tbuckley/cabot-search huggingface dataset:
Adoptive cell therapy for melanoma patients using tumor-infiltrating lymphocytes, lymphodepleting chemotherapy, and low-dose interleukin-2.
Authors: Eva Ellebaek, Trine Zeeberg Iversen, Niels Junker, Marco Donia, Lotte Engell-Noerregaard, Mads Hald Andersen, Per thor Straten, Inge Marie Svane
Journal: Journal of Clinical Oncology (2012)

2574 Background: Adoptive T cell therapy is based on isolation of tumor infiltrating lymphocytes (TIL) from autologous tumor, in vitro activation and expansion, and the reinfusion of these cells into a lymphodepleted patient. Together with high-dose interleukin (IL)-2 this treatment has in a few other countries successively been given to patients with advanced malignant melanoma and an impressive 50% response rate has been observed. Here we report the experience from a Danish Translational Research Center using low-dose subcutaneous IL-2 injections. Methods: A pilot trial including patients with metastatic melanoma, PS ≤1, age &lt;70, measurable and progressive disease, and no CNS involvement. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of low-dose IL-2, 2 MIU/day. Results: Low-dose IL-2 considerably decreased the toxicity of the treatment with no grade 3-4 events related to this drug. Two of the 6 treated patients have an ongoing complete response (30+ and 7+ months), 2 patients had stable disease (4.5 and 5 months) and 2 patients progressed shortly after treatment. Five patients went through surgery but were not treated because of rapid disease progression (2), development of brain metastases (2) or the inability to grow cells (1). Tumor-reactivity of the infused cells and peripheral monocytes before and after therapy were analyzed. High tumor responses in the infusion products were correlated to clinical response and also an induction of tumor reactive T cells were seen in the peripheral blood for 1 patient in complete response. Conclusions: Complete and durable responses are induced after treatment with adoptive cell transfer in combination with low-dose IL-2 questioning the need for high and toxic doses of IL-2.
Up-regulation of inflammatory and thrombotic mediators in lung cancer and their modulation by oral anticoagulantion
Authors: J. Fareed, A. Ciftci, M. Demir, D. Hoppensteadt, G. Altiay, M. Tobu, O. Iqbal, D. Fareed, R. Bick, A. Sheikh
Journal: Journal of Clinical Oncology (2007)

7705 Background: Venous thromboembolic events (VTE) are associated with lung cancer and significantly contributes to the increased mortality in these patients. While the increased prevalence of VTE is fully recognized in lung cancer, its pathogenesis is not fully understood at this time. Even the patients undergoing therapeutic interventions are at high risk to develop VTE. Profiling of surrogate markers of thrombosis and inflammation provides an opportunity to understand the pathogenesis of thrombosis in these patients. Methods: In a prospective, randomized, controlled study patients with inoperable lung cancer (n=100) were randomized to receive chemotherapy, radiation and warfarin (INR 1.5–2.5) or chemotherapy, radiation without warfarin (n=50). Blood samples were drawn prior to and after the second treatment cycle with warfarin. All samples were analyzed for such inflammation markers as the tumor necrosis factor alpha (TNF a), CD 40 ligand (CD 40L), C-reactive protein (CRP), interleukin 1 beta (IL-1β), asymmetric dimethylarginine (ADMA) and nitric oxide (NO). In addition, prothrombin fragment F1.2 (F1.2) and thrombin antithrombin complex (TAT) were also measured. Results: The results are summarized in the following table . All of the surrogate markers of inflammation showed a decreased trend (13–50%) in the warfarin treated group, whereas the non-warfarin treated group exhibited an increase (18–46%) in all markers except CRP and ADMA. The markers of thrombin generation were down regulated in the warfarin treated group. Conclusions: The levels of various inflammatory markers are upregulated in lung cancer suggesting a pathogenic role of this process in lung cancer. Warfarin down regulated the inflammatory and thrombogenic processes in contrast to the non-warfarin treated group. The clinical relevance of these observations require additional analysis. No significant financial relationships to disclose. [Table: see text]
Relevance of circulating tumor cells (CTC) in the progression of metastatic breast cancer
Authors: A. Altimari, S. Quercia, E. Benedettini, M. Rosati, E. Capizzi, A. Bernardi, M. Fiorentino, C. Zamagni, A. D'Errico Grigioni, A. A. Martoni
Journal: Journal of Clinical Oncology (2007)

