tbuckley/cabot-search huggingface dataset:
Gemcitabine plus cisplatin combination as second-line treatment in patients with metastatic breast cancer (MBC)
Authors: D. Ajarim, A. Ezzat, S. Bazarbashi, M. Rahal, M. El Foudeh, C. Pai, M. Raja
Journal: Journal of Clinical Oncology (2004)

774 Background: Gemcitabine and Cisplatin are active drugs in the treatment of MBC; this combination proved its effectiveness in the second line setting after failure of previous therapy that included anthracyclines and/or taxanes. Objectives: The objective of the study is to evaluate the efficacy and safety of Gemcitabine plus cisplatin as second-line chemotherapy in patients with MBC who have failed previous first line treatment that included anthracyclines and/or taxanes. Methods: From June 2000 to February 2002, 25 pts received gemcitabine 1,000 mg/m2 30 min infusion on d1, 8- Cisplatin 75 mg/m2 d1-q21. Eligibility criteria: proven MBC not amenable to local therapy for curative intent; age 18–75 yrs; KPS >70%; prior chemotherapy with anthracyclines and/or Taxanes; previous hormonal therapy is allowed; adequate bone marrow, liver, and kidney functions; life expectancy exceeding 6 months; informed written consent. Patients' characteristics: Of the 25 patients enrolled in the study, 21 were evaluable; median age was 41 (27–73 years), anthracyclines were received in 20 patients (18 of them combined with taxanes), one patient received taxanes only as first line treatment for MBC. Hormonal therapy was received in 11 patients (52%). Metastatic sites were: Lung in 11 pts (52%), soft tissue (including lymph nodes) in 8 pts (38%), liver in 14 pts (66%), bone in 10 pts (48%), and more than one site of involvement was present in 15 pts (71%). Results: All 25 patients were evaluable for toxicity while only 21 patients were evaluable for response. There was no CR, 6 pts achieved PR (29%), 4 pts SD (19%), and PD in 11 pts (52%). Hematologic toxicity mainly anemia grade 3/4 in 33.3%/8.3% of pts, neutropenia 20.8%/4.1%, non-hematologic toxicity mainly Grade III N & V in 21% of pts. Conclusions: Gemcitabine plus cisplatin is active in patients with MBC previously treated with anthracyclines and/or taxanes; the toxicity of this combination is manageable. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly
A Validated Prognostic Multigene Expression Assay for Overall Survival in Resected Colorectal Cancer Liver Metastases
Authors: Vinod P. Balachandran, Arshi Arora, Mithat Gönen, Hiromichi Ito, Simon Turcotte, Jinru Shia, Agnes Viale, Nikol Snoeren, Sander R. van Hooff, Inne H.M. Borel Rinkes, René Adam, T. Peter Kingham, Peter J. Allen, Ronald P. DeMatteo, William R. Jarnagin, Michael I. D'Angelica
Journal: Clinical Cancer Research (2016)

Risk stratification after surgery for colorectal cancer liver metastases (CRLM) is achieved using clinicopathologic variables, however, is of limited accuracy. We sought to derive and externally validate a multigene expression assay prognostic of overall survival (OS) that is superior to clinicopathologic variables in patients with surgically resected CRLM.We measured mRNA expression in prospectively collected frozen tumor from 96 patients with surgically resected CRLM at Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY). We retrospectively generated a 20-gene molecular risk score (MRS) and compared its prognostic utility for OS and recurrence-free survival (RFS) with three common clinical risk scores (CRS). We then tested the prognostic ability of the MRS in an external validation cohort (European) of 119 patients with surgically resected CRLM at the University Medical Center Utrecht (Utrecht, the Netherlands) and Paul Brousse Hospital (Villejuif, France).For OS in the MSKCC cohort, MRS was the strongest independent prognosticator (HR, 3.7-4.9; P < 0.001) followed by adjuvant chemotherapy (HR, 0.3; P ≤ 0.001). For OS in the European cohort, MRS was the only independent prognosticator (HR, 3.5; P = 0.007). For RFS, MRS was also independently prognostic in the MSKCC cohort (HR, 2.4-2.6; P ≤ 0.001) and the European cohort (HR, 1.6-2.5; P ≤ 0.05).Compared with CRSs, the MRS is more accurate, broadly applicable, and an independent prognostic biomarker of OS in resected CRLM. This MRS is the first externally validated prognostic multigene expression assay after metastasectomy for CRLM and warrants prospective validation. Clin Cancer Res; 22(10); 2575-82. ©2016 AACR.
Evaluation of the prognostic significance of activated STAT3 expression levels in head and neck squamous cell carcinoma (HNSCC)
Authors: E. Pectasides, P. Kountourakis, G. Fountzilas, B. A. Burtness, A. Psyrri
Journal: Journal of Clinical Oncology (2008)

