected in clinical lung cancer cases, with amplification of CCT4 gene in SqCLC cases linked to decreased survival. Conclusions: These results indicate that targeted inhibition of CCT through CT20p treatment is a promising treatment approach for those cancers like SCLC that currently lack effective therapeutics to sustain progression-free survival.
A lung cancer-derived CRAF mutation to activate ERK pathway and to predict sensitivity to LY3009120 and trametinib.
Authors: Noeparast Amir , De Greve Jacques , De Brakeleer Sylvia , Bahadur Shahi Rajendra , Teugels Erik 
Published: September 2018

e23197 Background: During the Belgian FIELT II clinical study, two non-small cell lung cancers among 41 were found to harbor a CRAF mutation. One of these mutations (P207S) was previously found in fibrosarcoma and characterized as not activating the ERK pathway at higher levels compared to the wild-type CRAF. The other mutation (P261A) has never been reported in cancer but found in Noonan syndrome. CRAF mutations can be oncogenic thereby activation of the ERK pathway. Serine 259 is a negative regulatory site and its phosphorylation is essential for keeping the CRAF auto-inhibited. P261A CRAF prevents phosphorylation of S259 but its role in cancer and its possible response to small molecule inhibitors has yet to be uncovered. Methods: We generated recombinant CRAF expression vectors by site-directed mutagenesis and investigated the ERK pathway activation status induced by CRAF mutants, in HEK293T cells and BEAS-2B (lung epithelial) cells. We tested the effect of candidate inhibitors at a clinically relevant dose on ERK pathway activity in BEAS-2B cells expressing CRAF mutants. Results: Expression of P261A CRAF in both HEK293T and BEAS-2B cells leads to increased ERK pathway activation compared to wtCRAF, accompanied by decreased phosphorylation of S259. P207S CRAF induces ERK pathway activity at levels comparable to wtCRAF and we observed that co-expression of BRAF with P207S CRAF does not lead to increased ERK activity compared to wtCRAF/BRAF. RAF-inhibitors LY3009120 and AZD-628 suppress ERK pathway activity induced by P261A CRAF in BEAS-2B cells. LY3009120 showed stronger ERK-inhibitory effect compared to AZD-628. In contrast, Dabrafenib (RAF-inhibitor) treatment of mutant or wtCRAF expressing cells leads to paradoxical ERK activation. Combinatorial treatment of LY3009120 with Trametinib (MEK-inhibitor) leads to stronger ERK-inhibitory effects compared to either single agent treatment in cells expressing mutant CRAF. Conclusions: The P261A CRAF mutation is ERK pathway activating and predicts sensitivity to LY3009120 and Trametinib. CRAF inhibition should be clinically explored in lung cancers and perhaps other cancers with sensitizing CRAF mutations.
Exploring a possible relationship of germline CDKN2A mutations with breast cancer in a multigene panel cohort.
Authors: Horcasitas Darling J , LaDuca Holly , Yussuf Amal , Chisholm Ginger , Chavez Jonah R , Campbell Fontaine Annette , Panos Smith Laura 
Published: September 2018

