tbuckley/cabot-search huggingface dataset:
Phase II study of gemcitabine and vinorebline in patients with persistent or recurrent platinum-resistant ovarian or primary peritoneal cancer: A study of the Korean Cancer Study Group.
Authors: Sook Hee Hong, Jae Ho Byun, Soohyeon Lee, Hoon-Gu Kim, Hyo Jin Lee, Kyung Hae Jung, Sang-Cheol Lee, Na-Ri Lee, Jina Yun, Dae-Sik Hong, In Sook Woo, Kyong Hwa Park, Sun Young Rha
Journal: Journal of Clinical Oncology (2014)

5568 Background: To evaluate the antitumor activity and safety of gemcitabine and vinorelbine in patients with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer Methods: A phase II trial was conducted by the Korean Cancer Study Group. Patients with cancer that progressed on platinum-based primary chemotherapy or recurred within 6 months were enrolled. One prior chemotherapy regimen for the treatment of persistent or recurren platinum resistant disease was allowed. Vinorelbine at 25mg/m2 followed by gemcitabine 1000mg/m2was administered intravenously on day 1 and 8 every 3weeks . Dose delay and adjustment was permitted for toxicity. Treatment was continued until disease progression or unacceptable adverse effects. Results: From December, 2011 to January, 2013, 44 patients were enrolled. A total of 219 cylces (median, four: range one to 24cycles) of vinorelbine and gemcitabine were administered, with fifteen (34.1%) of patients receiving six or more cycles. Two patients (4.5%) had a complete response and seven patients (15.9%) had partial responses, with a median duration response of 9.4 (95% Confidential Interval (CI) 4.6-18.3) months. Nineteen patients (43.18%) had stable disease for a median of 3.6 (95% CI: 2.5-4.4) months. Twelve patients (27.3%) had progressed disease. Four patients (9.0%) were not assessable. Median progression-free survival was 3.4 (95% CI: 2.5-4.2) months, and overall survival was 12.2 months. Grade 3 or 4 neutropenia, the most frequent toxicity occurred in 50% of patients. 4 patients experienced grade 3 febrile neutropenia and one patient experienced grade 4 febrile neutropenia. Non- hematologic toxicities were tolerable. A 25% dose reduction was required for 33patients (75%; 61.8% of cycles). No treatment related death observed. Conclusions: Gemcitabine and vinorelbine combination chemotherapy has sufficient activity in the treatment of recurrent platinum-resistant ovarian cancer at the dose and schedule tested to warrant further investigation. Clinical trial information: NCT01196559.
Modified FOLFOXIRI plus cetuximab (cet) as induction treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Preliminary results of the phase II randomized Macbeth trial by GONO group.
Authors: Chiara Cremolini, Fotios Loupakis, Lisa Salvatore, Sara Lonardi, Francesca Battaglin, Teresa Gamucci, Roberta Grande, Francesca Di Fabio, Fabiola Lorena Rojas Llimpe, Laura Ferrari, Mariaelena Casagrande, Sara Lucchesi, Giuseppe Tonini, Maria Banzi, Chiara Valsuani, Domenico C. Corsi, Gabriella Fontanini, Daniela Tomcikova, Luca Boni, Alfredo Falcone
Journal: Journal of Clinical Oncology (2014)

3596 Background: Phase II trials investigated the combination of a triple chemotherapy regimen with anti-EGFR monoclonal antibodies reporting promising activity but some concerns about the safety profile. The optimal maintenance regimen to be adopted following chemotherapy + an anti-EGFR is also not well established. The aims of MACBETH trial are to evaluate the activity and safety of 1st-line mFOLFOXIRI plus cet and to explore the role of maintenance with cet or bev in unresectable and molecularly selected mCRC pts. The study initially enrolled KRAS exon 2 wt pts, but after amendment only RAS and BRAFwt pts were eligible. Methods: Pts are randomized to receive an induction treatment of up to 8 cycles of mFOLFOXIRI + cet (cet 500 mg/sqm, irinotecan 130 mg/sqm, oxaliplatin 85 mg/sqm, 5 l-LV 200 mg/sqm, 