tbuckley/cabot-search huggingface dataset:
Influence of aetiological factors for breast cancer on outcome after diagnosis
Authors: G. C. Barnett, M. Shah, K. Redman, S. Goodward, D. F. Easton, B. A. Ponder, P. D. Pharoah
Journal: Journal of Clinical Oncology (2005)

762 Background: Risk factors which influence the incidence of breast cancer may also affect survival after diagnosis. Methods: We studied the prognostic effects of reproductive history, height, weight, body mass index (BMI), smoking history, alcohol intake and prior use of the combined oral contraceptive pill (COC) and hormonal replacement therapy (HRT) in 4816 women who had taken part in the population-based SEARCH-breast cancer study. Hazard ratios (HRs) for death (all causes) were estimated using Cox proportional hazards survival model for each risk factor. Multivariate analysis was performed adjusting for grade, stage and age at diagnosis. Results: Median follow up was 5.27 years. On univariate analysis, reproductive history, age at menarche and menopause, menopause status at diagnosis, smoking history, prior use of HRT and COC were not seen to influence prognosis. Tumour grade and stage had a highly significant impact on overall survival (p<0.0001). Increasing height and decreasing weight were associated with a decreased risk of death. BMI was associated with a HR for death of 1.03 (95%CI 1.02–1.05; p=0.0002) per unit increase. Women who were in the highest quartile of BMI were 1.6 times more likely to die (95%CI 1.2–2.0) than those in the lowest quartile. Improved prognosis was seen with increasing current alcohol consumption. The HR for death was 0.98 per unit alcohol consumed per week (95%CI 0.96–0.99; p=0.0043); intake of 14 or more units was associated with a HR of 0.69 (95%CI 0.49–0.96). Previous alcohol intake did not significantly affect outcome. The effects of BMI and current alcohol consumption were not attenuated after adjusting for grade and stage. However, the effect of alcohol intake was marginally significant at the 5% level after adjusting for multiple comparisons. Conclusions: Our finding that an increase in BMI is associated with a negative impact on survival supports previously published data. The apparent benefit of alcohol intake has not been described before. Other studies have either shown no effect or poorer outcome in heavy drinkers. Our findings are preliminary and may simply be due to chance or confounding; or may reflect a true biological effect. Further work is needed to clarify these alternatives. No significant financial relationships to disclose.
Comparing gemcitabine-based combination chemotherapy with gemcitabine alone in inoperable pancreatic cancer: A meta-analysis
Authors: H. Liang
Journal: Journal of Clinical Oncology (2005)

4110 Background: In inoperable pancreatic cancer, many randomized controlled trials documented that gemcitabine-based chemotherapy had higher objective remission rate, but no more survival than gemcitabine alone. Methods: MEDLINE and EMBASE searches were supplemented by information from trial registers. Randomized controlled trials for gemcitabine-based combination chemotherapy and gemcitabine alone in inoperable pancreatic cancer(from 1996 to 2004). A quantitative meta-analysis using updated information basing on inclusion criterion from all available Randomized controlled trials was carried out by two reviewers. The primary meta-analysis was based on overall survival, including 6 months’s survival rate and 1 year’s survival rate.The second was objective remission rate, progress free survival or time to progress, clinical benefit rate and toxicity. Results: he Meta-analysis included 19 Randomized controlled trials. In inoperable pancreatic cancer, there was a significant improvement for gemcitabine-based combination group in 6 months’s survival rate (RD=4%,P=0.02;RD,Risk difference= risk in the gemcitabine-based combination group - risk in the gemcitabine alone group), objective remission rate (RD=5%,P=0.01), and 6 months’ progress free survival/time to progress(RD=10%,P<0.00001). And there was a marginal significant improvement for gemcitabine-based combination group in 1 year’s survival rate(RD=3%,P=0.05),and clinical benefit rate (RD=7%,P=0.06). WHO grade 3–4 toxicity was higher for gemcitabine-based combination group for neutropenia (RD=7%,P=0.04), thrombocytopenia (RD=6%,P=0.002), vomiting/nausea(RD=3%,P=0.04). Conclusions: In inoperable pancreatic cancer, gemcitabine-based combination chemotherapy improved overall survival, objective remission rate and progress free survival/time to progress significantly,but more toxicity than gemcitabine alone. It is first to document that gemcitabine-based chemotherapy improve overall survival significantly than gemcitabine alone in inoperable pancreatic cancer. No significant financial relationships to disclose.