e23218 Background: Germline mutations in CDKN2A have been known to increase the risk of melanoma and pancreatic cancer compared to the general population. With the advent of multi-gene panels, individuals who may not have melanoma or pancreatic cancer are undergoing CDKN2A analysis. Previous studies in homogenous populations have suggested that breast cancer risks may also be increased in CDKN2A. This study aims to further evaluate a possible relationship of CDKN2A mutations with breast cancer through a series of case-control comparisons. Methods: Clinical histories and molecular results were retrospectively reviewed for patients undergoing CDKN2A analysis as part of two diagnostic pan-cancer panels at a single laboratory to ascertain CDKN2A mutation carriers (n = 104) and patients negative for all genes analyzed (n = 20,280). Patients with a personal and/or family history (1st and 2nd degree relatives) of pancreatic cancer and/or melanoma were excluded from case-control analysis. Results: The majority of CDKN2A mutation carriers (82.6%, n = 86/104) had a personal history of cancer documented on the test requisition form. The most common cancers were breast (n = 38, 52.8%), melanoma (n = 37, 43.0%) and pancreatic (n = 6, 7.1%). The average age of breast cancer diagnosis in this cohort was 49.3 years (range 25-84). Family history of breast, melanoma, and/or pancreatic cancer was reported for 54.9%, 46.1%, and 34.3% of CDKN2A mutation carriers, respectively. Females with breast cancer were not more likely to test positive for a CDKN2A mutation than females with cancer other than breast (OR = 0.84, p = 0.79) or unaffected females (OR = 1.02, p = 1). Conclusions: Although CDKN2A mutations were not significantly associated with breast cancer in this cohort, these findings do not necessarily rule out an association of CDKN2A mutations with breast cancer, particularly if risks are moderate or if genotype-phenotype correlations exist. Additional studies involving breast cancer cases unselected for age and family history and/or longitudinal studies of CDKN2A carriers are needed to better understand the relationship between CDKN2A and breast cancer risk.
Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration.
Authors: Shi Qian , Sobrero Alberto F. , Shields Anthony Frank , Yoshino Takayuki , Paul James , Taieb Julien , Sougklakos Ioannis , Kerr Rachel , Labianca Roberto , Meyerhardt Jeffrey A. , Bonnetain Franck , Watanabe Toshiaki , Boukovinas Ioannis , Renfro Lindsay A. , Grothey Axel , Niedzwiecki Donna , Torri Valter , Andre Thierry , Sargent Daniel J. , Iveson Timothy 
Published: September 2018

LBA1 The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Sunday, June 4, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Routine molecular screening of advanced refractory cancer patients: An analysis of the first 2490 patients of the ProfilER Study.
Authors: Tredan Olivier , Corset Veronique , Wang Qing , Varnier Romain , Pacaud Camille , Torroja Alexia , Luppi Nicolas , Ezzalfani Monia , Myard Magali , Jiang Xiaojun , Attignon Valéry , Pissaloux Daniel , Baudet Christian , Cassier Philippe Alexandre , Fayette Jérôme , Carbonnaux Mélodie , Bonneville-Levard Alice , Viari Alain , Pérol David , Blay Jean-Yves ,   LYric Profiler Author's Group
Published: September 2018

LBA100 The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Saturday, June 3, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Web-based stress management for newly diagnosed cancer patients (STREAM): A randomized, wait-list controlled intervention study.
Authors: Hess Viviane , Grossert (equal contributor) Astrid , Alder Judith , Scherer Sandra , Handschin Barbara , Borislavova Borislava , Degen Sven , Faessler Alexandra , Hartung Jennifer , Schibli Sarah , Werndli Celine , Gaab Jens , Berger Thomas , Zumbrunn Thomas , Urech Corinne 
Published: September 2018

LBA10002 The full, final text of this abstract will be available at abstracts.asco.org at 2:00 PM (EDT) on Friday, June 2, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm).
Authors: Robson Mark E. , Im Seock-Ah , Senkus Elżbieta , Xu Binghe , Domchek Susan M. , Masuda Norikazu , Delaloge Suzette , Li Wei , Tung Nadine M. , Armstrong Anne , Wu Wenting , Goessl Carsten Dietrich , Runswick Sarah , Conte Pier Franco 
Published: September 2018

LBA4 The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Sunday, June 4, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
A randomized phase II/III study comparing stereotactic body radiotherapy (SBRT) versus conventional palliative radiotherapy (CRT) for patients with spinal metastases (NCT02512965).
Authors: Sahgal Arjun , Myrehaug Sten , Dennis Kristopher , Liu Mitchell , Chow Edward , Wong Rebecca , Butler James B. , Greenspoon Jeffrey Noah , Fehlings Michael G , Maralani Pejman , Masucci Laura , Lee Young , Brundage Michael Donald , Liu Stanley K. , Ding Keyue , Hum Maaike , Parulekar Wendy R. 
Published: September 2018