21066 Background: metastatic breast cancer is an incurable disease. Molecular tumor staging methods are required for a better therapeutic approach. Patients and Methods: eight mL blood samples were drawn from 20 patients (pts) (mean age 61.9±9) with metastatic breast cancer at the time of the beginning of a new chemo- or hormonal treatment line. Median follow-up was 7±4.5 months. Twenty- five female healthy blood donor volunteers were used as controls. Blood samples were screened for the presence of circulating tumor cells (CTC) with a quantitative PCR method using molecular probes for human mammaglobin (hMAM) and cytokeratin 19 (CK19). Relative quantification of hMAM and CK19 RNA was obtained using a blood sample infected with known concentrations of MDA-MB453 cells as calibrator. Results: none of the healthy controls was hMAM positive while the cut-off for CK19 was calculated as the mean value of the controls plus two standard deviations. Nine of 20 (45%) pts were hMAM positive, 15/20 (75%) CK19 positive, while 18/20 (90%) pts were positive for at least one marker (CTC positive). Among the 14 (70%) pts who had a disease progression 7 died. Seven of 9 hMAM positive (78%) and 11/15 (73%) CK19 positive pts had disease progression. All the 14 pts who had disease progression were CTC positive while the only 2 CTC negative pts were free from progression at the time of last follow-up. Conclusions: (1) Multiple (hMAM, CK19) rather than single marker detection should be preferred for CTC blood screening in breast cancer. (2) Combined hMAM and CK19 evaluation might identify pts at higher risk of tumor progression and might be useful for stratification and decision making in metastatic breast cancer pts. No significant financial relationships to disclose.
Expression of MET and HGF in bladder cancer tumorigenesis and invasion.
Authors: Randy F. Sweis, Petros Grivas, Alexander T. Pearson, Kathleen C. Day, Mark L. Day, Maha Hussain
Journal: Journal of Clinical Oncology (2012)

4573 Background: The human MET gene encodes the hepatocyte growth factor (HGF) tyrosine kinase receptor. Limited studies in human bladder cancer have demonstrated that expression of MET protein is linked with disease progression and survival. We hypothesized that the expression of both MET and its ligand HGF are altered in bladder cancer. Methods: Expression of MET and HGF in human bladder tissues was explored using Oncomine, an online compendium of cancer transcriptome profiles. The largest relevant dataset was identified and contained 157 samples (Sanchez-Carbayo, et al. 2006). Normalized and log2 transformed mRNA expression values for Affymetrix U133 microarray probe sets corresponding to the genes of interest were compiled and averaged for each gene. Mann-Whitney U testing was used to compare means. Nominal and standard least squares logistic regression was used to evaluate the predictive significance of, and relevance of clinicopathologic variables on, gene expression. Statistical analyses were carried out using JMP 9.0.2. Results: Expression of MET and HGF was compared across subsets of normal bladder tissue (n=48), superficial tumors (n=28), and invasive tumors (n = 81). Relative to normal tissue, MET expression was greater in superficial (p = 0.0008) and invasive tumors (p&lt;0.0001). HGF expression was reduced in both invasive and superficial tumors vs. normal tissue (both p&lt; 0.0001), but was higher in invasive vs. superficial tumors (p= 0.0007). In a logistic regression model of tumor samples, both MET and HGF correlated with tumor invasion (model p=0.0003). Interaction between MET and HGF was not significant (p=0.55). Neither MET nor HGF expression was predicted by regression using age, gender, grade, or nodal stage (p=0.16 and 0.27, respectively). Conclusions: Decreased HGF expression and MET over-expression are strongly associated with tumorigenesis and invasion in bladder cancer. The reduction in HGF expression is blunted in invasive vs. superficial tumors, suggesting a potential loss of negative feedback in more aggressive tumors. Expression of both genes could not be predicted by modeling clinicopathologic variables. MET signaling represents a potential therapeutic target in bladder cancer.
Development of a geriatric vulnerability score (GVS) in elderly advanced ovarian cancer (AOC) patients (pts) treated in first line: A prospective GINECO trial.
Authors: Gilles Freyer, Beatrice E. Weber, Daniela Lebrun-Jezekova, Fabien Tinquaut, Olivier Tredan, Emmanuel Sevin, Laetitia Stefani, Eric Pujade-Lauraine, Claire Falandry
Journal: Journal of Clinical Oncology (2012)