Type 2 Diabetes Genetic Predisposition, Obesity, and All-Cause Mortality Risk in the U.S.: A Multiethnic Analysis
Authors: Aaron Leong, Bianca Porneala, Josée Dupuis, Jose C. Florez, James B. Meigs
Journal: Diabetes Care (2016)

Type 2 diabetes (T2D) is associated with increased mortality in ethnically diverse populations, although the extent to which this association is genetically determined is unknown. We sought to determine whether T2D-related genetic variants predicted all-cause mortality, even after accounting for BMI, in the Third National Health and Nutrition Examination Survey.We modeled mortality risk using a genetic risk score (GRS) from a weighted sum of risk alleles at 38 T2D-related single nucleotide polymorphisms. In age-, sex-, and BMI-adjusted logistic regression models, accounting for the complex survey design, we tested the association with mortality in 6,501 participants. We repeated the analysis within ethnicities (2,528 non-Hispanic white [NHW], 1,979 non-Hispanic black [NHB], and 1,994 Mexican American [MA]) and within BMI categories (<25, 25-30, and ≥30 kg/m(2)). Significance was set at P < 0.05.Over 17 years, 1,556 participants died. GRS was associated with mortality risk (OR 1.04 [95% CI 1.00-1.07] per T2D-associated risk allele, P = 0.05). Within ethnicities, GRS was positively associated with mortality risk in NHW and NHB, but not in MA (0.95 [0.90-1.01], P = 0.07). The negative trend in MA was largely driven by those with BMI <25 kg/m(2) (0.91 [0.82-1.00]). In NHW, the positive association was strongest among those with BMI ≥30 kg/m(2) (1.07 [1.02-1.12]).In the U.S., a higher T2D genetic risk was associated with increased mortality risk, especially among obese NHW. The underlying genetic basis for mortality likely involves complex interactions with factors related to ethnicity, T2D, and body weight.
A phase I study of zoledronic acid (ZA) and low-dose cyclophosphamide (CTX) in children with recurrent/refractory neuroblastoma (NB): A New Approaches to Neuroblastoma Therapy (NANT) study
Authors: H. Russell, Y. DeClerck, T. Ara, S. Groshen, J. G. Villablanca, A. Marachelian, J. Park, H. Katzenstein, K. Matthay, S. Blaney
Journal: Journal of Clinical Oncology (2009)

10022 Background: ZA, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone metastases occur in 60% of children with advanced NB. A xenograft mouse model demonstrated ZA with low dose chemotherapy delayed progression of NB bone lesions prompting a phase I trial of ZA. Methods: Three dose levels of intravenous ZA (2, 3, or 4 mg/m2) administered every 28 days were evaluated with continuous daily oral CTX (25 mg/m2/day) in patients with recurrent/refractory NB and bone metastases. The primary objective was to determine a recommended dose of ZA for future trials. PKs with the first dose of ZA and serial serum IL-6 levels (stimulator of osteoclast activity) were evaluated. Results: 21 patients (14 male), median age 7.9 years (0.8–26.6 years), were enrolled at ZA dose levels 2 mg/m2 (n=4), 3 mg/m2 (n=3), and 4 mg/m2 (n=13). Seventy-five cycles were administered with median of 1 cycle per patient (range 1–18). Two DLT (Gr 3 hypophosphatemia) occurred at 4 mg/m2 ZA. Other Gr 3 or 4 toxicities included hypocalcemia (n = 2), elevated transaminases (n = 2), neutropenia (n = 2), anemia (n = 1), lymphopenia (n = 1), and hypokalemia (n = 1). A fracture related to osteosclerosis occurred after 18 cycles. There were no renal or dental complications. There was 1 complete response, 9 stable disease median 4.5 cycles (range 3–18), and 10 progressions (central review pending). At 4 mg/m2, mean serum IL-6 levels decreased from 3.9 pg/mL (95% CI: 2.8–5.2 pg/mL) (n = 11) to 2.9 pg/mL (95% CI: 1.8–4.4 pg/mL) after cycle 1 (n = 8). ZA PK were similar to adults. Conclusions: ZA with low dose CTX is well tolerated with evidence of clinical benefit in children with recurrent/refractory NB. The recommended ZA dose for future study is 4 mg/m2 every 28 days. No significant financial relationships to disclose.