5FU infusion 2400 mg/sqm over 48h q2w), followed by cet until disease progression (PD) or the same regimen followed by bev until PD. Primary endpoint is 10 months-Progression Free Rate (10m-PFR). Target accrual is 136 pts. Results: Between November 2011 and January 2014, 212 pts were screened and 94 pts were randomized in 18 Italian centers. At the data cut-off of Dec 2013, 72 pts completed the induction phase. Pts' characteristics were: median age 59 yrs, ECOG PS 0 92%, synchronous metastases 79%, multiple sites of disease 60%, NRAS mutated 4.2%, BRAF mutated 2.8%. The median number of administered cycles was 8. Main grade 3-4 toxicities were neutropenia (34.7%), febrile neutropenia (2.7%), diarrhoea (21.3%), skin rash (14.7%), stomatitis (6.7%), neurotoxicity (2.7%). One (1.4%) and 50 (69.4%) pts achieved CR and PR, respectively (RR in the intention to treat population: 70.8%). Ten (13.9%) pts reported SD (DCR: 84.7%) and 4 (5.6%) progressed. Seven (9.7%) pts did not undergo response assessment. Out of 65 pts evaluable for RECIST response, RR and DCR were 78.5% and 93.8%, respectively. Conclusions: A short “induction” treatment with mFOLFOXIRI + cet, according to the present schedule, shows a feasible safety profile with encouraging activity. The trial is still ongoing and updated results will be presented. Clinical trial information: 2011-000840-70.
Cardiovascular magnetic resonance imaging compared to echocardiogram for detecting doxorubicin-induced cardiotoxicity.
Authors: Haleem J. Rasool, Tahir Tak, Paula Gill, James Edward Novotny, Camilla Jaekel, Rifat T. Elkhatib, Jonathan Ticku, Emily R Boland, Angus Marshall
Journal: Journal of Clinical Oncology (2014)

1068 Background: Doxorubicin is a standard treatment for breast cancer, lymphoma, and leukemia. The benefits of doxorubicin are limited by its potential for cardiotoxicity. In this study we investigated whether MRI is superior to echocardiogram in detecting a reduction in cardiac systolic function indicative of doxorubicin toxicity. Methods: We studied all eligible prospective patients ages 18 years and above who presented to Mayo Clinic Health System, La Crosse WI, for the treatment of breast cancer or lymphoma and who were offered treatment with doxorubicin with curative intent dosing (240 - 300 mg/m2) between March 1, 2009 and October 2013. Patients received baseline cardiac MRI and echocardiogram. Both studies were repeated after 4 cycles of treatment. Ejection fraction calculated by both methods was compared and analyzed using the T-test. Results: We enrolled 28 eligible patients between the ages of 39 and 78 years. Twenty six patients received baseline echocardiogram and cardiac MRI. Eighteen patients completed the post treatment studies after 4 cycles of doxorubicin. Seven patients declined to undergo post treatment studies. The average baseline EF by echocardiogram was 61.5% and by MRI was 61.8%. Post treatment EF by echocardiogram was 60.9% and by MRI was 57.1%. There was no statistically significant drop in EF by echocardiogram while there was a statistically significant drop in EF using cardiac MRI (p value < 0.05). Cardiac MRI findings alone did not lead to any doxorubicin dose reductions. Conclusions: Cardiac MRI is superior to echocardiogram in detecting doxorubicin induced reduction in cardiac systolic function. Echocardiogram is less expensive and more convenient for patients while MRI may be more sensitive in detecting doxorubicin cardiotoxicity. A larger study to confirm these findings is needed.
Walking Away from Conveyor-Belt Medicine
Authors: Fabrizio Elia, Franco Aprà
Journal: New England Journal of Medicine (2019)

The phone rings in our emergency department. A community hospital is sending us a 70-year-old patient whose aortic endoprosthesis appears to be out of place, his aortic aneurysm at risk for a new rupture. The race is on. The conveyor belt starts moving.
