tbuckley/cabot-search huggingface dataset:
Antimelanoma differentiation‐associated protein 5 antibody level is a novel tool for monitoring disease activity in rapidly progressive interstitial lung disease with dermatomyositis
Authors: T. Matsushita, K. Mizumaki, M. Kano, N. Yagi, M. Tennichi, A. Takeuchi, Y. Okamoto, Y. Hamaguchi, A. Murakami, M. Hasegawa, M. Kuwana, M. Fujimoto, K. Takehara
Journal: British Journal of Dermatology (2016)

Antimelanoma differentiation‐associated protein (anti‐MDA)5 antibodies are associated with rapidly progressive interstitial lung disease (RP‐ILD) in patients with clinically amyopathic dermatomyositis (CADM) or dermatomyositis (DM). We aimed to evaluate the relevance of monitoring anti‐MDA5 antibody levels for the management of RP‐ILD in patients with CADM or DM. Twelve patients with CADM (n = 10) or DM (n = 2) accompanied by RP‐ILD were included. Baseline characteristics and outcomes were recorded. Serial measurements of anti‐MDA5 antibody levels were measured. All patients were treated with corticosteroids, tacrolimus and intravenous cyclophosphamide. All patients achieved RP‐ILD remission after combined immunosuppressive therapy for a mean of 6·8 months, with significant decreases noted in the mean anti‐MDA5 antibody levels at remission. Six (50%) patients became anti‐MDA5 antibody negative after therapy. After a mean follow‐up of 31 months, RP‐ILD relapse was observed in four (33%) patients in both the anti‐MDA5 antibody sustained positive group and the negative conversion group. However, relapsed patients in the sustained positive group relapsed earlier than those in the negative conversion group. Thus, a decrease in anti‐MDA5 antibody levels during remission was associated with longer remission. Relapses were associated with a reincrease of anti‐MDA5 antibody levels in four of four (100%) patients. In contrast, none of the patients without reincrease in anti‐MDA5 antibody exhibited symptoms of relapse during follow‐up. Therefore, reincrease in anti‐MDA5 antibody levels was associated with relapse. The anti‐MDA5 antibody level is a novel parameter for monitoring and a good predictor of RP‐ILD relapse in patients with CADM or DM.
PENELOPE/AGO-OVAR 2.20: A double-blind placebo (PLA)-controlled randomized phase III ENGOT trial evaluating chemotherapy (CT) with or without pertuzumab (P) for platinum-resistant ovarian cancer.
Authors: Christian Kurzeder, Jose Maria Del Campo, Patricia Pautier, Felix Hilpert, Angiolo Gadducci, Petronella Ottevanger, Domenica Lorusso, Ignace Vergote, Isabel Bover, Michel Fabbro, Frederik Marmé, Yolanda Garcia, Frédéric Selle, Martina Gropp-Meier, Beatriz Pardo, Ulrich Freudensprung, Ru-Amir Walker, Antonio Gonzalez-Martin
Journal: Journal of Clinical Oncology (2014)