Differential expression of insulin like growth factor binding protein-4 (IGFBP4) in melanoma progression
Authors: J. Z. Yu, H. Yee, M. Warycha, P. Christos, R. Shapiro, R. Berman, A. Pavlick, L. Liebes, P. Brooks, I. Osman
Journal: Journal of Clinical Oncology (2007)

8557 Background: Members of the IGFBP family are thought to regulate tumor progression through both IGF-dependent and independent mechanisms. Moreover, IGFBPs may exhibit distinct functions depending on whether they are present locally in tissue or systemically. Our preclinical data suggest that IGFBP4 serves as an endogenous inhibitor of angiogenesis and melanoma tumor growth. To examine the clinical validity of our observations, we compared IGFBP4 expression in tissue and sera in primary melanoma patients with a low risk of metastases versus patients with established metastatic disease. Methods: Eighty-nine melanoma patients (primary stage IA, n=57; metastatic, n=32; 44 M, 45 F; Median Age=56) prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group at the NYU School of Medicine were studied. IGFBP4 protein expression in tumors was assessed in 83 patients using goat anti-human IGFBP4 antibody (R&amp;D Systems) in an immunohistochemical assay. For each case, the percentage of tumor cells that stained positively was estimated. IGFBP4 concentration in the serum was measured in 64 patients by an ELISA assay (Diagnostic Systems Laboratories, Inc.). Fifty-eight patients had both sera and tumor specimens available for correlation. Results: The median IGFBP4 expression in tumor specimens from primary patients was 70% compared to 5% in metastatic patients (P=0.002, Wilcoxon rank-sum test). The median concentration of IGFBP4 in sera was 43.8 ng/ul in primary patients versus 41.0 ng/ul in metastatic patients (P=0.83). A weak association between IGFBP4 expression in tissue and IGFBP4 shedding in sera was observed (Spearman correlation coefficient=0.16, P=0.24) in the 58 cases with both sera and tissue available. Conclusions: Our data demonstrate that IGFBP4 expression in melanoma clinical specimens decreases in the progression from primary to metastatic melanoma, consistent with its potential role as an inhibitor of angiogenesis. Data also suggest that IGFBP4 tissue expression may be more clinically relevant than its sera shedding. Future studies using a larger sample size and extended follow up are needed to further define the role of IGFBP4 in melanoma progression. No significant financial relationships to disclose.
Abstract 9730: Hepatic Apolipoprotein M Overexpression Increased Total Sphingosine 1-phosphate Mass and Ameliorate Insulin Resistance in Diet Induced Obesity Mice
Authors: Makoto Kurano, Kazuhisa Tsukamoto, Ryunosuke Ohkawa, Masumi Hara, Junko Iino, Hitoshi Ikeda, Yutaka Yatomi
Journal: Circulation (2012)

Backgrounds : Sphingosine 1-phosphate (S1P) is a vasoprotective lipid mediator that is mainly carried on HDL and albumin in the circulation. Since S1P riding on HDL was recently shown to bind to apolipoprotein M (apoM), which is derived from liver, we analyzed the possible involvement of liver in S1P metabolism. Moreover, while both apoM and S1P have been proposed to be involved in glucose metabolism, we also investigated the modulation of glucose metabolism by the overexpression of apoM in mice liver. Methods and Results : Using adenoviruses, we overexpressed apoM in HepG2 cells and mice livers and found that both the medium/plasma and cell/liver S1P contents increased. Among lipoprotein subclasses, S1P contents and ApoM increased mainly in HDL fractions. The incubation of S1P in the conditional medium of apoM-overexpressing HepG2 cells interfered with S1P degradation. Failure of HeLa cells to release S1P extracellularly (despite efficient ApoM production and intracellular S1P production) suggests that liver possesses special machinery for S1P export. Furthermore, adenoviral hepatic overexpression of apoM resulted in increase in the S1P level of plasma but not of blood cells, while combination of hepatic apoM overexpression and intraperitoneal administration of C 17 -sphingosine resulted in the increase in the C 17 -S1P level both in livers and in plasma, but again not in blood cells. Regarding glucose metabolism, we found that hepatic apoM overexpression improved fasting blood glucose (Control 156.2 mg/dL vs ApoM 104.8 mg/dL) and ameliorated insulin resistance in diet induced obesity mice, which were partially inhibited by administering VPC23019 , an S1P receptor 1 antagonist, but not JTE013, an S1P receptor 2 antagonist, rather with JTE013 insulin resistance tended to be improved more than treated with vehicle. Conclusions : These results suggest liver involvement in S1P dynamism through production of apoM, which increases circulating plasma S1P by augmenting the S1P output from livers and modifies extracellular S1P metabolism. Regarding the function of ApoM-S1P, ApoM-S1P might ameliorate insulin resistance depending on S1P receptor 1.
