tbuckley/cabot-search huggingface dataset:
Inhibition of migration and invasion of gastric cancer cells by Snail-regulated MiR-375 through JAK2 targeting.
Authors: Xu Yanjun, Zhou Tianhua, Si Jianmin, Zhuo Wei
Journal: Journal of Clinical Oncology (2014)

56 Background: Migration and invasion of cancer cells are essential process during cancer metastatic procession. In gastric cancer, cells invasion into the surrounding tissue is a crucial early step. However, the mechanisms have not been fully understood. MicroRNAs, which are a class of small single-stranded non-coding RNA, participate in the malignant progressions of cancer, including metastasis. We study the association between specific dysregulated miRNA and specific metastasis step of gastric cancer, which will provide insights into the potential mechanisms of gastric cancer cells migration, invasion and metastasis. Methods: The expression of miR-375 was assayed using the quantitative real-time PCR analysis. Scratch-wound healing assay, Transwell migration and invasion assay were conducted to study the migration and invasion abilities of cells. Animal experiment was also conducted to examine the effect on liver and lung metastases by overexpression of miR-375. Luciferase assay was conducted to study the association between Snail and miR-375. Results: MiR-375 is downregulated in gastric cancer cells with greater migration and invasion abilities. The expression level of miR-375 is decreased in gastric cancer tissues from metastasis-positive patients compared with that from metastasis-free patients. Overexpression of miR-375 inhibits the migration and invasion abilities of gastric cancer cells. JAK2, which may be a target gene of miR-375, could reverses miR-375 induced inhibition of gastric cancer cells migration and invasion. Liver metastasis was not detected in mice injected with miR-375 overexpressed cells but was apparent in mice injected with cells which were transfected with control vector. The transcription factor Snail, which binds directly to the putative promoter of miR-375, could reduce the expression level of miR-375 significantly. A distinct inverse correlation was found between miR-375 expression and Snail mRNA level. Conclusions: These findings demonstrate that tumor suppressor miR-375, whose expression is directly regulated by the transcription factor Snail, inhibits gastric cancer cells migration, invasion and metastasis by targeting an important protein JAK2.
Screening for somatic mutations in esophageal squamous cell carcinoma using OncoMap 4.0.
Authors: Chi Hoon Maeng, Shan Lu, Se Hoon Park, Paul Van Hummelen, Laura E. MacConaill, Kyoung Mee Kim, Jeeyun Lee
Journal: Journal of Clinical Oncology (2012)

27 Background: Analysis of gene mutations in tumor specimens is essential to treat cancers with molecular target agents. Given the high incidence of metastatic esophageal squamous cell carcinoma in East Asia, we screened for the presence of somatic mutations using OncoMap 4.0 with the aim of establishing novel treatment strategy. Methods: We analyzed 87 tissue specimens obtained from 80 patients who were pathologically confirmed of esophageal squamous cell carcinoma and received 5-fluoropyrimidine/platinum-based chemotherapy. OncoMap 4.0 is designed to interrogate &gt;700 mutations in 113 genes. Tumor specimens were prepared from primary cancer sites in 70 patients and from metastatic sites in 17 patients. In order to test the concordance between primary and metastatic sites from the patient for mutations, we analyzed 7 paired (primary-metastatic) specimens. All specimens were formalin-fixed paraffin embedded tissues and tumor content was &gt; 70%. Results: In total, we have detected 23 mutations out of 87 specimens tested. The most frequent mutation was PIK3CA mutation (four E545K, five H1047R and one H1047L) (N=10, 11.5%) followed by MLH1 V384D (N=7,8.0%), TP53(R306, R175H and R273C)(N=3, 3.5%), BRAF V600E (N=1, 1.2%), CTNNB1 D32N (N=1, 1.2%), and EGFR P733L (N=1, 1.2%). Distributions of somatic mutations were not different according to anatomic sites of esophageal cancer (cervical/upper, mid, lower). In addition, there was no difference in mutations between primary-metastasis paired samples. Conclusions: PIK3CA and BRAF mutations can be new targets for novel molecular agents to treat esophageal squamous cell carcinoma.
A phase I dose and exposure escalation study of 5-day intermittent oral lapatinib (Lp) therapy in patients with HER2-overexpressing breast cancer (BC).
Authors: A. J. Chien, K. Koch, G. Auerback, H. S. Rugo, M. E. Melisko, J. W. Park, E. Khanafshar, K. Ordovas, P. N. Munster, M. M. Moasser
Journal: Journal of Clinical Oncology (2011)