Metabolic Syndrome Is Common Following Haematopoietic Cell Transplantation (HCT) and Is Associated with Increased Cardiovascular Disease and Second Cancers: An EBMT Cross-Sectional Non-Interventional Study
Authors: Diana M Greenfield, Nina Salooja, Christophe Peczynski, Steffie van der Werf, Helene Schoemans, Kate Hill, Agostino Cortelezzi, Maria Teresa Lupo Stanghellini, Zubeyde Nur Ozkurt, Mutlu Arat, Bernd Metzner, Pascal Turlure, Alicia Rovo, Gérard Socié, Mohamad Mohty, Arnon Nagler, Nicolaus Kroeger, Thomas Luft, Myriam Labopin, Thang Han, André Tichelli, Rafael F Duarte, Grzegorz W Basak, John A Snowden
Journal: Blood (2018)
Identification and targeting of novel CDK9 complexes in acute myeloid leukemia
Authors: Elspeth M. Beauchamp, Sameem M. Abedin, Sara G. Radecki, Mariafausta Fischietti, Ahmet Dirim Arslan, Gavin T. Blyth, Angela Yang, Connor Lantz, Alissa Nelson, Young Ah Goo, Imo Akpan, Elizabeth A. Eklund, Olga Frankfurt, Eleanor N. Fish, Paul M. Thomas, Jessica K. Altman, Leonidas C. Platanias
Journal: Blood (2018)
Dichotomous Toll-like receptor responses in chronic lymphocytic leukemia patients under ibrutinib treatment
Authors: Maria Gounari, Stavroula Ntoufa, Marina Gerousi, Maria Giovanna Vilia, Theodoros Moysiadis, Konstantia Kotta, Nikos Papakonstantinou, Lydia Scarfò, Andreas Agathangelidis, Eleonora Fonte, Pamela Ranghetti, Athanasia Nenou, Aliki Xochelli, Marta Coscia, Alessandra Tedeschi, Niki Stavroyianni, Marta Muzio, Kostas Stamatopoulos, Paolo Ghia
Journal: Leukemia (2019)
Anti-proliferative and apoptotic effects of chamomile extract in various human cancer cells
Authors: Janmejai Srivastava, Sanjay Gupta
Journal: Cancer Research (2007)

4207  Chamomile (Matricaria chamomilla), one of the most popular herbs, known for centuries for its medicinal values is consumed in the form of tea equivalent to over one million cups per day. Aqueous standardized extract of chamomile contains ~1.2% apigenin and 0.5% essential oils. Chamomile has been valued as a relaxant for digestion and nerves and frequently used as a mild sedative to calm nerves and reduce anxiety. It has many reported medicinal uses against skin irritation, inflammation, sore gums and general wound healing.Other proven actions of the herb include anti-ulcer, anti-bacterial, liver stimulation and anti-mycotic effects. Apart from its broad spectrum medicinal use, the anticancer properties of chamomile have not been evaluated. Here we assessed the anticancer properties of chamomile against various human cancer cell lines. Dry flower powder (~ 1 g) was subjected to aqueous and methanolic extraction, freeze dried, sterilized and used for cell culture. Exposure of cells with methanolic chamomile extract caused minimal growth inhibitory responses in normal human prostate epithelial cells (PrEC) and virally transformed normal human prostate epithelial cells (PZ-HPV-7). In sharp contrast, chamomile treatment resulted in significant decrease in cell viability in various human cancer cell lines. The IC50 values after 72 h chamomile exposure to human prostate cancer cells, LNCaP, DU145 and PC-3 ranged between 100-200 μg/mL. The IC50 values for aqueous chamomile extract ranged from 1500-3000 μg/mL. Similar growth inhibitory responses were observed in other human cancer cell lines viz. HeLa (cervical adenocarcinma), RKO (colon carcinoma), T-47D (breast carcinoma), and HT1080 (fibrosarcoma) after chamomile treatment. Chamomile exposure resulted in significant apoptosis in all prostate cancer cell lines as evident from (i) DNA fragmentation, (ii) fluorescence microscopy, and (iii) cell death detection ELISA. Further, pure apigenin and its analogues viz. apigenin-7-glucoside, apigenin-7-O-neohespiridoside and apiin were evaluated for their anti-proliferative properties in cancer cells. Amongst the agents tested, apigenin was most effective in inhibiting prostate cancer cell growth (IC50 at 24 h, 12-50 μg/mL) followed by apigenin-7-glucoside (IC50 at 24 h, 125-150 μg/mL), whereas apigenin-7-O-neohespiridoside and apiin exhibited weak responses in cancer cells. HPLC analysis of aqueous and methanolic chamomile extract confirmed apigenin-7-glucoside as the major constituents of chamomile, whereas some minor components were also observed. This study represents the first observation demonstrating the anticancer effects of chamomile and warrants detailed investigation on its mechanism of action to translate this herbal remedy for its use in cancer patients. (Grant support: USPHS grants NCCAM RO1 AT002709 and NIH RO1CA1085)
Lysophosphatidic acid-induced transactivation of the EGF receptor regulates connexin43-mediated gap junctional communication in ovarian surface epithelial cells.