6015 Background: Signal transducers and activators of transcription (STAT) are a highly conserved family of latent transcription factors that are activated in the cytoplasm in response to growth factor stimulation, after which they translocate to the nucleus to regulate gene expression. Although constitutive activation of STAT3 has been reported in HNSCC, the prognostic significance of STAT3 activation has not been clearly determined. In the present study, we sought to investigate the relationship between nuclear STAT3 expression and outcome in patients with HNSCC using a method that allows subcellular localization and quantification of proteins in paraffin-embedded tissue. Methods: A tissue microarray composed of 102 specimens from primary HNSCC cases was constructed. Protein expression levels for nuclear STAT3 were analyzed using an immunofluorescence-based assay that provides an automated, quantitative analysis of expression within subcellular compartments (AQUA). In this system, an anti-cytokeratin antibody conjugated to Cy3 is used to define pixels as tumor within each tissue spot. The intensity of STAT3 expression is then measured using Cy5 conjugated antibody with signal amplification. Primary study endpoints were progression-free survival and overall survival. Survival analysis was performed by Kaplan-Meier method with log-rank test for determining statistical significance. Results: Mean follow-up time for the cohort was 36 months. Seventy of 102 cases had sufficient tissue for AQUA analysis. In univariate survival analysis there was a significant correlation between nuclear STAT3 expression and 5- year progression-free (PFS) and overall survival (OS). Using the median as a cutpoint, high nuclear STAT3 expression was predictive for better PFS (p=0.05) and OS (p=0.03). In multivariable survival analysis, adjusting for well-characterized prognostic variables, nuclear STAT3 expression retained its prognostic significance for OS at 5 years (95%CI: 0.88–0.98, p=0.015). Conclusions: These findings support a role for activated STAT3 expression in HNSCC and provide initial evidence that activated STAT3 may be a marker for improved overall survival independent of other prognostic markers. No significant financial relationships to disclose.
Role of metalloproteinase-7 in oxaliplatin acquired resistance in colorectal cancer cell lines
Authors: V. Almendro, J. Maurel, J. Augé, G. Laus, J. Domingo-Domenech, E. Fernández, P. Gascon
Journal: Journal of Clinical Oncology (2006)

20042 Background: Mechanisms responsible for acquired resistance in colorectal cancer (CRC) tumors are not well understood. Anticancer drugs have been shown to enhance FASL expression by NF-kB induction. Additionally Metalloproteinase (MMP)-7 is over-expressed in CRC and has been shown to inhibit apoptosis by cleavage of FASL. We have previously shown in vivo that, sFASL increment was associated with acquired chemoresistance. Therefore we speculate that inhibition of MMP-7 or NF-kB can reverse chemoresistance in CRC cell lines. Methods: We generated an oxaliplatin-resistant cells (HT29R) from a p53 mutated (HT29) cell line. Both cell lines were cultured for 72h with different concentrations of oxaliplatin, BAY11–7085 (inhibitor of NF-kB activation), 0.01 mM of the MMP-7 inhibitor 1,10-Phenanthroline monohydrate (1,10-PM) and 100 ng/ml of DX2 monoclonal antibody. Different drug combinations were performed. Citotoxicity was determined by the MTS method, and cell cycle was analysed at 72h. Cell lines were characterized for MMP-7 expression (ELISA), NF-KB (Western-Blot), Fas expression (immunohistochemistry) and FasL expression (Western-Blot). Results: FAS was down-expressed in HT29R compared to HT29. The HT29R cells showed a IC50 for oxaliplatin 2-fold higher than normal cells. Treatment with 1,10-PM decrease MMP-7 levels (p &lt; 0.005) compared with untreated cells. Additionally, inhibition of MMP-7, restore IC50 values after oxaliplatin treatment in HT29R without changes in NF-KB expression. This oxaliplatin-resistant cell line, presents also sensibility for BAY11–7085, without affecting MMP-7 levels. Finally the addition of oxaliplatin to the MMP-7 inhibitor, increase FAS-mediated apoptosis (induced by DX2 antibody), suggesting that FASL cleavage is responsable of sensitivity. Conclusions: Reversal of oxaliplatin chemo-resistance can be obtained either by MMP-7 or NF-kB inhibition. Both drugs induced sFASL decrement, by inhibiting cleavage or expression, respectively. No significant financial relationships to disclose.
Multiple myeloma is characterized by widespread epigenomic alterations with prognostic implications.
Authors: C. J. Heuck, J. Mehta, N. Pulliam, R. Meagher, L. Zhou, E. Vickrey, E. Voigt, J. Greally, A. Verma, S. Singhal
Journal: Journal of Clinical Oncology (2010)

