tbuckley/cabot-search huggingface dataset:
Methylation of the mitotic checkpoint genes BUB3 and BUBR1 in lung cancer
Authors: N. Alzein, J. Van Deursen, J. Molina
Journal: Journal of Clinical Oncology (2004)

9558 Background: The mitotic checkpoint is a failsafe mechanism for the cell to ensure accurate chromosome segregation during mitosis. Mutations in genes encoding essential checkpoint proteins lead to chromosome instability and promote carcinogenesis. The BUB3 and BUBR1 genes are essential components of the mitotic checkpoint pathway. AIM: To determine the role of aberrant promoter methylation of the genes BUB3 and BUBR1 in lung cancer. Materials and Methods: We performed Restriction Landmark Genomic Scanning (RLGS) in 20 Non-Small Cell Lung Cancer (NSCLC) samples and found the mitotic checkpoint gene BUR1 to be methylated. We then decided to look for methylation in other members of the BUB family. DNA was isolated from 53 microdissected freshly frozen NSCLC samples. Bisulphite treated DNA was then subjected to MSP following standard techniques. Results: BUR1 was found to be methylated in 47% (25/53) samples and BUB3 to be methylated in 45% (24/53) samples. It was surprising for us to find that the combination of both genes is methylated in 77% of the lung cancer samples analyzed. Conclusions: methylated of the mitotic checkpoint genes BUB3 and BUBR1 is a common epigenetic event in lung cancer. No significant financial relationships to disclose.
Adjuvant multimodality treatment in patients with high-risk prostate cancer following radical prostatectomy: Results of a prospective clinical phase-II trial
Authors: D. Thüer, C. Ohlmann, D. Pfister, U. Engelmann, A. Heidenreich
Journal: Journal of Clinical Oncology (2007)

15557 Background: High risk prostate cancer (PCA) is associated with a high frequency of PSA relapse. Even with adjuvant androgen deprivation therapy about 50% of patients experience systemic recurrences within 5 years. Docetaxel has demonstrated significant activity in men with metastatic androgen independent PCA, zoledronic acid has been shown to significantly inhibit the development of osseous metastases. It was the aim of the current prospective clinical phase-II trial to evaluate safety and clinical efficacy of early multimodality treatment in high risk PCA after radical prostatectomy (RPE). Methods: Between 3/2004 and 12/2005 25 patients with high risk PCA following RPE were recruited. High risk PCA was defined by a risk of biochemical progression &gt; 70% according to the postoperative Kattan nomograms. Adjuvant therapy consisted of androgen deprivation with LHRH analogues for 12 months, zoledronic acid at 4mg every 3 months and docetaxel at 75 mg/qm for six consecutive cycles. Adjuvant treatment was initiated 4 to 6 weeks after surgery. Follow-up examination were undertaken every 3 months with PSA serum determinations; in case of PSA increase 2 consecutive measurements at 4 weeks intervals were performed. Time to progression defined the time interval between initiation of therapy and first PSA relapse. Results: The mean follow-up is 20.5 (6–31) months. Adjuvant multimodality treatment was well tolerated in all patients with grade 3/4 hematotoxicity in 3 (12%) and gastrointestinal toxicity in 5 (16%) patients; 2 (8%) developed significant oncolysis with surgical intervention. In none of the patients the dosage of docetaxel or the number of cycles had to be reduced. Currently, 4 (16%) patients have developed PSA relapse with 2 exhibiting osseous metastases and 2 having died. Median time to progression was 14.5 (10–16) months. Conclusions: The clinical efficacy appears to be lower than expected with a 16% progression rate and a 8% mortality rate after only 20 months of follow-up. Adjuvant multimodality treatment of high risk PCA after RPE can be applied without significant treatment-associated side effects. Currently ongoing clinical phase-III trials have to further validate the concept of adjuvant chemotherapy. No significant financial relationships to disclose.
Abstract 17492: Vitamin D Improves Endothelial Function In Experimental Hypertension
Authors: Branko Simic, Matthias Hermann, Timo Speer, Kerstin Spliethoff, Frank Ruschitzka, Thomas F Luscher
Journal: Circulation (2012)