e11077 Background: The highly effective treatment of HER2-amplified BC has proven challenging due to signal buffering capacity inherent in the functionally relevant HER2-HER3 target. HER2-HER3 signaling can be inactivated by doses of Lp that fully inactivate the HER2 kinase. In mouse models, such doses are not tolerable in continuous administration, but are tolerable and highly effective in intermittent dosing. We have begun the clinical translation of this treatment strategy. Methods: We conducted a phase 1 dose-escalation study of a 5-day course of Lp in women with advanced HER2-overexpressing BC. Lp was administered with anti-diarrheal prophylaxis on days 1-5 of a 14 day cycle. Dose escalation was conducted in cohorts of 3 per standard 3+3 design with plasma Lp level monitoring, rigorous cardiac assessment, and exploratory tumor pharmacodynamic studies. Results: 29 patients (pts) have been enrolled to date and 26 are evaluable for toxicity. Lp has been evaluated across doses ranging from 1750 mg/day up to 7000 mg/day in twice-daily dosing. No dose-limiting toxicities, grade 4 or serious adverse events (AEs) were noted. Three pts experienced grade 3 diarrhea. Other common AEs included grade 1 and 2 diarrhea (19 pts), nausea (14 pts), fatigue (13 pts), rash (11pts). Plasma Lp concentrations varied considerably among pts and plateaued with increasing oral dose, failing to achieve the target plasma concentrations associated with high efficacy in preclinical models. Four pts had a partial response, 7 pts had a transient 5-day response, and 2 patients had stable disease for greater than 6 months. These responses were related to systemic exposure. In an attempt to break through the pharmacokinetic ceiling, current cohorts are evaluating exposure-enhancing strategies including the food-effect, inhibition of CYP3A4, and further dose fractionation. Conclusions: Lp dose and exposure can be safely and significantly increased through intermittent dosing but reach a bioavailability ceiling that currently precludes effective translation of the treatment hypothesis. Ongoing cohorts are pursuing novel pharmacokinetic approaches to enhance Lp exposure.
Dexametasone during induction, re-induction and maintenance pulses in low risk ALL patients (Brazilian Cooperative ALL-93 Protocol - GBTLI ALL-93)
Authors: S. R. Brandalise
Journal: Journal of Clinical Oncology (2005)

8543 Background: Dexametasone (DEXA) therapeutic concerns perhaps overthrow its benefits in ALL patients (pts). The GBTLI ALL-93 protocol for ALL treatment in children recommended DEXA instead of Prednisone, considering its higher antileucemic activity and also its higher CNS penetrance. Objective: To compare in a prospective randomization the maintenance therapy for 130wk in comparison with 103wk duration. Methods: Form October 1993 to September 1999, 454 consecutive pts aged 18 years or younger with newly diagnosed low risk ALL were enrolled in GBTLI ALL-93 treatment protocol. Patients were not elegible for the study if they had received any corticosteroid or chemotherapy previously. Low risk pts were defined according to age ≥1 <10 years and WBC at diagnosis <50,000/mm3. 7 pts were excluded due to previous use of corticoid and wrong risk classification. Treatment: 447 pts received remission induction therapy with DEXA 6mg/m2/daily x 28, VCR 1,5mg/m2/wk x 4, Daunomycin 25mg /m2/wk x 4, L-ASP 10.000 U/m2/dose IM x 8, Ara-C 75mg/m2/dose/SC x 8 and TIT therapy (x2). Intensification therapy with MTX 2g/m2/wk x 4 in 24 h continuous infusion with LCV rescue 15mg/m2/dose x 4, 6MP- 50mg/m2 daily x 21 and TIT therapy (x4). Re-induction therapy: Dexa 6mg/m2 daily x 21, VCR 1,5mg/ m2/wk x 4, L-ASP 10,000 U/m2/dose IM x 4, 6-MP 50mg/m2/daily x 14, Ara-C 75 mg/m2/dose x 4 and TIT therapy (x3). No CNS irradiation was given. One randomization was done for 130 wk or 103 wk maintenance therapy duration. Maintenance treatment: 6-MP 50mg/m2 daily, MTX 25mg/m2/wk and TIT therapy every 8 weeks during all treatment. Only for the pts with initial WBC > 10,000 < 50,0000/mm3, DEXA (4mg/m2/day x 7)/VCR (1,5mg/m2/dose x 1) pulses were done till the week 77 of therapy. Results: Of the 447 pts enrolled 429 (96%) achieved remission at day 28. EFS rate was 80% ± 2,2% at 5 years. CNS relapse rate was 0,9%. At 6 years follow-up, there was no difference in EFS rates between 130 wk or 103 wk maintenance therapy duration. Conclusions: Dexametasone was a safe drug in GBTLI ALL-93 Protocol therapy. At 6 years follow-up there was no difference in the EFS rates concerning 130wk versus 103 wk maintenance treatment. No significant financial relationships to disclose.
Vera Alma Sullivan
Authors: Rosalind Hirst, Joyce Newcombe
Journal: BMJ (2017)