8117 Background: Multiple Myeloma (MM) is a slowly progressing disease with poor clinical outcome. Recent evidence suggests that epigenetic alterations such as aberrant CpG methylation may play a role in MM genesis but so far have not been studied in a global comprehensive manner. Methods: We evaluated the genome wide DNA methylation of CD138+ plasma cells from 29 patients with MM and 4 normal controls by using the HELP (HpaII tiny fragment enriched ligation mediated PCR) assay. Results: This high resolution array based assay analyzed 25,626 HpaII amplifiable fragments corresponding to 14,214 gene promoters and revealed widespread methylation changes in MM that were not restricted to CpG islands. Unsupervised hierarchical clustering of MM samples formed two groups based on DNA methylation profiles. Group 1 had more epigenetic similarity with the normal controls and was characterized by predominantly aberrantly hypo-methylated loci when compared to controls. On the other hand, group 2 was more epigenetically different from controls and was characterized by both aberrantly hyper and hypo methylated loci. Various novel genes were universally hypomethylated in myeloma (Zap70, ERBB3, KLF3) and the NFkappaB, TGFbeta and PI3K pathways were the dominant functional pathways targeted by hypomethylation (Ingenuity pathway analysis). Most importantly, the DNA methylation profiles were able to distinguish clusters with differing prognosis. Samples in Group 2 had worse prognostic features and were more likely to have non-IgG isotype involvement (p=0.0006), a plasma cell labeling index ≥0.3 (p=0.018) and complex cytogenetic abnormalities on FISH (p=0.000007). We furthermore observed a significantly lower Hb (mean Hb group 2=10.3, Mean Hb group 1= 12.2, p=0.0023) and a higher beta2 microglobulin level (mean group 1=2.91, mean group 2= 6.55, p=0.030) in Group 2 samples. Conclusions: Global methylation profiling shows widespread aberrant marks in MM with hypomethylation as the predominant change in myeloma plasma cells. DNA methylation analysis indentifies 2 distinct clusters of MM samples with differing prognosis and reveals novel epigenetic targets in different prognostic groups of myeloma. No significant financial relationships to disclose.
Shining a Light on the Dark Side
Authors: Elizabeth Allemann
Journal: Annals of Internal Medicine (2016)

Letters5 January 2016Shining a Light on the Dark SideElizabeth Allemann, MDElizabeth Allemann, MDFrom Missouri City, Missouri.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L16-0015 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Thank you for shining this light. As a family physician, I hear stories weekly of physicians who discount the lived experiences of women. Reading Laine and colleagues' editorial (1) and the anonymous article (2), I am inspired to reflect also on my own practice, now and in the past, and to pledge to do better, to listen more deeply, to honor all stories, but especially to find room in my heart to understand those who live their lives differently than I do, who make choices I would not, to see myself in “others” and “those people.” We ...References1. Laine C, Taichman DB, LaCombe MA. On being a doctor: shining a light on the dark side [Editorial]. Ann Intern Med. 2015;163:320. [PMID: 26280419]. doi:10.7326/M15-1144 LinkGoogle Scholar2. Anonymous. Our family secrets. Ann Intern Med. 2015;163:321. [PMID: 26280420]. doi:10.7326/M14-2168 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Missouri City, Missouri.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L15-0513. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoOn Being a Doctor: Shining a Light on the Dark Side Christine Laine , Darren B. Taichman , and Michael A. LaCombe Shining a Light on the Dark Side Christine Laine , Darren B. Taichman , and Michael A. LaCombe Shining a Light on the Dark Side Alvaro F. Vargas Pelaez Shining a Light on the Dark Side Gaetan Sgro , Mark T. Gladwin , Alexander Teng , Akshata Moghe , and Shanta M. Zimmer Shining a Light on the Dark Side Shafik Dharamsi Shining a Light on the Dark Side Linda Ray Shining a Light on the Dark Side Jordan Cohen and Richard I. Levin Metrics 5 January 2016Volume 164, Issue 1Page: 70KeywordsDisclosureHeart ePublished: 5 January 2016 Issue Published: 5 January 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
A phase I trial of liposomal doxorubicin (D), bevacizumab (A), and temsirolimus (T) in advanced malignancy
Authors: J. W. Moroney, R. L. Coleman, D. S. Hong, J. J. Wheler, C. Ng, D. C. Bodurka, G. Falchook, A. Naing, T. Helgason, R. Kurzrock
Journal: Journal of Clinical Oncology (2009)