Introduction  Vitamin D deficiency is  becoming a world occurring phenomenon, with more than 1 billion  elderly people affected in both sexes and all ethnic groups. Several  comprehensive studies showed a direct link between low vitamin D  plasma levels and periphery artery disease, hypertension, relative  risk of myocardial infarction, increased mortality due to both  chronic heart failure and sudden cardiac death, and all-cause and  cardiovascular mortality. However, despite large-scale randomized  clinical trials with vitamin D supplements, the molecular mechanisms  of vitamin D activity on the cardiovascular endpoints are still  needed to be elucidated.   Hypothesis  We hypothesized that vitamin D increases nitric oxide  bioavailability, affects endothelial nitric oxide expression (eNOS)  and normalizes endothelial function in liquorice-induced  hypertension.   Methods  Endothelial function was analyzed in isolated aortic rings from 12-14 weeks old Wistar-Kyoto rats (WKY) treated with liquorice (3g/L) in drinking water (L) and compared to those which were co-administered with 1,25-dihydroxyvitamin D (L+D) (80 and 40 ng/day), or placebo (P) for three weeks.   Results  Acetylcholine-induced endothelium dependent vasorelaxation in aortic rings from liquorice-treated WKY was impaired compared to either placebo-treated WKY or WKY which were co-administered with vitamin D (P   Conclusion  Our study demonstrates that vitamin D treatment can improve endothelial function in experimental hypertension. Underlying mechanisms may include increased eNOS expression and reduced oxidative stress in endothelium.
Plasma melatonin and the hormone-dependency of human breast cancer.
Authors: D N Danforth, L Tamarkin, J J Mulvihill, C S Bagley, M E Lippman
Journal: Journal of Clinical Oncology (1985)

We studied the 24-hour plasma melatonin profile in three groups of women: normal individuals, women with breast cancer, and women at high risk for breast cancer, to determine the relationship of plasma melatonin to this malignancy. The mean daytime (nadir) and mean nighttime (peak) plasma levels for the normal subjects were 9.1 pg/mL and 70.9 pg/mL, respectively. The mean daytime and nighttime plasma levels, and the range of melatonin day to night differences for women with breast cancer and women at high risk for breast cancer were comparable to each other and to the normal subjects, with no statistically significant differences noted. The patients with breast cancer demonstrated a striking correlation between the melatonin diurnal rhythm and the steroid receptor content of the primary tumor. Women with estrogen (ER) or progesterone (PR) receptor-positive tumors had a significantly lower mean plasma melatonin day to night difference than did patients with ER- or PR-negative tumors. Further, a strong inverse correlation was observed between the plasma melatonin concentration and the quantities of ER and PR in the primary tumor: the lower the plasma melatonin concentration the greater the amount of either receptor in the primary tumor. Plasma melatonin did not correlate with tumor glucocorticoid receptor content or stage of breast cancer among these patients, or with menopausal status, age, parity, or the plasma levels of estrone, estradiol, progesterone, follicle-stimulating hormone (FSH), or luteinizing hormone (LH) among all individuals studied. Plasma melatonin was also independent of the degree of risk for breast cancer among the high-risk patients. These findings suggest an important relationship between the plasma melatonin diurnal rhythm and the hormone dependency of human breast cancer, and may have implications for both the prognosis and treatment of this malignancy.
Phase II clinical trials of combination S-1 plus low-dose twice weekly cisplatin for advanced or recurrent gastric cancer
Authors: A. Tsuji, S. Morita, M. Uchida, K. Okamoto, M. Morita, T. Horimi
Journal: Journal of Clinical Oncology (2006)

