tbuckley/cabot-search huggingface dataset:
A phase II neoadjuvant trial of sequential triweekly nanoparticle albumin-bound paclitaxel and cyclophosphamide followed by 5-fluorouracil/epirubicin/ cyclophosphamide in the treatment of operable breast cancer.
Authors: Norio Masumoto, Takayuki Kadoya, Ai Amioka, Keiko Kajitani, Akiko Emi, Hideo Shigematsu, Rumi Haruta, Tsuyoshi Kataoka, Kazuo Matsuura, Morihito Okada
Journal: Journal of Clinical Oncology (2014)

1066 Background: Nanoparticle albumin-bound (nab) Paclitaxel has shown favorable efficacy and toxicity profiles compared to other taxanes in the treatment of metastatic breast cancer. In this phase II trial, we evaluated a nab-paclitaxel-containing neoadjuvant regimen in patients with operable breast cancer. Methods: Fifty-five women with operable breast cancer without prior treatment were enrolled. All patients were to receive tri-weekly nab-paclitaxel and cyclophsphamide (TRI-ABC) followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) every 3 weeks for 4 cycles. Tri-weekly trastuzumab was administered concomitant with TRI-ABC in HER2-positive (HER2+ or 3+) patients. Primary endpoint was pathologic complete response (pCR; CR) rate in breast cancer tissue and lymph nodes. Secondary endpoints included clinical response, safety, rate of breast conserving surgery and disease-free survival. Results: Fifty-four patients received at least 1 dose of chemotherapy and were included in this analysis. All patients completed 4 cycles of TRI-ABC and 50 completed 4 cycles of FEC. The pCR rate was 36.5% (19/54). More patients with HER2-positive or triple-negative cancer experienced a pCR [59% (10/17) for HER2-positive, 57% (8/14) for triple-negative] compared with those of ER-positive/HER2-negative cancer [4% (1/23)]. The most significant toxicities were grade 2/3 neuropathy (16%) in TRI-ABC and grade 3/4 febrile neutropenia (7%) in FEC. Conclusions: TRI-ABC and FEC containing neoadjuvant regimen was well tolerated and showed favorable efficacy, especially in patients with chemo-sensitive breast cancer. These results suggest that albumin-bound paclitaxel based neoadjuvant regimen should be further evaluated in patients with ER-negative or HER2-positive breast cancer. Clinical trial information: 000007180.
Anti-metastatic and anti-proliferative effects of xanthorrhizol, a natural sesquiterpenoid from Curcuma xanthorrhiza.
Authors: Min-Ah Choi, Seong Hwan Kim, Won-Yoon Chung, Jae-Kwan Hwang, Kwang-Kyun Park
Journal: Cancer Research (2005)

279  Recent evidence suggests that multiple cross talk among tumor cells and various host cells trigger the metastatic pathways. However, there are no drugs available to inhibit the metastasis of cancer cells. Accordingly, there have been many studies aimed at screening natural products for their anti-metastatic potentials. Xanthorrhizol is a sesquiterpenoid compound from the rhizome of Curcuma xanthorrhiza and is widely used as a traditional medicine in Indonesia. Therefore, this study used an in vivo mouse lung metastasis model (using a tail vein injection of a murine colon cancer cell line, CT26, onto Balb/c mice) and a tumor mass formation assay (using an intraperitoneal (i.p.) injection of a metastatic melanoma cell, B16BL6, onto C57BL6 mice) to evaluate the anti-metastatic activity of xanthorrhizol. Interestingly, xanthorrhizol inhibited the intra-abdominal tumor masses formation and the formation of tumor nodules in the lung tissue. These results suggested that xanthorrhizol possesses anti-metastatic activity in vivo. In order to examine the mechanism of the anti-metastatic action of xanthorrhizol in the mouse lung metastasis model, the expression pattern of several intracellular signaling molecules with the lung tissues including tumor nodules were evaluated. Higher expression levels of COX-2, MMP-9, p-ERK, Akt, and procaspase-9 in the metastatic group were observed, but these were attenuated by a treatment with xanthorrhizol. Furthermore, xanthorrhizol exhibited anti-proliferation and pro-apoptotic activity in colon cancer cells via the inhibition of the cell proliferation, the induction of the DNA fragmentation and the morphological changes in xanthorrhizol-treated cancer cells. Overall, xanthorrhizol exerts its anti-metastatic activity in vivo and its anti-cancer activity in vitro via the metastasis-related multiplex signal pathway.
Inhibitory role of annexin A1 in breast cancer cell proliferation and tumor growth
Authors: Yong Li, Ying Hu, Jinsong Liu, Constance Albarracin
Journal: Cancer Research (2008)