TPS5613 Background: Adding P to gemcitabine (GEM) for platinum-resistant ovarian cancer improved progression-free survival (PFS) in a subset of patients (pts) with low tumor HER3 mRNA expression [Makhija 2010]. PENELOPE (NCT01684878) comprises a safety run-in (Part 1, complete) and PLA-controlled randomized assessment of CT ± P (Part 2, below). Methods: Eligible pts have: measurable/non-measurable recurrent platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer (progression during or within 6 mo of completing ≥4 platinum cycles); centrally tested low HER3 mRNA expression (concentration ratio ≤2.81 by qRT-PCR on cobas z480); and have received ≤2 prior lines of CT. The primary Part 2 objective is to determine if PFS (assessed by independent review committee; IRC) is superior with P + CT vs PLA + CT. The key secondary endpoint is overall survival (OS). Both endpoints are part of a closed testing procedure. Additional endpoints include investigator-assessed PFS, objective response rate (RECIST v1.1), safety (NCI CTCAE v4.0), quality of life (including EORTC QLQ-C30 and QLQ-OV28) and pharmacokinetic parameters. Translational studies aiming to scrutinize and validate the preselection concept by correlating markers of signal pathway activation with efficacy have been implemented. Additional exploratory analyses will include gene expression profiling. Investigators select CT (topotecan, paclitaxel or GEM) before 1:1 randomization to P or PLA. Treatment is continued until progression or unacceptable toxicity. Stratification factors are: selected CT; prior anti-angiogenic therapy; and platinum-free interval (<3 vs 3–6 mo). The planned Part 2 enrollment is 154 pts. Recruitment to each CT cohort is capped at 1/3 of the total sample size. Primary PFS analysis will be done after 109 IRC-assessed PFS events, providing 95% power to detect a PFS hazard ratio (HR) of 0.50 (median PFS 1.4→2.8 mo) with 2-sided log-rank at α=0.05. Final OS analysis is planned after 129 deaths in Part 2, providing 80% power to detect an OS HR of 0.61 (median OS 8.4→13.8 mo); 2-sided log-rank at α=0.05. By 27 Jan 2014, 62 pts were randomized. Clinical trial information: NCT01684878.
Proteomic signatures of colorectal cancer to identify distinct and reproducible subgroups and to reflect prognosis.
Authors: Michael Sangmin Lee, Callisia Clarke, Zhi-Qin Jiang, Ganiraju C. Manyam, Feng Tian, Yiling Lu, Jeffrey Morris, Bradley McIntosh Broom, David Menter, Eduardo Vilar Sanchez, Imad Shureiqi, Kanwal Pratap Singh Raghav, Cathy Eng, George J. Chang, Iris Simon, Rene Bernards, Gordon B. Mills, Michael J. Overman, Dipen M. Maru, Scott Kopetz
Journal: Journal of Clinical Oncology (2015)

3612 Background: While colorectal cancer (CRC) has classically been categorized by gene expression, proteomic analysis directly elucidates the functional state of protein signaling, which may better reflect cellular behavior. We performed an antibody-based proteomic analysis (reverse-phase protein array; RPPA) of a large cohort of MD Anderson (MDACC) and The Cancer Genome Atlas (TCGA) samples to determine patterns of protein expression in CRC. Methods: Protein was extracted from 725 archived CRC tumor samples (263 MDACC discovery set, and 462 TCGA validation set), and RPPA was performed to determine the expression levels of 127 cellular proteins. Upon unsupervised hierarchical clustering, samples dichotomized with distinct patterns of protein expression. The proteins with highest discriminatory utility were identified by LIMMA in the discovery set and confirmed in the validation set. Clinical variables and DNA sequencing results were available for correlation. Results: Among the top 40 discriminant proteins for the dichotomized groups in each dataset, 24 were common to both and correlated with each other. One group was notable for high EMT/reactive stroma (high fibronectin, low E-cadherin), while the other group was notable for high TSC/MTOR (high MTOR, phospho-MTOR, Tuberin), and high RTK pathway components (high BRAF, HER2, HER3). This latter group also was notable for elevated beta-catenin and elevated phospho-AMPK. In the MDACC and TCGA cohorts, the high RTK group was more likely to have lymphovascular invasion (p = 0.023 in MDACC, p = 0.017 in TCGA) and less likely to have BRAF mutation (p = 0.011 in MDACC, p = 0.002 in TCGA). On multivariate Cox regression analysis of relapse-free survival of 171/233 Stage II-III MD Anderson patients with complete data, stage (HR 3.121, 95% CI 1.373-7.093, p = 0.007) and proteomic grouping (HR 2.105, 95% CI 1.037-4.274, p = 0.039) were significantly associated with inferior relapse-free survival, while age, BRAF mutation status, and lymphatic invasion status were not significant. Conclusions: CRCs appear to have distinct subsets defined by proteomic features. These findings reflect distinct differences in cellular function that have prognostic implications.
FDG-PET and CT as early predictors of outcome in NSCLC patients treated with erlotinib.
Authors: Robert Iannone, Jeffrey L. Evelhoch, Raymond Lam, Donald Alan Bergstrom, Bob Thornton, Gary A. Herman, P. David Mozley
Journal: Journal of Clinical Oncology (2012)