9079 Background: Two previous prospective GINECO studies in elderly patients have underlined the prognostic value of geriatric covariates (Co) on overall survival (OS) (Freyer G., et al. Ann Oncol. 2005 and Tredan O, et al Ann Oncol 2007). Methods: This open prospective trial was designed to confirm the impact of geriatric Co including psycho-geriatric Co on OS of elderly pts (≥70) with stage III-IV AOC treated in first line with 6 courses of carboplatin AUC5/3weeks. Geriatric Co were tested for their impact on OS in uni- and multivariate analyses. The best fitting proportional hazard model (GVS) was developed with the inclusion of major (MaC) and minor Co (miC). Results: From 08/2007 to 01/2010, 111 pts were included in 21 centres. A majority of pts displayed characteristics of vulnerability: age (median:78, range: 70-93, ≥80:41%), PS≥2: 43%, ≥3 major comorbidities: 27%, ≥4 comedications: 69%, ADL score&lt;6: 55%, IADL score&lt;25: 75%, HADS≥15:37%. A total of 74% of pts, however, completed planned chemotherapy. Gr3-4 haematological toxicity was observed in 50% of pts (thrombocytopenia [27%], anaemia [19%], and neutropenia [30%]) and gr3-4 non-haematological toxicity was fatigue (16%), anorexia (13%) and infection (10%). Median OS was 16.2 months (95%CI[14-21]). MaC were: albuminemia&lt;35g/L; ADL score &lt;6; IADL score &lt;25 and miC: lymphopenia&lt;1G/L; HADS£14. The survival score=exp(0.320*Number [MaC] +0.354*Number[miC]) was validated upon a bootstrap analysis. Using a cutoff of 3, the simplified GVS score = Number[MaC] + Number[miC] discriminated two groups with significantly different OS :11.5 vs 21.7 months; HR=2.94; p&lt;10 -4 , but also treatment completion rates: 65.4% vs 82.1%; OR=0.41; p=0.04; severe adverse events (SAE): 52.7% vs 28.6%; OR=2.8; p=0.009 and unplanned hospital admissions: 52.8% vs 30.3% OR=2.6; p=0.02. Conclusions: The GVS identified a group of pts at high risk of severe toxicity, early treatment stopping, unplanned hospitalization and poor outcome. GVS provides a useful tool to identify vulnerable pts in future elderly AOC trials.
Single center experience treating adults with <i>FLT3</i>-mutated acute myeloid leukemia (AML).
Authors: Anna B. Halpern, Rangesh Kunnavakkum, Loren Joseph, Wendy Stock, Olatoyosi Odenike, Lucy A. Godley, Michael J. Thirman, Andrew S. Artz, Dorothy Sipkins, Hongtao Liu, Gordana Raca, Michelle M. Le Beau, Richard A. Larson
Journal: Journal of Clinical Oncology (2012)

6562 Background: Activating mutations of the fms-like tyrosine kinase-3 (FLT3) gene are common in AML. Depending upon the allele mutation fraction, these mutations have been associated with poor outcomes in prospective multi-center trials. Methods: We studied a consecutive series of adults with FLT3-mutated leukemia at our institution since we began testing in 2006 through Sept 2011. Clinical characteristics and patient (pt) outcomes were extracted through a retrospective chart review and analyzed using logistic regression and Cox proportional hazard models. Results: We identified 73 pts with a FLT3 mutation (71 with AML and 2 with myelodysplasia with &lt;20% blasts). 62 (85%) presented to our institution at initial diagnosis; 11 (15%) were diagnosed elsewhere and seen by us only at relapse. 44 (60%) were men and 51 (70%) were white. Median age was 62 yrs (range, 19-90); 48% were &lt;60 yrs old. 63 (86%) had an internal tandem duplication (ITD) mutation, 9 (12%) had the D835 point mutation (TKD), and 1 had both. An NPM1 mutation was also present in 26 (36%). Median white blood cell count at diagnosis was 53 x 10 3 /µL (range, 0.8 - 466). 34 (47%) had monocytic morphology (M4 or M5). 8 (11%) pts had favorable karyotypes; 50 (68%) had normal karyotypes; 13 (18%) had unfavorable karyotypes. 58 (79%) received standard induction therapy (anthracycline + cytarabine for most; ATRA + arsenic trioxide for 3 with APL); 46/58 (79%) achieved a complete remission (CR). Including the 15 pts who received only low intensity therapies, 40/64 (63%) with an ITD and 6/9 (67%) with a TKD mutation achieved CR. 31 (42%) pts received an allogeneic transplant, 21 in first CR (CR1) and 10 after relapse. Median overall survival (OS) for the whole group was 417 days (95% CI: 291-780); it was 684 days for those diagnosed at our institution and 285 days for those seen only after relapse. Median disease-free survival (DFS) in CR1 was 417 days. Median OS for pts transplanted in CR1 was 1262 days from initial diagnosis and 416 days for those transplanted after relapse. DFS did not differ with or without a transplant (median, 526 vs 305 days; p=.64). Conclusions: FLT3-mutated AML is heterogeneous. Our single center experience is similar to that reported from multi-center trials.
Abstract 15776: Long-term Prognostic Value of the Get With the Guidelines-heart Failure Risk Score in Acute Decompensated Heart Failure With Reduced or Preserved Left Ventricular Ejection Fraction
Authors: Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Tsutomu Kawai, Masahiro Seo, Iyo Ikeda, Eiji Fukuhara, Jun Nakamura, Makoto Abe, Kiyomi Kayama, Masatsugu Kawahira, Kazuya Tanabe, Masatake Fukunami
Journal: Circulation (2017)