896  Annexin A1 (ANXA1) has diverse roles in apoptosis, proliferation, and in calcium-mediated and tyrosine kinase signaling. Alterations in ANXA1 expression have been described in several tumor types, including breast cancer. However, the precise role and function of ANXA1 in breast cancer have yet to be established. Our major goal was to investigate the role and function of ANXA1 in breast cancer. First, we evaluated ANXA1 expression in breast cancers with known histologic, pathologic and clinical characteristics. Immunohistochemical studies of breast cancer tissues demonstrated altered ANXA1 expression with progression of breast cancer and is consistent with some reports. ANXA1 has heterogeneous expression in benign ductal epithelial cells and prominent expression in myoepithelial cells. ANXA1 expression is maintained in the myoepithelial cells of ductal carcinoma in situ but is lost in the epithelial component of invasive ductal carcinoma. Analysis of tissue microarrays of human invasive breast tumors and corresponding axillary lymph node metastasis demonstrated loss of ANXA1 expression in 79% of breast tumors. Second, we evaluated ANXA1 function in breast cancer using cellular in vitro and mouse in vivo models. Stable overexpression of ANXA1 in breast cancer cell lines reduced cell proliferation and caused a 50% decrease in anchorage-independent growth in soft agar. Stable knockdown of ANXA1 expression with small inhibitory RNAs (siRNAs) in breast cancer cell lines caused a two- to three-fold increase in anchorage-independent growth in soft agar and tumor growth in nude mice. In conclusion, our studies indicate that ANXA1 has a potential role in the suppression of breast cancer cell growth. Furthermore, the stable breast cancer cell lines we have developed will be useful in further characterizing the function of ANXA1 in breast cancer.
How office based gyneco-oncologists in Germany apply antiemetic guidelines in patients receiving AC-containing (neo) adjuvant chemotherapy.
Authors: Joerg Peter Schilling, Hans-Joachim Hindenburg
Journal: Journal of Clinical Oncology (2014)

e20646 Background: Supportive care guidelines are an important instrument to maintain quality of treatment and quality of life in cancer patients (pts). However, there are limitations in guideline adherence and application of guideline changes such as the change of antiemetic risk category of anthracycline plus cyclophosphamide (AC)-containing chemotherapy. ASCO recommends prophylaxis with 5-HT3-receptorantagonist (RA), Neurokinin1-RA and dexamethasone (DEX). Methods: The objective of our online survey was to evaluate the awareness of modern antiemetic guidelines (GL) among German office based gyneco-oncologists and the usage of the guidelines in pts receiving AC-containing chemotherapy in everyday practice. 49 practices used the ODM Quasi GYN system for the documentation of data on institutions, patients, knowledge and application of antiemetic GL. Antiemetic treatment was documented in 250 breast cancer pts who received cycle 1 and 3 of AC chemotherapy (80% adjuvant, 20% neoadjuvant). Results: Awareness of antiemetic GL: AGO* 76%, ASCO 82%, NCCN 31%, MASCC 22%; application of GL: AGO 57%, ASCO 53%, MASCC 12%, NCCN 8%, none (2%). 94% of gyneco-oncologists were aware of the change of the emetic group of AC in the ASCO GL. 84% stated they already actively used triple drug antiemesis, 12% planned to do so, 4% said they were not going to use the triple drug schedule. Antiemetic treatment documentation in 246 pts: Cycle 1: 82 pts (33%) received the triple drug schedule according to GL, 113 (46%) a combination of 5HT3-RA and DEX. Cycle 3: triple drug schedule: 35%, 5HT3-RA +Dex: 44%. 4 pts were lost to follow up. * AGO - German Working Group of Gynecologic Oncology. Conclusions: Despite a broad awareness of current antiemesis guidelines and of the classification of AC-chemotherapy as highly emetogenic, only 33% of pts received the triple combination according to GL in the first cycle of AC and only 35% in the third cycle.
Molecular characterization of advanced refractory prostate cancer.
Authors: Charles E. Myers, Ryan P. Bender, Sherri Z. Millis, Rebecca Feldman
Journal: Journal of Clinical Oncology (2014)