Vera Alma Sullivan gained her initial degree at Queen’s University Belfast, having trained at the Royal and City hospitals in Belfast. She specialised in psychiatry at Purdysburn Mental Hospital, Muckamore Abbey, and Holywell Hospital. This was a formative period as the 1946 Mental Health Act (NI) introduced provision for mentally handicapped patients by establishing the Special Care Service in Northern Ireland. From 1959 until 1989 …
Combined DNA-methylation intensity and clinical risk score to stratify patients for high-grade disease.
Authors: Leander Van Neste, Grant Stewart, Sandra Marlene Gaston, William E. Grizzle, George W. Adams, Gary P Kearney, Jonathan I Epstein, David James Harrison, Alan W. Partin, Wim Van Criekinge
Journal: Journal of Clinical Oncology (2016)

51 Background: Prostate cancer (PCa) diagnostics remains challenging due to fear of over-diagnosis and overtreatment. Due to low accuracy of PSA too many men are biopsied that do not have a subsequent PCa diagnosis or that have indolent disease. Furthermore, persistent risk factors and fear of missed PCa leads to many unnecessary repeat biopsies. Most prostate tumors have epigenetic DNA-methylation aberrations, which display a field effect that can be observed in normal-appearing surrounding tissue, and that could help alleviate biopsy-sampling errors. Methods: A training cohort of methylation-positive men with a negative index biopsy followed by either a Gleason score (GS) ≥ 7 (n=43) or cancer-negative (n=226) repeat biopsy was evaluated. Using the initial negative biopsy, men were stratified for the likelihood of harboring high-grade PCa focusing on a methylation intensity algorithm involving GSTP1, RASSF1 and APC. This algorithm was validated in a cohort of 102 men, with either a PCa-free (n=20), GS6 (n=46), or GS≥7 (n=36) biopsies. Results: The methylation intensity-based algorithm was developed on PCa-negative index biopsies and optimized to predict the presence of GS≥7 cancer in a repeat biopsy. The methylation intensity was significantly higher in GS≥7 compared to PCa-free repeat biopsies (p&lt;0.001). Men with GS6 PCa detected upon repeat biopsy exhibited intermediate intensities. When combined into one model with clinical risk factors (age, pathology, DRE, PSA), an area under the curve (AUC) of 0.762 was obtained, which was significantly higher than the AUC of PSA (0.574; p=0.004) or the AUC of the clinical risk as calculated by the PCPT risk calculator (0.618; p=0.029). In the validation set, an AUC of 0.818 was obtained, with higher intensities for men with GS≥7 disease compared to men with GS6 PCa (p=0.002). Conclusions: The risk score can identify clinically significant cancer in PCa-negative biopsies and is strongly correlated with the GS of PCa-positive biopsies. The risk score could better stratify men for the need for repeat biopsy and the risk of harboring occult clinically significant PCa. The same algorithm could be used to segregate likely under-graded men from active surveillance candidates.
Significance of preoperative butyrylcholinesterase as an independent predictor of survival in patients with muscle-invasive bladder cancer treated with radical cystectomy.
Authors: Takuya Koie, Chikara Ohyama, Shingo Hatakeyama, Atsushi Imai, Takahiro Yoneyama, Yasuhiro Hashimoto
Journal: Journal of Clinical Oncology (2016)