Background: The Get with The Guidelines (GWTG) heart failure (HF) risk score was developed in the GWTG inpatient HF registry to predict in-hospital mortality but has not been fully validated for po...
Prediction of lymph node metastasis and prognosis in colorectal cancer patients using slug and vimentin expression.
Authors: Yuji Toiyama, Hiromi Yasuda, Susumu Saigusa, Yoshinaga Okugawa, Koji Tanaka, Yasuhiro Inoue, Keiichi Uchida, Yasuhiko Mohri, Tsutomu Tabata, Ajay Goel, Masato Kusunoki
Journal: Journal of Clinical Oncology (2012)

e14029 Background: Slug plays a critical role in regulating the epithelial-mesenchymal transition (EMT) by down-regulation of epithelial markers and up-regulation of mesenchymal markers. The purpose of the present study was to evaluate the clinical significance of Slug and Vimentin expression in colorectal cancer (CRC) and to perform in vitro characterization of Slug’s function. Methods: At first, the biological role of Slug in CRC was assessed by RNA interference in CRC cell lines to assess tumor progression, invasion and migration. We next analyzed Slug and Vimentin expression in surgical tissue specimens from 181 CRC patients by quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Results: Knockdown of Slug in siRNA knockdown studies resulted in induction of EMT markers, inhibited cancer cell proliferation, invasion and migration abilities. Slug and Vimentin expression in cancer tissues was significantly higher in patients with high T stage, lymph node involvement, liver metastasis and advanced TNM stage. We also observed a significant correlation between Slug and Vimentin expression in CRC (rho = 0.467). Increased Slug and Vimentin expression were significantly associated with poor prognosis in Stage I-IV (p&lt;0.0001, p=0.0005, log-rank test) and Stage II (p= 0.04, p=0.012, log-rank test) Furthermore, increased Slug expression was an independent predictive marker of lymph node metastasis (p=0.012) and prognostic factor (p= 0.025). Conclusions: Our data demonstrate that evaluation of Slug and Vimentin could be valuable in the identification of patients with lymph node metastasis or poor prognosis in CRC.
RNA methylomes reveal the m6A-mediated regulation of DNA demethylase gene SlDML2 in tomato fruit ripening
Authors: Leilei Zhou, Shiping Tian, Guozheng Qin
Journal: Genome biology (2019)

Methylation of nucleotides, notably in the forms of 5-methylcytosine (5mC) in DNA and N6-methyladenosine (m6A) in mRNA, carries important information for gene regulation. 5mC has been elucidated to participate in the regulation of fruit ripening, whereas the function of m6A in this process and the interplay between 5mC and m6A remain uncharacterized. Here, we show that mRNA m6A methylation exhibits dynamic changes similar to DNA methylation during tomato fruit ripening. RNA methylome analysis reveals that m6A methylation is a prevalent modification in the mRNA of tomato fruit, and the m6A sites are enriched around the stop codons and within the 3′ untranslated regions. In the fruit of the ripening-deficient epimutant Colorless non-ripening (Cnr) which harbors DNA hypermethylation, over 1100 transcripts display increased m6A levels, while only 134 transcripts show decreased m6A enrichment, suggesting a global increase in m6A. The m6A deposition is generally negatively correlated with transcript abundance. Further analysis demonstrates that the overall increase in m6A methylation in Cnr mutant fruit is associated with the decreased expression of RNA demethylase gene SlALKBH2, which is regulated by DNA methylation. Interestingly, SlALKBH2 has the ability to bind the transcript of SlDML2, a DNA demethylase gene required for tomato fruit ripening, and modulates its stability via m6A demethylation. Mutation of SlALKBH2 decreases the abundance of SlDML2 mRNA and delays fruit ripening. Our study identifies a novel layer of gene regulation for key ripening genes and establishes an essential molecular link between DNA methylation and mRNA m6A methylation during fruit ripening.
Trans-catheter arterial p53-gene-embolization using gelatin sponge particles in treatment of patients with advanced hepatocellular carcinoma.
Authors: Yuewei Zhang
Journal: Journal of Clinical Oncology (2013)