e16090 Background: Anti-androgens and taxanes are a mainstay of prostate cancer (PCa) treatment. These therapies, however, fail as the tumor progresses. Molecular characterization of advanced refractory PCa to identify actionable alterations was undertaken to enhance current treatment paradigms. Methods: 388 PCa cases were evaluated. A multiplatform approach of biomarker testing was used and included a combination of sequencing (NGS), protein expression (IHC) and gene amplification (ISH). Results: IHC was performed in ~350 patients, ISH was performed ~100 patients. Therapies not commonly used in PCa may be considered: cetuximab (47% EGFR IHC high, 13% EGFR amplified) and temozolomide, gemcitabine and fluorouracil based on low expression of MGMT (44%), RRM1 (69%) and TS (83%). Traditional PCa drugs including taxanes based on low TUBB3 (74%) or high TLE3 (45%), anti-androgens based on high AR (89%) and platinums based on low ERCC1 (72%) may also be of benefit. Based on NGS data from ~66 patients, the most commonly mutated pathways are TP53 (43%), PI3K/PTEN (16%) and Wnt (APC or CTNNB1) (11%); agents targeting these pathways are available in clinical trials. Single agent response rates in PCa have been disappointing or patients relapse. Additional analyses identified potential combination strategies. Forty percent of patients with low TS or RRM1 harbor mutations in TP53. Recent data (Blackwood, 2013) suggest the addition of Chk1 inhibitors potentiates response to chemotherapy in TP53-mutated patients. Dual targeting of AR and PIK3CA may be of potential benefit as 68% of patients with high AR expression exhibit PTEN loss. Twenty-one percent of patients exhibit low TUBB3 and high TLE3, a majority of which exhibit low ERCC1 (75%) or high expression of AR (98%), suggesting combination of taxanes plus carboplatin or anti-androgens, respectively. Forty-four percent of PCa lack actionable gene mutations by NGS, however 96% of these patients did have actionable targets identified by IHC and ISH platforms. Conclusions: Combining novel targeted agents with traditional treatments may achieve additive or synergistic effects. Utilization of IHC, ISH and mutational analysis results can identify combination treatment strategies for advanced refractory PCa.
Hepatic oligometastases treated with stereotactic body radiation therapy: Updated 10-year analysis of the Indiana University experience.
Authors: Ben Goodman, Higinia Rosa Cardenes, Mary A. Maluccio, Paul R. Helft
Journal: Journal of Clinical Oncology (2014)

3583 Background: Stereotactic body radiation therapy (SBRT) is a non-invasive, effective technique in the treatment of a limited number of liver metastases from solid tumors. We present the 10 year update of our single institution SBRT experience outcomes and toxicity. This is thought to be the largest single institution experience present in the literature. Methods: We treated 81 patients 89 different times, for a total of 106 lesions. Inclusion criteria were patients with 1-3 liver metastases without evidence of extra-hepatic progression, and at least 700 cc of liver (minus the GTV) receiving less than 1500 cGy. The majority of patients had colorectal primary cancers. Other diagnoses included: Non-colorectal GI, breast, ovarian, NSCLC, and others. Among the lesions treated the majority received prior chemotherapy. Results: The median overall survival was 31 months. Kaplan Meier survival estimates at 12, 24, 36, and 48 months were 85%, 61%, 34%, and 18%. The local control rate was 94% with Kaplan Meier estimates at 12, 24, 36, and 48 months being 95%, 90%, 90% and 90%. The observed toxicities noted among the 106 treatments included mostly CTC grade 1-2 toxicity with only two grade 4 and one grade 5 toxicity. There was no difference in the toxicity based on the primary site. The majority of patients had grade 1 to 2 non-hepatic GI toxicity, grade 1-2 fatigue or grade 1-2 chest wall pain. The most severe toxicity noted was 1 patient with grade 5 hepatic toxicity and 2 patients with grade 4 hepatic toxicity. In addition, two patients developed grade 1 pleural effusions thought to be secondary to treatment. Parameters affecting toxicity were evaluated based on grade 4-5 hepatic toxicity. Generalized estimating equation models were fit to test for an association between each categorical factor and grade 4-5 hepatic toxicity. Linear mixed models were used to test for an association between each continuous factor and grade 4-5 hepatic toxicity. The only patient with grade 5 toxicity was treated three different times to a total of four lesions. Conclusions: Stereotactic body radiation therapy is a safe and effective treatment for patients with 1-3 liver metastases with a limited toxicity profile.
Four-year survival in patients (pts) undergoing liver surgery after neoadjuvant triplet hepatic artery infusion (HAI) and intravenous cetuximab (IV-CET) for previously treated and unresectable liver metastases from kras <i>wt</i> colorectal cancer (LM-CRC) (European trial OPTILIV, NCT00852228).
Authors: Francis Levi, Michel Ducreux, Denis Michel Smith, Mohamed Hebbar, Céline Lepère, C. N. J. Focan, Rosine Guimbaud, Pasquale F. Innominato, Carlos Carvalho, Salvatore Tumolo, Stephanie Truant, Denis Castaing, Abdoulaye Karaboué, Valerie Boige, Mohamed Bouchahda, Philippe Rougier, Rene Adam
Journal: Journal of Clinical Oncology (2014)