e13508 Background: Liposomal doxorubicin (D) and bevacizumab (A) are active drugs in multiple malignancies. Unfortunately, resistance mechanisms have been described for each that limit their efficacy following repeated exposure. These include aberrant activation of alternate signaling pathways, such as PI3K/AKT/mTOR and upregulation of hypoxia inducible factor (HIF-1α). We therefore added temsirolimus (T), an agent known to inhibit mTOR and to downregulate HIF-1α, to the combination of D and A. The objectives of this trial were to assess the safety of this combination, obtain preliminary efficacy data and to identify biologic correlates for treatment response. Methods: D, A and T were administered intravenously on a 21 day cycle. D, A and T were given day 1, and T was administered alone weeks 2 and 3. A standard 3+3 trial design was used for dose escalation; 6 dose levels are planned. Patient serum and biopsies were also collected pre- and post-treatment for batched analysis to assess biologic response correlates. Results: 6/12 treated patients are evaluable (remaining patients have not yet completed 1st restaging). 5 patients are male; median age (all patients) 53, range 12 to 59. Median number of prior treatments = 5, range 2 - 8. At first restaging, 2/2 patients with endometrial cancer were found to have ≥ 25% decrease in tumor size (RECIST), and one patient with colorectal carcinoma had a 15% decrease. 1 patient had stable disease. One of the patients with endometrial cancer and extensive intra-abdominal disease who showed rapid tumor regression (≥ 25% decrease at 2 months) developed an entero-colonic fistula, and chose hospice care. Grade 2 stomatitis and fatigue (CTCAEv3)have also been seen. The current doses being used are 20mg/m2 of D and 5mg/m2 of A every 21 days, and 25mg of T every 7 days (dose level 3). Conclusions: Preliminary data indicate that the combination of D, A and T has anti-tumor activity and is well tolerated at the doses used. Patients with intra-abdominal disease who experience rapid tumor regression may be at risk for fistula formation. Biomarker analysis for modulation of the mTOR signal (via PI3K mutations or other aberrations) and the HIF-1α pathway is ongoing. No significant financial relationships to disclose.
Abstract 12073: Identification of Critical Level of Blood Volume Reduction in a Swine Model of Hemorrhagic Shock
Authors: Vesna Borovnik-Lesjak, Kasen Whitehouse, Alvin Baetiong, Brian Currie, Jeejabai Radhakrishnan, Raul J Gazmuri
Journal: Circulation (2012)

Background: Acute reduction in intravascular volume is a life-threatening emergency associated with high risk of initial death or subsequent organ dysfunction. In a swine model of hemorrhagic shock...
Efficacy and safety of anti-PD-1 antibody (Nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant ovarian cancer.
Authors: Junzo Hamanishi, Masaki Mandai, Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Toshinori Murayama, Shunsuke Chikuma, Satoshi Morita, Masayuki Yokode, Akira Shimizu, Tasuku Honjo, Ikuo Konishi
Journal: Journal of Clinical Oncology (2014)

5511 Background: Programmed death-1 (PD-1) is a co-inhibitory receptor expressed on activated T cells which regulates antitumor immunity. Nivolumab is a fully-humanized IgG4 that blocks the engagement of PD-1 by PD-1 ligands. Here we report the first trial for clinical application of nivolumab in ovarian cancer patients. Methods: Nivolumab was administered every 2 weeks to patients with advanced or relapsed, platinum–resistant ovarian cancer, at the doses of 1 or 3 mg/kg during two cohort examination (10 patients each). The phase II efficacy trial defined 1st endpoint of response rate, and second endpoints of safety, and disease control rate. Patients receivednivolumab up to 6 cycles (4 doses/cycle) of treatment or until PD or disease progression. Response rate was assessed by RECIST v1.1, and adverse events were evaluated by CTCAE v4.0. The data were cut-off on January 1, 2014. Results: Fifteen patients were treated with nivolumab (1 mg/kg: n=10, 3mg/kg: n=5), and evaluated. Median duration of therapy was 14 wks. There was one patient who had severe adverse drug reaction with fever, disorientation and gait disturbance. Clinical response rates were shown in Table. At the time of data cut off, one of the three partial responders had responses for 5 months, and the other two were on study with response for 4 and 10 months. Conclusions:Nivolumab at 1 mg/kg cohort is well tolerated and has encouraging clinical efficacy for advanced or relapsed, platinum-resistant ovarian cancer patients. 3 mg/kg cohort is now under investigation. Clinical trial information: UMIN000005714. Dose Total (n) CR PR SD PD NE RR DCR 1 (mg/kg) 10 0 2 3 4 1 2/10 (20%) 5/10 (50%) 3 (mg/kg) 3 0 1 1 1 0 1/3 (33%) 2/3 (67%) Total 13 0 3 4 5 1 3/13 (23%) 7/13 (54%) Abbreviations: RR: response rate; CR+PR; DCR: disease control rate; CR+PR+SD.
Abstract 15613: Adherence to the Mediterranean Diet is Inversely Associated with Advanced Glycation Endproduct Carboxymethyllysine among Male Middle-Aged Twins
Authors: Silvia C Eufinger, Viola Vaccarino
Journal: Circulation (2012)