10573 Background: Tumor metabolism as assessed by FDG-PET is an early biomarker for clinical benefit in oncology. This multi-national study evaluated associations of changes in mean standardized uptake values (SUV mean ) of FDG and tumor burden with disease control rates (DCR: CR+PR+SD), PFS and OS in 48 NSCLC patients (EGFR mutants or favorable clinical/demographic characteristics) treated with erlotinib. The primary hypothesis was that changes in SUV mean at day 8 predicted DCR. Methods: Patients were scanned by FDG-PET (twice pre-therapy, 1 and 3 weeks post-therapy) and CT (same as FDG-PET and every 6 weeks post-therapy until progression or death). Early response biomarkers included the decrease in SUV mean (DiSUV), sum of diameters (DiSOD) and sum of volumes (DiSOV). For the primary hypothesis, metabolic response (MR) was defined as a decrease of &gt;2SD the variability between baseline PET scans (30%). Exploratory analyses of the biomarkers at various thresholds were performed. Results: The primary hypothesis was met: DCR was 34.6% (80% CI: 17.5%, 48.2%) higher in patients with a MR at day 8 (p = 0.033); the association was stronger for day 22. The table compares hazard ratios derived from the "optimal" % decrease (smallest upper 80% confidence limit) over the 10% to 50% (by 10%) range for all biomarkers and time points, by PFS and OS. Conclusions: FDG-PET was predictive for clinical responses after 8 days of treatment. Comparing all biomarkers, DiSOV had stronger associations than both DiSUV and DiSOD with PFS or OS. For NSCLC treated with erlotinib in this clinical context, the decrease in CT-based tumor volume may be a better early predictor of clinical outcome than FDG-based SUV mean . [Table: see text]
Abstract 2423: Deep phenotyping of dissociated solid tumor cells from breast cancer specimens
Authors: Aaron J. Middlebrook, Peter Llontop, Mary Beth Hanley, Warren Porter, Friedrich Hahn, Eileen Snowden, Rainer Blaesius, Smita Ghanekar
Journal: Cancer Research (2016)

Abstract Exploring tumor heterogeneity with the goal of improving outcome has led to the need to glean as much information as possible at an individual cell level from these valuable specimens. Traditional approaches to solid tumor analyses fail to reveal the diverse range of cellular compartments beyond tumor cells that comprise the tumor microenvironment. A comprehensive approach to tumor interrogation requires efficient tissue dissociation to facilitate analysis at the single-cell level. Compared to current methods, single-cell analysis of tumor derived cell suspensions by flow cytometry has the potential to provide a more thorough understanding of the many subpopulations within the tumor microenvironment and the cell-to-cell interactions that govern this space. Here, we demonstrate an efficient workflow that enables comprehensive cell analysis of solid tumors from breast cancers. After dissociating human breast cancer biopsies from primary tumors into cell suspension, we analyzed the immune compartment and the cancer/stromal cell compartment by multicolor flow cytometry, using 26 markers. A comprehensive analysis of this data set reveals the heterogeneity within the tumor microenvironment on a phenotypic level, which might have potentially significant correlations to the clinical status and molecular phenotype of the cancer. These results encourage the expansion of the use of flow cytometry as a means of solid tumor biopsy analysis, highlighting the potential clinical value of this approach in disease management. Citation Format: Aaron J. Middlebrook, Peter Llontop, Mary Beth Hanley, Warren Porter, Friedrich Hahn, Eileen Snowden, Rainer Blaesius, Smita Ghanekar. Deep phenotyping of dissociated solid tumor cells from breast cancer specimens. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2423.
Long-term Outcome of an Organ Preservation Program After Neoadjuvant Treatment for Rectal Cancer
Authors: Milou H. Martens, Monique Maas, Luc A. Heijnen, Doenja M. J. Lambregts, Jeroen W. A. Leijtens, Laurents P. S. Stassen, Stephanie O. Breukink, Christiaan Hoff, Eric J. Belgers, Jarno Melenhorst, Rob Jansen, Jeroen Buijsen, Ton G. M. Hoofwijk, Regina G. H. Beets-Tan, Geerard L. Beets
Journal: JNCI Journal of the National Cancer Institute (2016)