373 Background: Butyrylcholinesterase (BChE) is an alpha-glycoprotein found in the nervous system and liver. Its serum level is reduced in many clinical conditions, such as liver damage, inflammation, injury, infection, malnutrition, and malignant disease. In this study, we analyzed the potential prognostic significance of preoperative BChE levels in patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). Methods: We retrospectively evaluated 327 patients with MIBC who underwent RC from 1996 to 2013 at a single institution. Serum BChE was routinely measured before operation in all patients. Covariates included age, gender, preoperative laboratory data (anemia, BChE, lactate dehydrogenase, C-reactive protein), clinical T (cT) and N stage (cN), tumor grade, and RC with/without neoadjuvant chemotherapy. Univariate and multivariate analyses were performed to identify clinical factors associated with overall (OS) and disease-free survival (DFS). Univariate analyses were performed using the Kaplan-Meier and log-rank methods, and the multivariate analysis was performed using a Cox proportional hazard model. Results: The median BChE level was 187 U/L (normal range, 168–470 U/L). The median age of the enrolled patients was 69 years, and the median follow-up period was 51 months. The 5-year OS and DFS rates were 69.6% and 69.3%, respectively. The 5-year OS rates were 90.1% and 51.3% in the BChE ≥ 168 and &lt; 168 U/L groups, respectively (P &lt; 0.001). The 5-year DFS rates were 83.5% and 55.4% in the BChE ≥ 168 and ≤ 167 U/L groups, respectively (P &lt; 0.001). In the univariate analysis, BChE, cT, cN, and RC with/without neoadjuvant chemotherapy were significantly associated with both OS and DFS. Multivariate analysis revealed that BChE was the factor most significantly associated with OS, and BChE, cT, and cN were significantly associated with DFS. Conclusions: This study validated preoperative serum BChE levels as an independent prognostic factor for MIBC after RC.
Molecular characterization of circulating tumor cells (CTCs) of patients with neuroendocrine prostate cancer (NEPC).
Authors: Himisha Beltran, Jessica Louw, Myriam Kossai, Rachel Krupa, Dena Marrinucci, Juan Miguel Mosquera, David M. Nanus, Scott T. Tagawa, Ryan Dittamore, Mark A. Rubin
Journal: Journal of Clinical Oncology (2014)

177 Background: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that commonly arises in later stages of castration resistant prostate cancer (CRPC), especially with visceral metastases in the setting of a low prostate-specific antigen (PSA). The genes AURKA and MYCNare frequently amplified. There are no reliable serum markers to identify patients that are transforming to NEPC and incidence of circulating tumor cells (CTCs) in these patients is unknown. Detection of NEPC has clinical implications as these patients are often treated with platinum chemotherapy rather than with androgen receptor (AR) targeted therapies. Methods: Ten men with metastatic NEPC underwent metastatic tumor biopsy and blood collection for CTC analysis utilizing the Epic Sciences platform. Clinical characteristics, pathologic and molecular features including exome sequencing of metastatic tumors, serum PSA and neuroendocrine (NE) markers, CTC count by CellSearch were obtained on all patients. AURKA and MYCNamplification were assessed by FISH in both tumors and Epic CTCs. Results: Sites of metastases included liver (6 out of 10), bone (9 out of 10), lymph nodes (8 out of 10), pleura (1 out of 10), and lungs (2 out of 10). Serum PSA, CellSearch CTCs, and serum NE markers were variable including 4 out of 10 patients with PSA less than 1 ng/ml (range 0.02-9.39) and 3 out of 5 evaluated patients with CTC count of zero (range 0 to 94). Four out of 7 evaluated tumors displayed amplification of AURKA and MYCN. Epic CTCs demonstrated frequent clusters, dim/low cytokeratin suggesting epithelial plasticity, and low AR expression. Patients were subsequently treated with platinum (4 out of 10), AURKAinhibitor (4 out of 10), or hormonal therapy (2 out of 10). Conclusions: PSA, serum NE markers, and CTC count by CellSearch may not be reliable in identifying patients with CRPC that have NE features. Epithelial plasticity potentially arising from epithelial-mesenchymal transition may explain lack of detection using conventional CTC assays. The Epic Sciences CTC platform is capable of detecting CTCs from patients with NEPC and CTCs are molecularly similar to metastatic biopsies. Epic CTCs may be useful in the earlier detection of NEPC and inform patient selection for therapy.
Impact of ethnic neutropenia disparity analysis in NSABP breast trials of postoperative doxorubicin (A)/cyclophosphamide (C)
Authors: C. R. Thomas, J. W. Wilson, E. P. Mamounas, P. C. Raich, A. Lagrange, J. J. Dignam, D. L. Wickerham, N. Nolmark
Journal: Journal of Clinical Oncology (2005)