Introduction:  Accelerated biological aging is thought to increase the severity of cardiovascular diseases through a network of unifying pathways, including inflammation, oxidative stress, and accumulation of advanced glycation endproducts (AGEs). Adherence to the Mediterranean diet has been inversely linked with markers of inflammation and oxidative stress. However, no previous study has examined whether markers of biological aging, particularly AGEs such as carboxymethyllysine (CML), are associated with the Mediterranean diet.   Hypothesis:  Greater adherence to the Mediterranean diet is associated with decreased levels of CML.   Methods:  A sample of 426 male middle-aged twins, including 129 monozygotic and 84 dizygotic twin pairs, with no previous history of coronary heart disease, was recruited from the Vietnam Era Twin Registry. All twins completed the Willett food-frequency questionnaire and the Mediterranean diet score (MDS) was calculated. AGEs were measured using commercially available kits. Robust regression analysis was used to examine the association between adherence to the Mediterranean diet and CML within pairs.   Results:  The mean age of the twins was 55 years (SD=3.0) and 95.8% were white. Within-pair differences in the MDS were assessed using a continuous scale. A 1-unit within pair absolute difference in the MDS was associated with a 1.7% ( P  P    Conclusions:  Adherence to the Mediterranean diet is inversely associated with CML, an advanced glycation endproduct that promotes accelerated biological aging, independent of traditional CVD risk factors and shared familial and genetic factors. Our study supports the importance of a healthy diet for vascular health and for the deceleration of early vascular aging.
A phase II study of chemoradiotherapy in patients with stage II, III esophageal squamous cell carcinoma (ESCC): (JCOG 9906)
Authors: K. Muro, A. Ohtsu, S. Ishikura, N. Boku, H. Takiuchi, H. Saito, K. Kaneko, Y. Miyata, Y. Komatsu, K. Shirao
Journal: Journal of Clinical Oncology (2007)

15137 Background: The study objective was to evaluate the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin and 5- fluorouracil (5FU) in patients with stage II, III ESCC. Methods: Patients with clinical stage II or III (T1N1 or T2–3N0–1 and M0) thoracic ESCC, age of 70 or younger, preserved organ functions were eligible. Treatment consisted of two courses of cisplatin 40 mg/m 2 (day 1, 8) and 5FU 400 mg/m 2 /day (days 1–5, 8–12), q5w combined with concurrent radiotherapy of 60 Gy in 30 fractions over 8 weeks with 2-week break. For responders, two courses of chemotherapy of cisplatin 80 mg/m 2 (day 1) and 5FU 800 mg/m 2 /day (days 1–5) q4w were added. The primary endpoint was overall survival and the secondary endpoints were response, toxicity, and progression-free survival. Results: From April 2000 to March 2002, 76 patients were accrued from 12 institutions. Characteristics of all patients were as follows: median age of 61 (range 39–70), male/female; 68/8, PS 0/1; 59/17, stage IIA/IIB/III; 26/12/38. There were two ineligible cases with inadequate liver function and T4 disease. Grade 4 neutropenia, leukopenia, and anemia occurred in 1.3%, 1.3% and 2.6%. Grade 3/4 esophagitis, stomatitis and infection occurred in 17%, 8% and 17%. Grade 3/4 late toxicities occurred in the following incidences; esophagus (dysphagia, mucositis, stenosis, and fistula) in 13%, pericardial effusion in 17%, pleural effusion in 8%, and radiation pneumonitis in 4%. There were 4 treatment related deaths due to late toxicities such as esophageal fistula, radiation pneumonitis, and the other cardiopulmonary diseases. Of eligible 74 patients, there were 50 complete responses (CRs) with a CR rate of 68% (95% Confidence Interval (CI): 56–78%). Median survival time was 31 months and the 2, 3-year survival rates were 55% (95% CI: 43–67%), 47% (95% CI: 36–59%), respectively. Conclusion: CRT for stage II, III ESCC is effective with acceptable acute toxicities, however, careful follow up is necessary for late toxicities. No significant financial relationships to disclose.