14013 Background: We reported the efficacy and safety of combined S-1 + low-dose consecutive cisplatin therapy for advanced or recurrent gastric cancer (Clin Cancer Res. 10:1664–9, 2004). However, this procedure was complicated because the daily dosage of CDDP was necessary. We confirmed that 6 mg/m 2 dosage of twice weekly Cisplatin were maintained equal protein binding Pt concentration after daily treatment of 3 mg/m 2 dosage of Cisplatin. We examined an effect and safety of a Combination S-1 plus low-dose twice weekly Cisplatin treatment. Methods: All the subjects were admitted to the hospital as inpatients for the first 2 weeks of therapy. S-1 was administered orally daily at the daily dose level of 80 mg/m 2 (administered in two divided doses). Cisplatin 6 mg/m 2 was administered by intravenous drip infusion over 30 minutes on 2days of the week (Day1 and Day4). Each treatment cycle consisted of 4 weeks of drug administration followed by a 2-week drug-free period (6 weeks in total). Results: 32 patients were enroled in this study. The response was rated as complete response in 1 case, partial response in 24 cases and stable disease in 5 cases. The response rate was 78.1% (25/32). The median survival time was 10.3 months. The response rate did not differ between previously untreated patients and patients who had received prior treatment. The major adverse reactions to the therapy were bone marrow suppression and gastrointestinal symptoms. The total incidence of grade 3 or more severe adverse reactions was 15.6% (5/32). Conclusion: Combination S-1 + low-dose twice weekly Cisplatin therapy thus appears to be highly efficacious and safe, offers promise as a useful treatment strategy even at outpatient clinics. [Table: see text] No significant financial relationships to disclose.
Multicenter Phase II Study to Evaluate a 28-Day Regimen of Oral Fluorouracil Plus Eniluracil in the Treatment of Patients With Previously Untreated Metastatic Colorectal Cancer
Authors: Sridhar Mani, Howard Hochster, Thomas Beck, Eric M. Chevlen, Mark A. O’Rourke, Charles H. Weaver, William N. Bell, Robin White, Chip McGuirt, Jeremey Levin, John Hohneker, Richard L. Schilsky, Jacob Lokich
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To determine the efficacy of fluorouracil (5-FU) plus eniluracil when administered to patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: In this single-arm phase II study, patients with previously untreated metastatic colorectal cancer received oral eniluracil plus 5-FU (10:1 dose ratio), at 5-FU doses of 1.00 mg/m 2 or 1.15 mg/m 2 twice daily (every 12 hours) for 28 consecutive days repeated every 5 weeks (one cycle). Treatment continued until there was documented disease progression or unacceptable toxicity. RESULTS: Thirty and 25 patients were enrolled at a starting dose of 1.00 mg/m 2 and 1.15 mg/m 2 , respectively. Fourteen (25%) of 55 patients (95% confidence interval, 15% to 39%) had a partial response, and 20 patients (36%) had stable disease. The median durations of the partial responses and stable disease were 23.9 weeks (range, 12.3 to 52.1+ weeks) and 24.1 weeks (range, 17.1 to 55.6+ weeks), respectively. The median durations of progression-free and overall survival were 22.6 weeks (range, 21.0 to 29.0 weeks) and 59 weeks (range, 4 to 84+ weeks), respectively. The response rate in the 1.15 mg/m 2 –dose group was similar to the 1.00 mg/m 2 –dose group (28% v 23%, respectively). Severe (grade 3/4) nonhematologic treatment-related toxicity included diarrhea (nine patients), nausea/vomiting (one patient each), mucositis (two patients), and anorexia (one patient). Severe hematologic toxicities were rare. At the 1.15 mg/m 2 –dose level, two patients exhibited grade 3 granulocytopenia, and two patients had grade 3 anemia. CONCLUSION: The response rate with oral 5-FU plus eniluracil is comparable with that observed with infusional 5-FU or bolus 5-FU and leucovorin. The toxicity profile of this oral regimen is acceptable for use in an outpatient home-based setting.
Infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) versus capecitabine plus oxaliplatin (CAPOX) as first line treatment of metastatic colorectal cancer (MCRC): Results of the safety and efficacy analysis
Authors: H.-T. Arkenau, H. Schmoll, S. Kubicka, A. Kretzschmar, W. Freier, T. Seufferlein, U. Graeven, A. Grothey, A. Hinke, R. Porschen
Journal: Journal of Clinical Oncology (2005)

3507 Background: In a previous phase III study the FUFOX regimen has shown superior response rates to bolus 5-FU/FA (Mayo Clinic protocol) in patients with MCRC (Grothey, ASCO 2002). The combination of capecitabine (CAP) and oxaliplatin (OX) has demonstrated good efficacy and safety results in recent phase II studies. In August 2002 we initiated a phase III trial to compare FUFOX and CAPOX as first line therapy in patients with MCRC. Here, we present the results of the safety and efficacy analysis. Patients and methods: From August 2002 to August 2004 476 patients (m:f = 299:177; median age 65 (range 32–86)) have been randomized to receive either FUFOX (234 pts. arm A: 5-fluorouracil 2000mg/m2 24h infusion, folinic acid 500mg/m2, oxaliplatin 50mg/m2 d1,8,15,22; q5 wks) or CAPOX (242 pts arm B: capecitabine 1000mg/m2 bid d1–14, oxaliplatin 70mg/m2 d1 and 8; q3 wks). All patients had measurable metastatic disease, ECOG performance status 0–2, normal renal and hepatic function. Results: To date 2123 cycles (841 FUFOX, 1282 CAPOX) are evaluable for toxicity (median number of cycles per patient: arm A: 4, range 1–10; arm B: 6, range 1–19). Both regimens showed comparable toxicity profiles with more HFS (hand-foot-syndrome) in the CAPOX arm. Median follow-up time was 28 weeks in both arms. Based on 233 events currently observed, median progression free survival (PFS: primary study endpoint) was 35 weeks in the FUFOX arm and 30 weeks in the CAPOX arm, respectively. Secondary efficacy parameters and PFS are detailed in table1. Conclusions: For the first time these data show that both FUFOX and CAPOX have comparable toxicity profiles and response rates in first line treatment of MCRC. Mature data on PFS will be presented at the meeting. No significant financial relationships to disclose.
Polyacrylamide: An Improved Surface for Cloning of Primary Tumors Containing Fibroblasts2
Authors: Tobi L. Jones, J. Stephen Haskill
Journal: JNCI Journal of the National Cancer Institute (1973)