TPS10129 Background: Innovative radiotherapy technology and modern imaging capabilities enable the use of Stereotactic Body Radiotherapy (SBRT) to treat patients with spinal metastases to optimize tumour control and palliation compared to standard conventional radiotherapy. No randomized clinical trial evidence exists directly comparing the two treatment strategies. Methods: SC.24 is a Canadian Cancer Trials Group randomized phase II/III study comparing standard conventional radiotherapy (20 Gy/5fr) to SBRT (24 Gy/2fr) in patients with solid tumours and MRI documented, painful spinal metastases suitable for RT. The primary accrual objective for the phase II portion of the study was met in January 2017 and the study continues as a randomized phase III study with a primary outcome measure of complete pain response at 3 months post radiotherapy. Secondary objectives include: measurement of complete pain response at 6 months; radiation site progression free survival at 3 and 6 months; adverse event profile, health related QOL and compliance with RT QA measures. Biobanking for future correlative studies is included in study design. Statistical design: The statistical assumptions for the phase III study include estimated complete pain response rates of 10% and 30% for the CRT and SBRT treatment arms respectively. Using a two sided alpha = 0.05 and power = 80% the sample size for the phase III study is 152, taking into account a 5% drop out rate. Conduct to Date: Study activation: July 2015. Accrual to date: 58. Supported by CCSRI grant 021039 Clinical trial information: NCT02512965.
Phase 1/2, multicenter, non-randomized, open-label, multiple-dose first-in-human study of U3-1402 (anti-HER3 antibody drug conjugate) in subjects with HER3-positive metastatic breast cancer.
Authors: Kogawa Takahiro , Yonemori Kan , Naito Yoichi , Noguchi Emi , Shimizu Chikako , Tamura Kenji , Hosono Ako , Matsubara Nobuaki , Sugihara Masahiro , Ogawa Hayao , Majima Shuji , Yu Channing , Ueno Suguru , Takano Toshimi 
Published: September 2018

TPS1116 Background: There is a need for effective late-line treatments in metastatic breast cancer. HER3 overexpression in breast cancer is associated with poor prognosis, but there is as yet no approved targeted treatment against HER3. U3-1402 is a novel antibody-drug conjugate (ADC) comprised of a fully humanized anti-HER3 antibody (patritumab) covalently conjugated via a cleavable peptide linker to a derivative of the topoisomerase I inhibitor exatecan. After U3-1402 binds to HER3 on the tumor cell surface, it is internalized and leads to apoptosis via inhibition of topoisomerase I. This ADC achieves a high drug-to-antibody ratio of ~8:1. Methods: This is a Phase 1/2, multicenter, non-randomized, open-label, multiple-dose, first-in-human study in subjects with HER3-positive metastatic breast cancer. The study consists of 3 parts: Dose Escalation, Dose Finding, and Phase 2. In Dose Escalation, safety and tolerability of U3-1402 are evaluated and the maximum tolerated dose is determined using the modified continuous reassessment method with escalation with overdose control. In Dose Finding, the recommended phase 2 dose (RP2D) of U3-1402 is determined using continued assessment of safety and efficacy as well as pharmacokinetic data of U3-1402. Efficacy and safety of the RP2D are further evaluated in Phase 2 part. Patients with locally advanced or metastatic breast cancer who have disease refractory to standard treatment, who cannot tolerate standard treatment, or for whom no standard treatment is available, will be enrolled. Key inclusion criteria include HER3-positive tumor, ECOG performance status 0–1, and measurable disease based on RECIST version 1.1. HER3 expression in tumor tissue will be evaluated with immunohistochemistry at a central laboratory. Prior chemotherapy regimens are restricted to 6 or fewer in Dose Finding and Phase 2, but not in Dose Escalation. Patients will receive U3-1402 intravenously every 3 weeks until unacceptable toxicity or disease progression. Enrollment of an estimated 80 patients is ongoing. Clinical trial information: 02980341.
A phase 1b study of safety and immune response to PVX-410 vaccine alone and in combination with durvalumab (MEDI4736) in HLA-A2+ patients following adjuvant therapy for stage 2/3 triple negative breast cancer.
Authors: Isakoff Steven J. , Tolaney Sara M. , Tung Nadine M. , Adams Sylvia , Soliman Hatem Hussein , Brachtel Elena F , Habin Karleen R. , Bauer Louisa J , Ellisen Leif W. , Severgnini Mariano , Barry William Thomas , Peterkin Doris 
Published: September 2018