Interferon Does Not Prolong Progression-Free Survival After ProMACE-MOPP
Authors: Fernando Cabanillas, Richard I. Fisher, Michael LeBlanc, Thomas Miller
Journal: Journal of Clinical Oncology (2000)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.18.3322 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10986069 Interferon Does Not Prolong Progression-Free Survival After ProMACE-MOPP Fernando CabanillasxFernando CabanillasSearch for articles by this author Richard I. FisherxRichard I. FisherSearch for articles by this author , Michael LeBlancxMichael LeBlancSearch for articles by this author , Thomas MillerxThomas MillerSearch for articles by this author Show More M.D. Anderson Cancer Center Houston, TXCardinal Bernardin Cancer Center Maywood, IL https://doi.org/10.1200/JCO.2000.18.18.3322 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse18092000In Reply:Dr Cabanillas correctly points out that the conclusions of S8809 that “interferon alfa consolidation after intensive chemotherapy with anthracycline-containing chemotherapy and radiotherapy does not prolong the progression-free survival or overall survival of patients with low-grade non-Hodgkin’s lymphoma” only apply to the exact treatment regimen utilized in that large, randomized trial. The words for that conclusion were chosen by the authors because they represent the exact language of the Food and Drug Administration–approved indication, an approval that was generalized from other specific anthracycline-containing regimens to all such regimens. Unfortunately, every published study in this area is unique; they all differ somewhat in patient selection criteria, treatment regimen, dose, and schedule. It is, therefore, essentially impossible to select the critical variables that might define success or failure. It was the hypothesis of this study that maximal cytoreduction was potentially important before the introduction of the interferon. As also presented, after intensive cytoreduction, 33% of patients had grade 3 toxicity to interferon and thus 40% failed to complete the entire treatment course as originally defined.