The aim of this study was to establish the oncological and functional results of organ preservation with a watch-and-wait approach (W&W) and selective transanal endoscopic microsurgery (TEM) in patients with a clinical complete or near-complete response (cCR) after neoadjuvant chemoradiation for rectal cancer.Between 2004 and 2014, organ preservation was offered if response assessment with digital rectal examination, endoscopy, and MRI showed (near) cCR. Watch-and-wait was offered for cCR, and two options were offered for near cCR: TEM or reassessment after three months. Follow-up included endoscopy and MRIs every three months during the first year, and every six months thereafter. Long-term outcome was assessed with Kaplan-Meier curves. Functional outcome was assessed with colostomy-free survival and Vaizey incontinence score (0 = perfect continence, 24 = totally incontinent).One hundred patients were included, with median follow-up of 41.1 months. Sixty-one had cCR at initial response assessment. Thirty-nine had near cCR, of whom 24 developed cCR at the second assessment and 15 patients underwent TEM (9 ypT0, 1 ypT1, 5 ypT2). Fifteen patients developed a local regrowth (12 luminal, 3 nodal), all salvageable and within 25 months. Five patients developed metastases, and five patients died. Three-year overall survival was 96.6% (95% confidence interval [CI] = 89.9% to 98.9%), distant metastasis-free survival was 96.8% (95% CI = 90.4% to 99.0%), local regrowth-free survival was 84.6% (95% CI = 75.8% to 90.5%), and disease-free survival was 80.6% (95% CI = 70.9% to 87.4%). Colostomy-free survival was 94.8% (95% CI = 88.0% to 97.8%), with a good continence after watch-and-wait (Vaizey = 3.4, SD = 3.9) and moderate after TEM (Vaizey = 9.7, SD = 5.1).Organ preservation appears oncologically safe for selected rectal cancer patients with a cCR or near cCR after neoadjuvant chemoradiation when applying strict selection criteria and frequent follow-up, including endoscopy and MRI. The low colostomy rate and the good long-term functional outcome warrant discussing this option with the patient as an alternative to major surgery.
Abstract LB-058: Linker variation and structure-activity relationship analyses of salicylic, benzoic and hydroxamic acid-based small molecule Stat3 inhibitors
Authors: Peibin Yue, Francisco Lopez-Tapia, Christine Brotherton-Pleiss, Marcus Tius, James Turkson
Journal: Cancer Research (2016)

Abstract Benzoic acid, salicylic acid and hydroxamic acid-based small molecules have been reported that inhibit Stat3 activation. However, the structural basis for their Stat3-inhibitory activities are not clearly defined. To investigate the molecular determinants for activity and to derive structurally optimized analogs of improved pharmacokinetic parameters and potency, we conducted a computer-aided molecule optimization program and synthesized new analogs of the previously reported lead Stat3 inhibitors, BP-1-102 (IC50, 6.8 ± 2.5), SH4-54 (IC50 4.4 ± 0.3), and SH5-07 (IC50 3.9 ± 0.6). All three leads are based on N-methylglycinamide scaffold with its two amine moieties condensed with three different functionalities. The three functionalities or the CH2 group of the glycolamide scaffold were separately modified to generate a series of compounds, some of which show improved potency compared to the corresponding parental compounds. Specifically, H012, H070 and H072 had improved inhibitory activity against Stat3 DNA-binding activity in vitro, with IC50 of 3.0 ± 0.9, 2.4 ± 0.4, and 2.2 ± 0.9 μM, respectively. The replacement of the pentafluorobenzene or the cyclohexylbenzene with other components was detrimental to activity and led to decreased potency of the new analogues, as did the substitution of the benzene of the pTyr-mimetic moiety with heterocyclic components containing nitrogen and oxygen elements. Pharmacokinetic study showed that analog H058 has improved permeability in Caco-2 bidirectional permeability studies, compared to the lower relative permeability of the lead agents. Ala-based analogs, such as H048 and H058, were low in microsomal stability, presumably due to the labile methyl groups of the Ala. Select active analogs inhibited constitutive Stat3 activation and the DNA-binding activity of Stat3 in cancer cells, and they further decreased the growth, colony formation, and migration of human cancer cells harboring persistently active Stat3. Studies together demonstrate a significant progress towards developing a more suitable Stat3 inhibitor with drug-like features. Additional efforts are focused on refining the physicochemical properties to further improve the activity and efficacy and ultimately furnish suitable Stat3-inhibiting candidates for clinical application. Citation Format: Peibin Yue, Francisco Lopez-Tapia, Christine Brotherton-Pleiss, Marcus Tius, James Turkson. Linker variation and structure-activity relationship analyses of salicylic, benzoic and hydroxamic acid-based small molecule Stat3 inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-058.
CELL SPECIFIC DELIVERY OF THE RHO-KINASE INHIBITOR Y27632 ATTENUATES ACTIVATION OF HEPATIC STELLATE CELLS IN VITRO AND IN ACUTE CCL4-INDUCED LIVER INJURY
Authors: Marike van Beuge, Jai Prakash, Marie Lacombe, Eduard Post, Catharina Reker-Smit, Leonie Beljaars, Klaas Poelstra
Journal: Hepatology (2009)
5-weekly S-1 plus cisplatin combined with trastuzumab for HER2-positive gastric cancer (WJOG7212G): a phase II study
Authors: Shuichi Hironaka, Negoro Yuji, Kimura Yutaka, Uchino Keita, Shinozaki Katsunori, Matsuda Masanori, Yuji Miura, Yoshimura Kenichi, Boku Narikazu, Hyodo Ichinosuke
Journal: Annals of Oncology (2015)
Medical Informatics and the “Three Long, One Short” Problem of Large Urban Hospitals in China
Authors: Jingyao Dai, Xiaofei Wang, Francisco J. Ayala
Journal: JAMA (2016)