TPS1126 Background: Stage 2-3 triple negative breast cancer (TNBC) remains at high risk for recurrence despite modern adjuvant therapy. An important role for the immune system in TNBC has recently emerged. Tumor infiltrating lymphocytes (TILs) are correlated with improved prognosis and several PD-1/PD-L1 checkpoint inhibitors, including Durvalumab (DUR), demonstrated activity in metastatic TNBC. Vaccines are a promising approach to further enhance the immune response in many cancers including TNBC. PVX-410 (PVX) is a novel tetra-peptide vaccine against XBP1 (2 splice variants), CD138 and CS1 that was safe and induced immune responses in a phase 1b study in smoldering myeloma. XBP1 and CD138 are also over-expressed in TNBC. Methods: This Phase 1b multi-center, single arm study will enroll 20 HLA-A2+ female patients (pts) following completion of all adjuvant therapy for stage 2-3 TNBC. Pts will receive 6 doses of 800ug PVX (emulsified in Montanide (SC) and co-administered with Hiltonol (IM)) at 2-week intervals, and 2 doses of DUR 1500mg IV at the 4th and 6th vaccine visits. Eligible pts must be between 1-6 months from completing adjuvant therapy, have no prior autoimmune disease, and have residual disease if neoadjuvant therapy was used. The primary objective is to determine the safety and tolerability of the combination, and the key secondary objective is to determine the immune response to PVX + DUR. If ≤1 pt in the first 6 has a protocol defined dose limiting toxicity within 4 weeks after the first DUR dose, accrual will continue to 20 pts. Immune response will be assessed at baseline, pre-dose 4 PVX/dose 1 DUR, and 4 weeks after completing protocol therapy. Paired data in 20 pts provides 90% power to see a shift of 0.75 standardized units from baseline to 4 weeks post treatment with the signed rank test. Immune response will be determined by a FACs based assay of antigen specific CD3+CD8+ T lymphocyte response and IFN-γ production (intracellular staining) in patient PBMCs. Additional correlative studies, including T-cell PD-1 and tissue PD-L1, XBP1, and CD138, are planned. Currently 4 pts are enrolled. Clinical trial information: NCT02826434.
STELLAR: A phase 3, randomized, open-label study of eflornithine with lomustine vs lomustine for patients with first recurrence of anaplastic astrocytoma after RT and adjuvant temozolomide.
Authors: Levin Victor A. , Cruickshank Scott 
Published: September 2018

TPS2081 Background: Eflornithine irreversibly inhibits ornithine decarboxylase an enzyme that catalyzes the biosynthesis of putrescine, one of 3 polyamines in mammalian cells. Over 390 patients with anaplastic gliomas (AG) received eflornithine alone, with a nitrosourea, or the PCV combination in past clinical trials. A phase 3 randomized study of adjuvant chemotherapy with PCV vs eflornithine-PCV in 228 patients with AG found a median overall survival (mOS) increase from 61.1 to 75.8 months in the eflornithine-PCV arm. Methods: Patients must have histologically proven diagnosis of WHO grade 3 anaplastic astrocytoma (AA) with unequivocal evidence of first AA tumor progression or recurrence ≤ 3 months prior to randomization following surgical resection or biopsy, RT and temozolomide chemotherapy. Patients must have RT ≥ 6 months prior to randomization and have a KPS of ≥ 70. Randomization of 280 patients will be 1:1 with stratification to: Age (≤ 45 yrs, > 45 yrs), region (US, Ex-US), IDH1 status (wild, mutant), and prior surgeries (biopsy, 1-2 resections). Patients will receive eflornithine 2.8 g/m2 orally every 8 h on a 2 week on, 1 week off schedule, and lomustine 110 mg/m2 orally once every 6 weeks, or lomustine alone dosed at 110 mg/m2 orally once every 6 weeks. Lomustine will be limited to 6 cycles or 12 months of therapy. Eflornithine can be given up to 24 months in the combination arm. The primary endpoint will be OS. Secondary objectives include PFS and objective response rate (ORR) based on MRI. The study sample size was calculated by assuming true mOS of 12 months for lomustine monotherapy and true mOS of > 18 months for the eflornithine plus lomustine arm. Such an improvement represents a true hazard ratio of 0.667 (investigational arm/control arm). Inferential comparisons of OS will be performed using a stratified log-rank test with 137 patients per arm and total information of 194 deaths with 80% power to detect a 33% reduction in the OS failure hazard rate. The study is open at 55 sites in the USA, Germany and Italy with an additional 10-15 sites being evaluated in 3 additional countries. Study enrollment is expected through 2018. Clinical trial information: NCT02796261.