Authors: Darren J. Park, Rui Lin, Nelly Auersperg, Bonnie J. Warn-Cramer
Journal: Cancer Research (2005)

174  Lysophosphatidic acid (LPA) is released by activated platelets and induces disruption of connexin43 (Cx43)-mediated cell-to-cell communication and enhanced cell proliferation in wound repair. The identification of LPA-activated mediators that regulate the growth-suppressive function of the Cx43 gap junction protein in normal ovarian cells may provide some insight into the development of ovarian cancer. These studies measured gap junctional communication (GJC) in rat ovarian surface epithelial (ROSE) cells by microinjecting a fluorescent dye into single cells and counting the neighboring cells that became fluorescent by dye transfer. Changes in Cx43 phosphorylation were detected by migration differences on SDS-PAGE and activation of protein kinases was demonstrated by Western blotting with phospho-specific antibodies or by immune complex activity assays. LPA induced a dose- and time-dependent fall in GJC in ROSE cells. Pre-treatment with pertussis toxin or a MEK inhibitor (PD98059) blocked the fall in GJC and the increase in Cx43 phosphorylation, supporting a role for a Gi G protein-coupled receptor (GPCR) and Erk kinases in these effects. Pretreatment with the Src family kinase inhibitor PP2 attenuated the fall in GJC and the increased Cx43 phosphorylation. Gi-GPCRs induce c-Src and Erk activation through transactivation of a receptor tyrosine kinase. We pretreated ROSE cells with an EGF receptor (EGFR) inhibitor (PD153035) to examine the role for the EGFR in LPA-induced signaling. Inhibiting the EGFR blocked LPA-induced auto-phosphorylation of the receptor, reduced the extent of Cx43 phosphorylation and prevented the fall in GJC. A recent study by Cameron et al. (JBC 2003) suggested that Erk5 is more important than Erk1/2 in the regulation of GJC in EGF-treated cells. We found that pre-treating ROSE cells with pertussis toxin, MEK inhibitor, PP2 or the EGFR inhibitor prevented the downstream activation of Erk5 in LPA-treated cells. In cells treated with the EGFR inhibitor and then with LPA, Erk1/2 was activated but GJC did not fall. These studies demonstrated that LPA induced Cx43 phosphorylation and disruption of GJC though a Gi-GPCR-dependent signaling pathway that initiated transactivation of the EGFR and activated an Src family kinase and Erk kinases. Importantly, transactivation of the EGFR was required for Erk5 activation and Erk5 was key for the fall in GJC. Since LPA disrupts Cx43-mediated GJC and the down regulation of Cx43 enhances cell proliferation, it is plausible that deregulation of LPA-activated signaling may down regulate the growth-suppressive function of Cx43 in normal ovarian surface epithelial cells and allow proliferation of abnormal cells that arise during the proliferative cycles of wound repair associated with ovulation and thus contribute to the development of ovarian cancer.
Randomized phase II trial comparing IG-001 versus paclitaxel against first-line advanced ovarian cancer.