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Abstract LB-018: Loss of function mutations of an ETS repressor expand the ETS positive subset of prostate cancer
Authors: Rohit Bose, Wassim Abida, Wouter Karthaus, Joshua Armenia, Phillip Iaquinta, John Wongvipat, Michael Doran, Haley Hieronymus, Philip Watson, Patrick Sullivan, Yupu Liang, Nikolaus Schultz, Charles Sawyers
Journal: Cancer Research (2016)

Abstract Recent genomic profiling of both primary and metastatic prostate cancers has revealed novel loss-of-function point mutations and copy number deletions of the gene ERF, an ETS transcriptional repressor with a nearly identical DNA-binding domain to the TMPRSS2-ERG oncogene product. Furthermore, ERF homozygous loss or point mutations occur exclusive of the ERG upregulation that occurs in 50% of prostate cancers following fusion of androgen-regulated upstream genomic elements of TMPRSS2 to the ERG gene. We characterized the function of ERF, as well as its relationship to ERG using CRISPR and shRNA technology to investigate both normal prostate- and patient tumor-derived organoid cultures, as well as existing TMPRSS2-ERG positive models. In both normal prostate and tumor models lacking upregulated ERG, inhibition of the ERF repressor leads to an expansion of the androgen transcriptome, and recapitulates phenotypic features seen with ERG upregulation. Cistromic analysis reveals that ERF occupies androgen-receptor (AR) associated chromatin, overlapping with potential ERG sites. Accordingly, in the presence of the upregulated ERG oncogene, ERF is now unable to bind any AR associated chromatin, and the AR transcriptome is expanded. CRISPR-mediated loss of ERG in TMPRSS2-ERG positive models leads to a halt of tumor cell growth, but concomitant loss of the ERF repressor partially restores cellular proliferation. We conclude that ERF is an endogenous repressor of androgen signaling in normal prostatic tissue and a potential tumor suppressor in prostate cancer. It occupies chromatin associated with AR-regulated genes and inhibits their transcriptional regulation. Loss of ERF function, either by mutation or more frequently by competition with the TMPRSS2-ERG gene product, leads to an expansion of the androgen transcriptome. Thereby, the ETS positive subtype of prostate cancer, currently defined by an activating ETS fusion event (e.g. TMPRSS2-ERG) should be expanded to encompass genomic loss of a repressive ETS factor. Citation Format: Rohit Bose, Wassim Abida, Wouter Karthaus, Joshua Armenia, Phillip Iaquinta, John Wongvipat, Michael Doran, Haley Hieronymus, Philip Watson, Patrick Sullivan, Yupu Liang, Nikolaus Schultz, Charles Sawyers. Loss of function mutations of an ETS repressor expand the ETS positive subset of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-018.