e15024 Background: Treatment options for advanced hepatocellular carcinoma (HCC) are limited due to patients’ poor condition, and resistance to both chemo- and radio-therapy. Trans-catheter embolization (TAE) or Trans-catheter chemo-embolization (TACE) is the most widely used locoregional treatment for advanced HCC. But no solid evidences support the beneficial effect of the chemotherapy in TACE. Many advanced HCC patients also can’t tolerate the locoregional chemotherapy. The p53 gene has multiple anticancer functions and does not have any of the immune-inhibitory effects of chemo- or radio-therapy. The objectives of this study are to investigate TAE plus recombinant adenoviral human p53 gene (rAd-p53) in treatment of advanced HCC. Methods: Fifty-eight patients with advanced, unresectable HCC were randomly to two groups: TAE plus p53 group (TAE-p53G), or TAE group (TAEG). The study patients included 56 males and 2 females with an average age of 62.5 (53-89) years old and with Child-Pugh score A or B (42 or 16, respectively). The patients received 3 times of TAE plus rAd-p53 for TAE-p53G or TAE only for TAEG, once in a month for 3 months. The TAE materials consist of gelatin sponge particles (GSP) alone or plus 2-4 x 10 12 viral particles of rAd-p53, mixed into 30 ml suspension. The study endpoints included response rate, one-year survival, liver function, and adverse effects. Results: After 3-5 days of the first treatment, CT scan showed deceased tumor density in all the study cases. At 6 months after the first treatment, based on the RECIST standard, 31.0% (9/29) and 51.7% (15/29) patients in TAE-p53G achieved a complete response (CR) and partial response (PR), respectively, versus 17.2% (5/29) and 37.9% (11/29) of CR and PR in TAEG, respectively. One-year survival rates were 79.4% and 60.7% with median survival time of 11.7 and 8.3 months for TAE-p53G and TAEG, respectively. There are no significant changes of liver functions in both groups after treatment. Mild or median fever was observed in all the patients in TAE-p53G. No serious adverse events or complications observed. Conclusions: TAE using GSPs plus rAd-p53 is effective and safe treatments for advanced HCC.
<i>Clostridium difficile</i>-associated diarrhea in cancer patients treated with fidaxomicin or vancomycin.
Authors: Oliver A. Cornely, Mark Miller, Bruno Fantin, Kathleen M. Mullane, Yin Kean, Sherwood Gorbach
Journal: Journal of Clinical Oncology (2012)

9067 Background: Oncology patients are at risk for infections, including C difficile infection (CDI). Fidaxomicin (FDX) is a novel antibiotic highly specific for C difficile with improved sustained response compared with vancomycin (VAN). Another important clinical outcome of CDI is time to resolution of diarrhea (TTROD), corresponding to the duration of passing unformed bowel movements. Methods: 183 patients with a current diagnosis of cancer were compared to non-cancer patients from a combined population of 1105 subjects with CDI in two phase 3 trials comparing 10 days of treatment with FDX (400 mg/day) or VAN (500 mg/day). Number of unformed bowel movements (UBM) per 24 h was monitored. Response was considered as ≤3 UBM/24 h. Time to resolution of diarrhea was defined as time in hours from the first dose of study drug to the last UBM on the day preceding two days of ≤3 UBM/24 h. Kaplan-Meier survival analysis (K-M) used the log rank test for significance (p&lt;0.05). Results: The response rate at end of treatment was 79.2% for 183 patients with cancer, compared to 88.6% for 922 patients without cancer (p&lt;0.001). Median TTROD was longer by 45 h in patients with cancer than those without. In the VAN treatment group, median TTROD was 65 h longer in patients with cancer vs those without and significant by K-M. In the FDX group, although median TTROD was longer by 20 h in patients with cancer vs those without, the difference was not significant by K-M. For patients with cancer, TTROD was significantly shorter during treatment with FDX than with VAN. Conclusions: Patients with cancer responded more slowly to treatment for CDI than did non-cancer patients; however, resolution of diarrhea was more rapid by 49 h during treatment with FDX than with VAN. [Table: see text]