Association of Symptom Network Structure With the Course of Depression
Authors: Claudia van Borkulo, Lynn Boschloo, Denny Borsboom, Brenda W. J. H. Penninx, Lourens J. Waldorp, Robert A. Schoevers
Journal: JAMA Psychiatry (2015)

Major depressive disorder (MDD) is a heterogeneous condition in terms of symptoms, course, and underlying disease mechanisms. Current classifications do not adequately address this complexity. In novel network approaches to psychopathology, psychiatric disorders are conceptualized as complex dynamic systems of mutually interacting symptoms. This perspective implies that a more densely connected network of symptoms is indicative of a poorer prognosis, but, to date, no previous study has examined whether network structure is indeed associated with the longitudinal course of MDD.To examine whether the baseline network structure of MDD symptoms is associated with the longitudinal course of MDD.In this prospective study, in which remittent and persistent MDD was defined on the basis of a follow-up assessment after 2 years, 515 patients from the Netherlands Study of Depression and Anxiety with past-year MDD (established with the Composite International Diagnostic Interview) and at least moderate depressive symptoms (assessed with the Inventory of Depressive Symptomatology [IDS]) at baseline were studied. Baseline starting and ending dates were September 1, 2004, through February 28, 2007. Follow-up starting and ending dates were September 1, 2006, through February 28, 2009. Analysis was conducted August 2015. The MDD was considered persistent if patients had at least moderate depressive symptoms (IDS) at 2-year follow-up; otherwise, the MDD was considered remitted.Sparse network structures of baseline MDD symptoms assessed via IDS were computed. Global and local connectivity of network structures were compared across persisters and remitters using a permutation test.Among the 515 patients, 335 (65.1%) were female, mead (SD) age was 40.9 (12.1) years, and 253 (49.1%) had persistent MDD at 2-year follow-up. Persisters (n = 253) had a higher baseline IDS sum score than remitters (n = 262) (mean [SD] score, 40.2 [8.9] vs 35.1 [7.1]; the test statistic for the difference in IDS sum score was 22 027; P < .001). The test statistic for the difference in network connectivity was 1.79 (P = .01) for the original data, 1.55 for data matched on IDS sum score (P = .04), and 1.65 for partialed out data (P = .02). At the symptom level, fatigue or loss of energy and feeling guilty had the largest difference in importance in persisters' network compared with that of remitters (Cohen d = 1.13 and 1.18, respectively).This study reports that symptom networks of patients with MDD are related to longitudinal course: persisters exhibited a more densely connected network at baseline than remitters. More pronounced associations between symptoms may be an important determinant of persistence in MDD.
Stereotactic radiosurgery: A new paradigm for melanoma and renal cell carcinoma spine metastases.
Authors: A. Thiagaragan, Y. Yamada, D. M. Lovelock, B. W. Cox, M. J. Zelefsky, M. Bilsky
Journal: Journal of Clinical Oncology (2010)

2030 Background: Renal cell carcinoma (RCC) and melanoma metastatic to the spine present an especially vexing clinical scenario because responses to conventionally fractionated palliative radiotherapy are particularly poor. The advent of image guided treatment techniques, coupled with intensity modulated radiotherapy, have provided the mechanism to deliver high-dose single-fraction radiation safely to spinal metastases. We hypothesized that high dose single fraction radiation (spine SRS) would provide excellent radiographic local control and symptom palliation. Methods: All patients with metastatic RCC (n = 50) or melanoma (n = 30) treated with spine SRS between 2004-2008 were assessed prospectively every 3-4 months until death with serial MRI or CT spine imaging, visual analogue pain scale (VAS), narcotic use, and American Spine Injury Association (ASIA) scores. Each case was assessed for suitability in a multidisciplinary spine clinic or conference. No patient had previous surgery or radiation at the site of interest. Patients received 18-24 Gy in a single fraction (median 24 Gy). Actuarial statistical analyses were performed. Results: The overall median survival was 9 months (2-56 months). Ninety percent of patients achieved radiographic local control and 90% achieved durable symptom palliation. There was no difference in clinical outcome based upon histology (92% RCC vs. 89% Melanoma, p = 0.5). When the dose of radiation was assessed, there was a trend of worse outcomes in the low dose cohort (18-22Gy) when compared to the high dose group (24 Gy), 77% vs. 96% achieved durable local control (p = 0.12). All melanoma patients who received less than 24 Gy (mean 18Gy) experienced local relapse (p = 0.012). Toxicity was limited to grade 1 or 2 complications, and no spinal cord injury was encountered. Conclusions: While the long term local control of melanoma and renal cell carcinoma spine metastases is reported in the range of 30%-40% with conventionally fractionated radiotherapy, spine SRS appears to prove very high tumor control for even highly radioresistant histologies with minimal toxicity. High dose spine SRS (24 Gy) provides better results than lower dose treatment, especially for melanoma patients. No significant financial relationships to disclose.
Altered microRNAs in T Cells from Patients with Acquired Aplastic Anemia
Authors: Kohei Hosokawa, Pawel Muranski, Xingmin Feng, Keyvan Keyvanfar, Danielle M. Townsley, Bogdan Dumitriu, Jichun Chen, Sachiko Kajigaya, James G. Taylor, Christopher S. Hourigan, John Barrett, Neal S. Young
Journal: Blood (2014)