3589 Background: IV chemotherapy (chemo) downsizes LM-CRC in most pts. Yet less than 15% of those with previously unresectable LM and prior chemo undergo successful complete macroscopic LM resection (R0-R1). 4-y survival is 42% in all pts with LM resection (Livermetsurvey). Purpose is to determine disease-free survival (DFS) and OS in pts with R0-R1 partial hepatectomy after neoadjuvant HAI of irinotecan, oxaliplatin, and 5-fluorouracil and IV-CET for LM-CRC in the first multicenter trial testing this strategy. Methods: The 9 centers accrued 64 pts with 1-3 prior chemo, bilateral LM (84% pts), a median number of 10 LM, with largest diameter of 53 mm, spread in a median of 6 segments. First intent LM surgery was deferred for high LM number (72% of the pts), large size (69%), ill location (61%), extra-hepatic disease (2%), or other cause (12%). Liver surgery was performed whenever R0-R1 became feasible at q6-9 weeks multidisciplinary review. Results: LM surgery occurred 2.6 to 19.4 months (mo) after inclusion (median, 5.3). Single-, two- or three-stage R0-R1 hepatectomies were performed in 15, 3 and 1 pt respectively. LM resection was associated with younger age (median, 52 vs 60 y, p=0.01), less liver involvement (≤25% vs >25% tumor replacement, 68% vs 38% of the pts, p=0.025; median N of segments involved, 5 vs 7, p=0.015), and 1 rather than 2-3 prior chemo (46% vs 20% of the pts, p=0.01). Resection rate did not differ according to sex, PS, primary tumor stage or grade, LM bilaterality and number, prior resections, extrahepatic disease, or objective response rate (42% vs 40%). Median DFS was 15.7 mo [95% CI, 10- 21], with LM recurring in 11 pts (58%). Median OS was 18.7 mo [13-24] with no 4-y survivor among the 45 pts without LM resection. In contrast, median OS was 35 mo [31-40] in the 19 resected patients, with 45% [10.3 - 79.7] survival at 4-y (p<0.001). Conclusions: The combination of IV-CET with HAI-IFO deserves upfront evaluation as a most effective neoadjuvant treatment option within a medico-surgical strategy aiming at the eradication of LM-CRC. Clinical trial information: NCT00852228.
A Single-Cell Approach to Unraveling Abnormal Megakaryocyte Differentiation and Function in Myelofibrosis
Authors: Bethan Psaila, Elisabeth F Heuston, Dragana Milojkovic, Jens Lichtenberg, Stacie M Anderson, Ronald Hoffman, Irene Roberts, Adam J Mead, David M. Bodine, Nisc Comparative Sequencing Program, Nikolaos Barkas
Journal: Blood (2017)
Effect of a treat-to-target intervention of cardiovascular risk factors on subclinical and clinical atherosclerosis in rheumatoid arthritis: a randomised clinical trial
Authors: Benjamin Burggraaf, Deborah F van Breukelen-van der Stoep, Marijke A de Vries, Boudewijn Klop, Anho H Liem, Gert-Jan M van de Geijn, Noelle van der Meulen, Erwin Birnie, Ellen M van der Zwan, Jende van Zeben, Manuel Castro Cabezas
Journal: Annals of the Rheumatic Diseases (2019)