A method for establishing mouse tumor lines in culture used a polyacrylamide dish as the primary culture vessel. The unique feature of this culture system was the inability of fibroblasts to grow on the acrylamide surface; thus tumor cells grew without competition. Morphologic and growth characteristics of several established tumors were described. A study of the immunogenicity of some tumor lines demonstrated alterations of tumor cells as a consequence of culture.
Expression of endoglin CD105 and nestin to assess neoangiogenesis in peritumor tissue of glioblastoma.
Authors: G. Sica, G. Lama, C. Anile, M. Geloso, G. La Torre, P. De Bonis, G. Maira, L. Lauriola, M. Jhanwar-Uniyal, A. Mangiola
Journal: Journal of Clinical Oncology (2010)

2052 Background: Angiogenesis in peritumor tissue of glioblastoma (GBM) is an unsettled field of research. This study investigates neovascularization in the tumor surrounding areas by examining CD105 and nestin expression along with microvessel density (MVD) with the aim to establish a possible prognostic significance. Angiogenesis was further confirmed by investigating the presence in the vessel walls of pericytes, multipotent stem cells, which express alpha-smooth muscle actin (alpha-SMA). Methods: A cohort study was carried out including 40 patients. Tissue samples were obtained from tumors (first area) and white matter at a distance < 1 cm (second area) and between 1 and 3.5 cm (third area) from tumor margin. Immunohistochemistry was used to evaluate CD105, nestin and to determine MVD. The same technique was employed to study the expression of alpha-SMA. Co-localization of CD105 and nestin was performed using confocal microscopy. Patients' clinical characteristics, extent of resection and marker expression were correlated with survival. Results: CD105 immunoreactivity was restricted to the endothelial cells, which showed an intense cytoplasmic and membrane staining, in both GBM and peritumor tissue. Outside the tumor, CD105 and nestin immunoreactivity was present in both small microvessels and vessels which resemble GBM hyperplastic microvessels. In the tumor, CD105 and nestin were present in different compartments of the endothelium, while in the surroundings the 2 markers overlapped. Pericytes encircling hyperplastic endothelial cells were evident in all three areas. Univariate analysis revealed that a CD105-MVD value ≥ 8 in the third area was associated with a shorter survival (10 vs. 15 months; p = 0.026 log-rank test; p = 0.013, Breslow test) and Cox analysis indicated an about 3.5-fold increase in death risk. Conclusions: These results demonstrate that a tumor neoangiogenesis occurs in GBM peritumor tissue with intimate involvement of pericytes. Importantly, CD105-MVD in the area located at a greater distance from the tumor margin carries prognostic significance. No significant financial relationships to disclose.
A population-based study of pelvic serous carcinoma in Sweden: Primary site, FIGO stage and survival.
Authors: Elisabeth Avall-Lundqvist, Christian Staf, Maria Bjurberg, Christer Borgfeldt, Pernilla Dahm-Kahler, Henrik Falconer, Erik Holmberg, Preben Kjolhede, Karin Stalberg, Per Rosenberg, Thomas Hogberg
Journal: Journal of Clinical Oncology (2015)