Authors: Vuong N. Trieu, Monica Choi, Larn Hwang, Osmond D'Cruz
Journal: Journal of Clinical Oncology (2014)

5590 Background: IG-001 is a Cremophor-free, non-biologic, nanoparticle formulation of paclitaxel. Preclinical in vivo studies with IG-001 demonstrated a 3-fold increase in the MTD and a significantly increased antitumor efficacy over paclitaxel in multidrug-resistant human xenograft models. IG-001 has shown consistently positive response in Phase I/II clinical trials across five major cancer types: lung, breast, ovarian, pancreatic, and bladder cancers. The lack of effective therapy for chemoresistant patients with primary advanced epithelial ovarian cancer (EOC) underscores the need for new approaches to this disease. This study compared the response of IG-001 vs. paclitaxel in patients with primary advanced EOC. Methods: Preclinical efficacy of IG-001 vs. paclitaxel at equitoxic dose level was investigated in the paclitaxel resistant SKOV-3 xenograft model. Tumor bearing mice (n = 10/group) were treated i.v. with saline or equitoxic dose of paclitaxel (20 mg/kg) or IG-001 (60 mg/kg) on days 0, 4 and 8 (q3dx3). The safety and clinical efficacy of IG-001 vs. paclitaxel against EOC was evaluated in a Phase 1 (n = 18) and Phase II (n = 98) study. For the Phase I trial, six patients/dose level were treated with IG-001 at 220, 260, and 300 mg/m2. Phase II trial was a randomized, two-arm trial for advanced EOC (Experimental Arm: n = 50, IG-001 [260 mg/m2 IV] + Carboplatin [5 AUC IV 3 weeks, 6 cycles]; Control Arm: n = 48; paclitaxel [175 mg/m2 IV] + Carboplatin [AUC IV 3 weeks, 6 cycles]). Results: In the paclitaxel-resistant human SKOV-3 ovarian tumors, IG-001 was more effective than paclitaxel (p = 0.002, ANOVA). Though we did not reach MTD during our phase I study, 260 mg/m2was designated as the dose level for the phase II study. IG-001 + Carbo vs. paclitaxel + Carbo in patients with EOC demonstrated significant overall response rate (P = 0.017, Chi-square test) after 6 cycles/patient with 46% and 26% achieving complete response, respectively. Conclusions: IG-001 was found to be effective against EOC in preclinical and clinical studies. IG-001/Carboplatin combination chemotherapy was well-tolerated in women with advanced EOC and produced a doubling of overall response rates relative to those obtained with paclitaxel/Carboplatin-containing regimen. Clinical trial information: NCT01276548.
ANGIOMET: Analysis of the correlations between angiogenic markers and outcome in patients (p) with advanced nonsquamous NSCLC (NS-NSCLC) treated with carboplatin, paclitaxel, and bevacizumab (CPB).
Authors: Bartomeu Massuti, Eloisa Jantus-Lewintre, Jose Luis Gonzalez Arriba, Delvys Rodriguez Abreu, Oscar Juan, Manuel Domine, Mariano Provencio, Javier Garde, Ramon Garcia Gomez, Inmaculada Maestu, Ramon Maria Perez Carrion, Angel Artal, Christian Diego Rolfo, Josefa Terrasa, Juana Oramas, Ramon De Las Penas, Maria Sanchez Ronco, Javier De Castro, Rafael Rosell, Carlos Camps
Journal: Journal of Clinical Oncology (2014)

e19014 Background: In NS-NSCLC CPB achieved median OS > 1 y and supported use of B. A broad range of predictive/prognostic markers explored for B use. In VEGF pathway ligands and receptors play an important role in tumor angiogenesis and therapeutic efficacy. Altered levels of angiogenic factors in tumor or serum/plasma have been associated with prognosis and may be related with outcome when B is used. Methods: Advanced NS-NSCLC p were treated 1st-line with CPB. Primary end-point: PFS; secondary end-points: OS, RR, toxicity. Ancillary study designed to investigate relationship between angiogenic mediators, response and outcomes . 