Background Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease (CVD). No long-term intervention trials on CVD risk factors have been published, and a debate on the efficacy of controlling traditional risk factors in RA is ongoing. We aimed to evaluate a treat-to-target approach versus usual care regarding traditional CVD risk factors in patients with RA. Methods In this open-label, randomised controlled trial, patients with RA aged &lt;70 years without prior CVD or diabetes mellitus were randomised 1:1 to either a treat-to-target approach or usual care of traditional CVD risk factors. The primary outcome was defined as change in carotid intima media thickness (cIMT) over 5 years, and the secondary outcome was a composite of first occurrence of fatal and non-fatal cardiovascular events. Results A total of 320 patients (mean age 52.4 years; 69.7% female) with RA underwent randomisation and 219 patients (68.4%) completed 5 years of follow-up. The mean cIMT progression was significantly reduced in the treat-to-target group compared with usual care (0.023 [95% CI 0.011 to 0.036] mm vs 0.045 [95% CI 0.030 to 0.059] mm; p=0.028). Cardiovascular events occurred in 2 (1.3%) of the patients in the treat-to-target group vs 7 (4.7%) in those receiving usual care (p=0.048 by log-rank test). Conclusion This study provides evidence on the benefit of a treat-to-target approach of traditional CVD risk factors for primary prevention in patients with well-treated RA. Trial registration number NTR3873.
A chemogenomic screening platform for identification of protein kinase CK2 as a novel target for prosenescence therapy in PTEN-null tumors.
Authors: Madhuri Kalathur, Alberto Toso, Jingjing Chen, Ajinkya Revandkar, Claudia Danzer-Baltzer, Ian Frew, Andrea Alimonti
Journal: Journal of Clinical Oncology (2014)

11116 Background: Pten loss-induced cellular senescence (PICS) is characterized by the absence of hyper-replication, as well as lack of DNA damage response. Therapeutic enhancement of cellular senescence in tumors triggers an irreversible cell growth arrest and activation of a tumor immune response that can be used for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers but these therapies are not selective for cancer cells. Methods: We developed a combined chemical and shRNA screening platform to identify compounds that selectively enhance senescence in Pten deficient cells without affecting normal cells. By using this approach, we identified several Casein Kinase II (CK2) inhibitors as highly effective and selective pro-senescence compounds in Pten null cells and tumors. Results: We have identified CK2 inhibitors through our chemogenomic platform and furthur validated using shRNA kinase library. These compounds have enhanced the cellular senescence in Pten deficient cells. Mechanistically, we find that CK2 mRNA and protein levels are strongly up regulated in Pten null cells and PML is downregulated. Interestingly, CK2 transcription depends on the activation of signal transducer and activator of transcription 3, STAT3 that is highly phosphorylated in Pten null tumors. Treatment of Pten null prostate tumors with CK2 inhibitors has lead to the stabilization of PML thereby restoring its tumor suppressor activity; which then prompts more cells to enter senescence leading to tumor regression. Conclusions: Using our novel platform technologies we have discovered better pro-senescence compounds and systematically validating them in vitro and in vivo. We disocvered the possible mechanism behind the target based selective enhancement of senescence in Pten loss prostate cancer. These present findings for the first time showcase the proof-of-concept for the pro-senescence therapy.
Genome Wide Association Analyses Identify Pleiotropic Variants Associated with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Susceptibility
Authors: Junke Wang, Alyssa I. Clay-Gilmour, Ezgi Karaesmen, Abbas Rizvi, Qianqian Zhu, Li Yan, Leah Preus, Song Liu, Daniel Stram, Loreall Pooler, Xin Cheng, Christopher Haiman, David Van Den Berg, Amy Webb, Guy Brock, Elizabeth A. Griffiths, Stephen R. Spellman, Marcelo C Pasquini, Philip L. McCarthy, James M. Allan, Kenan Onel, Theresa E. Hahn, Lara E. Sucheston-Campbell
Journal: Blood (2018)
Cord Blood Transplantation in Adolescents and Young Adults with Acute Leukemia: On Behalf of Eurocord, Ctiwp and PDWP of EBMT
Authors: Hiromi Hayashi, Fernanda Volt, Jaime Sanz, Eefke J. Petersen, Nicolas Boissel, Rachael Hough, Noel Milpied, Emanuele Angelucci, Ibrahim Yakoub-Agha, Mauricette Michallet, Gerard Michel, Mahmoud Aljurf, Chantal Kenzey, Vanderson Rocha, Jean-Hugues Dalle, Peter Bader, Eliane Gluckman, Annalisa Ruggeri
Journal: Blood (2018)