6002 Background: Ethnic disparities in mortality from breast cancer are multifactorial. Ethnic neutropenia may, in part, lead to decreased chemotherapy dose in African American (AA) pts [Hershman, 2003]. Our working hypothesis is that AA pts have lower baseline WBC & thus receive lower doses of adjuvant AC. The specific aims were to: 1) confirm the observation of ethnic neutropenia in other studies and 2) determine if AC dose was decreased in AA pts enrolled in NSABP breast cancer postop adjuvant trials. Methods: Pooled AA and white (W) pts enrolled in NSABP trials B-15, B-16, B-18 (postop pts only), B-22, B-23, B-25, and B28 (N=10,680 total:1,041 AA pts and 9,639 W pts) were analyzed. Median (med) baseline WBC & ANC were compared in AA and W pts using the rank sum test. AC quantities in AA and W pts were compared using ANOVA with adjustment for BSA, age, protocol, & C regimen (600mg/m2 x4, 1200mg/m2 x2, 1200mg/m2 x4, 2400mg/m2 x2, 2400mg/m2 x4) and significant pairwise interactions among these variables. Outcome measures were total A received, total A received as a % of the total dose projected on the basis of BSA, and corresponding total C and % of C. Results: Med baseline WBC at enrollment: 6.7x109/L for AA & 7.2x109/L for W (p<0.001). Med baseline ANC: 3.69x109/L for AA & 4.3x109/L for W (p<0.001). After adjustment for BSA, age, protocol, and C regimen, AA was not a significant predictor of total A dose received (p=0.1561). AA ethnicity, jointly with its interaction with C regimen, was a significant predictor of total C dose received (p<0.0001), with AA pts receiving slightly more total C. AA was not a significant predictor of the percentage projected A dose or the percentage of projected C dose (p=0.484 & 0.103, respectively). Conclusions: This retrospective exploratory analysis suggest that despite lower baseline WBC and ANC, AA pts enrolled in these NSABP trials did not receive substantially lower A and C than did W pts. Current ethnicity-neutral dose modifications for AC-based breast trials are thus most likely clinically valid. Supported by NCI Grant U10 CA12027, CA37377,CA69651, CA69974] No significant financial relationships to disclose.
Course and predictors of postoperative outcomes in older patients with localized gastric adenocarcinoma treated preoperatively.
Authors: Nikolaos Charalampakis, Lianchun Xiao, Elena Elimova, Yusuke Shimodaira, Hironori Shiozaki, Prajnan Das, Aurelio Matamoros, Tara L. Sagebiel, Mariela A. Blum, Jeffrey H. Lee, Manoop S. Bhutani, Brian Weston, Paul F. Mansfield, Bruce D. Minsky, Brian D. Badgwell, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2016)

132 Background: Older patients with localized gastric adenocarcinoma (LGAC) suffer from substantial postoperative morbidity and mortality; however, postoperative outcomes in older patients who have received preoperative chemotherapy and/or chemoradiation have not been reported. Our study examined the impact of age and other covariates on baseline, surgical and postoperative characteristics and explored potential predictors of postoperative outcomes. Methods: Patients with LGAC who were treated with chemotherapy (n = 36; 18%) and/or chemoradiation (n = 167; 82%) followed by surgery (n = 203) were grouped in 2 categories by age: 1) ≥ 65 years old (n = 70) and 2) &lt; 65 years old (n = 133). The short-term outcomes included postoperative morbidity and mortality, and the long-term outcomes overall survival (OS) and progression-free survival (PFS). Potential predictors of 90-day postoperative outcomes were identified i) by age group and ii) by a number of other covariates. Descriptive statistics and survival analyses were utilized. Results: The 90-daypostoperative morbidity rate was similar in older and younger patients(61 vs 58%; p = 0.6549). The 90-day mortality rate did not differ statistically between the two groups (3 vs 0%; p = 0.1178). Although major Clavien grade III/IV complications after surgery were more common in older patients, this difference did not reach statistical significance (17 vs 12%; p = 0.3919). The long-term outcomes in terms of OS and PFS were also similar (p = 0.8629 and p = 0.558 respectively). The effect of patient age and ECOG PS on outcomes was not significant. Instead, other factors, such as Charlson comorbidity index (p = 0.0114), length of hospital stay (p = 0.0009), median operative time (p = 0.006) and presence of diabetes (p = 0.0282) were strong predictors of postoperative complications. Conclusions: Our data demonstrate that older patients with LGAC who received preoperative therapy had similar outcomes with younger patients but were more likely to demonstrate higher morbidity, although the differences were not statistically significant. Comorbidity indices provided more information than age in identifying postoperative short and long-term outcomes.