200 p St IIIB/IV NS-NSCLC and ECOG 0–2 prospectively included and treated with CPB 6 cycles followed by B maintenance. Ethical approval and informed consent for collecting peripheral blood samples and associated clinical data. Samples collected before treatment (basal) and at response evaluation (post). DNA obtained from leukocyte fraction (n=168). SNPs of angiogenic genes genotyped by PCR. Plasma levels of VEGFA and VEGFR2 determined by ELISA. Response RECIST.1 and toxicity CTCAEv.1. Results: P characteristics: median age 61 years [37-80], 67.2% male, 97.8% stage IV, 15.8% never-smokers, 100% caucasian, 88.2% adenoca. Median number of delivered CPB cycles 5. ITT RR (143 p): CR 1 (0.7%), PR 70 (48.9%), SD 52 (36.4%), PD 18 (12.6%), NE 2 (1.4%) Median PFS 6.91 months [6.16-7.65]; OS 14.57 months [11.83- 17.31]. No significant correlations between best response and the analyzed SNPs or plasmatic levels of VEGF and VEGFR2. VEGFR1 SNP rs9582036 (CC) was associated with shorter PFS (p=0.01) and OS (p=0.01). VEGFA SNP rs3025039 (CC) correlated with reduced OS compared with other genotypes (CT+TT) (p=0.009). No significant differences in PFS or OS were observed according to other SNPs . Lower levels (<median) of circulating VEGF (basal) with significant longer PFS (p=0.04 ) and a trend for OS (p=0.10). Conclusions: Multicentric trial with median OS 14.5 m achieved with CPB 1st-line in advanced NS-NSCLC p. Some VEGFR1 and VEGFA SNPs reduce CPB efficacy. In p with lower basal VEGF levels outcomes are improved. Clinical trial information: NCT01814163.
Association of polymorphisms in the CCL2/CCR2 axis with clinical outcome in localized advanced gastric cancer (AGC) patients (pts) from the United States and Japan.
Authors: Yu Sunakawa, Wu Zhang, Dongyun Yang, Takeru Wakatsuki, Yan Ning, Sebastian Stintzing, Stefan Stremitzer, Ana Sebio, Shinichi Yamauchi, Satoshi Matsusaka, Rita Elie El-Khoueiry, Syma Iqbal, Afsaneh Barzi, Mizutomo Azuma, Masahiko Watanabe, Wasaburo Koizumi, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

4052 Background: CCL2/CCR2 chemokine axis controls the recruitment of leukocytes to tissues during inflammation and has a number of tumor-promoting activities including the polarization of tumor associated macrophages which play immunosuppressive roles. Overexpression of CCL2 was associated with a higher risk of gastric cancer. We hypothesized that single nucleotide polymorphisms (SNPs) in genes encoding for CCL2/CCR2 axis may be associated with clinical outcome in pts with localized AGC. Methods: This study included 160 Japanese pts for evaluation set and 104 U.S. pts for validation set, with localized AGC treated with surgery alone or plus adjuvant therapy (stage Ib-IV; AJCC-6th). The median age were 68 (31-88) and 59 (26-85) years-old, median follow-up were 4 and 3.3 years, respectively. Genomic DNA was extracted from pts’ blood or tissues. Seven functional SNPs in genes encoding for CCL2/CCR2 axis, CCL2 (rs4586 and rs1024611) and CCR2 (rs743660, rs1799864, rs3138042, rs3918358, and rs3092964), were analyzed by PCR-based direct sequencing for association with disease-free survival (DFS) / time to recurrence (TTR) and overall survival (OS). Results: In the evaluation set, the univariate analysis showed pts with any T allele of CCL2 rs4586 had significantly longer DFS and OS compared to those with the C/C genotype (HR: 0.61; 95% CI: 0.39-0.96; P=0.03, HR: 0.58; 95% CI: 0.36-0.93; P=0.02, log-rank test, respectively) although median DFS and OS both had not been reached yet. This remained no significant upon multivariate analysis. In the validation set, pts with any T allele of CCL2 rs4586 had a trend toward shorter TTR (HR: 1.73; P=0.07) and significantly shorter OS compared to those with the C/C genotype (3.8 vs. 7.3 yrs; HR: 2.43; 95% CI: 1.14-5.18; P=0.01, log-rank test) in univariate analysis. Interestingly, the impact of the T allele on OS in the U.S. cohort was the opposite to that in the JPN cohort and reached statistical significance (P=0.001). Conclusions: Our results suggest that the CCL2 polymorphism, rs4586, may serve as a prognostic marker in pts with localized AGC and that there may be ethnic differences in immunoesurveillance impacting clinical outcome.