e16533 Background: The new paradigm shift for the origin and pathogenesis of epithelial ovarian cancer may have implications on population-based estimated survival rates if not taken into account. There are few population-based data in the literature reporting specifically on pelvic serous carcinoma (PSC). The aim of our study was to explore the distribution of PSC in relation to primary site, FIGO stage and survival. Methods: Nation-wide population-based cohort study of women ≥ 18 years, included in the Swedish Quality Registry (SQR) for primary cancer of the ovary, fallopian tube and peritoneum diagnosed during 2009-2013. ICD-O-3 coding was used (serous tumors codes 84413, 84603, 84613). Coverage in SQR was compared with the Swedish National Cancer Registry (SNCR). Coverage in SNCR is > 95% and morphologic verification 99%. Relative survival curves with 95% CI were estimated using the Ederer II method and the relative risks (RR) were estimated by a Poisson regression model. Results: The coverage in SQR was 94 %. Among 5510 women included in SQR, 77.6% had malignant tumor and 22.4% a borderline tumor. Serous carcinoma was diagnosed in 2364 women with primary site; ovary (71.9%), fallopian tube (8.7%), primary peritoneal (8.5%) and undesignated primary site (10.9%). FIGO stage III-IV was most common among serous ovarian cancer (79%), primary peritoneal (77%) and fallopian tube (70%). Among undesignated primary site, 54% of cases were unstaged and 46% allotted to FIGO stages III-IV. Estimated relative 3- and 5-year survival was for fallopian tube 65% and 54%, the ovary 60% and 38%, primary peritoneal 48% and 32% and for serous cancer of undesignated primary site 24% and 15%, respectively. Compared with serous fallopian tube cancer, undesignated primary site was associated with poorest survival (RR 3.86; 95% CI 2.84-5.24) followed by primary peritoneal (RR 1.76; 95% 1.26-2.46) and serous ovarian cancer (RR 1.35; 95% CI 1.02-1.78). Conclusions: Women with serous cancer of undesignated primary site have poorer survival than women with serous cancer with known primary site. Information about other primary sites of PSC needs to be taken into account when reporting and comparing survival rates of ovarian cancer.
Critical role for Hck-mediated phosphorylation of Gab1 and Gab2 docking proteins in interleukin-6-induced proliferation and survival of multiple myeloma cells.
Authors: K Podar, G Mostoslavsky, YT Tai, M Sattler, T Hayashi, LP Catley, T Hideshima, RC Mulligan, D Chauhan, KC Anderson
Journal: Blood (2003)
A microdosing study to identify chemoresistance in bladder cancer.
Authors: Helen Chow, Sisi Wang, Hongyong Zhang, Maike Zimmermann, Tzu-yin Lin, Tiffany Scharadin, Michael Malfatti, Christopher P. Evans, George Cimino, Kenneth Turteltaub, Ralph de Vere White, Paul T. Henderson, Chong-Xian Pan
Journal: Journal of Clinical Oncology (2015)

356 Background: DNA adduct formation and incorporation of gemcitabine into genomic DNA are critical steps in cancer cell response to platinum (Pt) and gemcitabine chemotherapy, respectively. We hypothesize that levels of Pt-DNA adducts and gemcitabine in genomic DNA below a threshold are predictive of chemoresistance. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring radiocarbon. By measuring 14 C bound to DNA, AMS was used to quantify carboplatin-DNA damage and gemcitabine incorporation into DNA after mice or patients received nontoxic “microdoses” of 14 C-labeled carboplatin or gemcitabine. Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1% of the therapeutic dose) or therapeutic dose of [ 14 C]carboplatin or [ 14 C]gemcitabine. Carboplatin-DNA adducts and gemcitabine incorporation in DNA were correlated with cell/tumor response to chemotherapy. In the Phase 0 trial, patients with advanced bladder or non-small cell lung cancer were treated with one microdose of [ 14 C]carboplatin followed by tumor sampling 24 hours later. Carboplatin-DNA adducts and other relevant parameters, such as pharmacokinetics and repair of DNA damage, were measured and correlated with cancer response to chemotherapy. Results: The levels of microdose-induced carboplatin-DNA damage were linearly proportional to that caused by the therapeutic dose (R 2 =0.92, p&lt;0.001); and correlated with chemoresistance to carboplatin. Low gemcitabine incorporation into DNA correlated to gemcitabine resistance in patient-derived bladder cancer xenografts (p&lt;0.001). In the Phase 0 trial, 18 patients have been enrolled. DNA damage induced by carboplatin was measured by AMS in peripheral blood mononuclear cells and, in some patients, in tumor tissues; and will be correlated with cancer response to chemotherapy. The pharmacokinetics and DNA adduct levels were linear between microdose and therapeutic doses. No microdose-related toxicity was observed. The radiation exposure was less than that of one chest X-ray per microdose. Conclusions: The levels of DNA damage induced by nontoxic microdosing carboplatin can potentially predict chemoresistance. The current status of the Phase 0 trial will be presented. Clinical trial information: NCT01261299.