tbuckley/cabot-search huggingface dataset:
Global genome damage is predictive of cancer patients’ outcome
Authors: Z. Zheng, A. Cantor, G. Bepler
Journal: Journal of Clinical Oncology (2005)

9542 Background: Genome damage is a hallmark of human cancer. Efforts at assessing the impact of global genome damage on tumor phenotype and patients’ outcome have focused on measurements of the relative DNA content in tumor cells compared to normal cells (DNA index) and the assessment of allele loss (loss of heterozygosity, LOH) at single or multiple selected loci that are thought to harbor genes important in cancer biology. Methods: We have adapted a global, high-resolution genotyping method for determination of global and unbiased genome damage and generated a global genome damage score (GGDS), which is a measure of the extent of damaged DNA in individual tumors. The score is a continuous variable from zero to one where zero indicates absence of any damage and one indicates complete damage. Results: In surgically resected human non-small-cell lung cancers, the GGDS ranged from 0.003 to 0.204 indicating that between 0.3–20.4% of the genome is damaged. Patients with high scores (>0.049) had a significantly worse outcome and their tumors expressed DNA damage repair genes at lower levels than those with low scores (median overall survival time 38.3 months vs. 94.0 months, p=0.007). The expression of genes involved in DNA damage repair was inversely correlated with GGDS. Conclusions: Our study of global high-resolution genome damage analysis in non-small-cell lung cancer convincingly demonstrates a statistically significant and clinically meaningful association with the in vivo tumor phenotype. This implies that the clinical behavior of tumors with low GGDS is relatively benign while tumors with high GGDS are aggressive resulting in early death of patients. Since GGDS determination is a robust and reliable technology, it can easily be integrated into clinical decisions on cancer care. For instance, adjuvant treatment of epithelial malignancies benefits only a minority of patients while toxicity is substantial. GGDS may prove useful in selecting patients at high risk for tumor-associated mortality for adjuvant therapeutic interventions. No significant financial relationships to disclose.
Day case surgery: not the whole answer to the NHS’s increasing demand for operations
Authors: Shreelata T Datta
Journal: BMJ (2015)

Appleby’s data briefing emphasises the success of day case surgery but omits several points in an overly simplistic approach.1 The benefits of day case surgery are not in dispute, but the success rate of such operations and its correlation with symptom resolution, as well as the cost of failed day cases resulting in further follow-up care …
Cytotoxicity of novel, small molecule, CRM1-selective inhibitors of nuclear export (SINE) in colorectal cancer (CRC) cells.
Authors: G. F. Draetta, S. Shacham, M. Kauffman, V. Sandanayaka, S. Schechter, J. Williams, R. Nir
Journal: Journal of Clinical Oncology (2011)

e14091 Background: In order to maintain their malignant phenotype, neoplastic cells must neutralize most of their tumor suppressor (TSP) and growth regulatory (GRP) proteins. CRM1, also called exportin 1, mediates the nuclear export of the majority of TSP/GRP, leading to their inactivation. Blockade of CRM1 with SINE induces cytotoxicity in neoplastic cells, but only reversible cell cycle arrest in normal cells. We report on the potential of SINE for the treatment of molecular subtypes of CRC. Methods: KPT-127 is a moderate potency, small-molecule SINE with broad-spectrum, tumor-selective cytotoxicity in vitro and in vivo tolerability. Twenty human CRC cell lines with distinct genotypes were tested for KTP-127-induced cytotoxicity after 72 hours using MTT assay. Mouse embryo fibroblasts (MEF) were cycling, normal controls. Genetic profiles of cells were obtained from the literature. In vivo efficacy and tolerability of KPT-127 were evaluated in HCT-116 xenografts. Results: Cytotoxicity IC50s were determined for the 20 CRC lines, and they were grouped into most quartiles, and the genotypes of most sensitive (<300nM) and most resistant (>1200nM) determined. The status of p53 or APC, or the presence of p16 methylation, K-ras mutations, microsatellite instability (MSI), EGFR, or Pgp (mdr1) did not correlate with killing by KPT-127. Moreover, HCT-116 p53Ð/Ð variant CRC line cytotoxicity was similar to that of the parenteral (p53+) line. Consistent with its action as an irreversible CRM1 inhibitor, expression of the multidrug resistance pump Pgp1 also did not affect KPT-127 potency. In HCT-116 xenografts, KTP-127 150mg/kg induced >80% tumor growth inhibition similar to irinotecan 30mg/kg twice weekly but without causing myelosuppression or other toxicities. Conclusions: KTP-127, a SINE that irreversibly blocks CRM1, kills a variety of CRC cell lines regardless of commonly used molecular prognostic markers including p53, K-ras, and Pgp status. KPT-127 has minimal effects on normal cells and is well tolerated with significant antitumor activity in vivo. More potent SINEs with improved pharmacokinetic profiles are being developed for clinical use as single agents and in combination.
A SARC phase II multicenter trial of imatinib mesylate (IM) in patients with aggressive fibromatosis
Authors: R. Chugh, R. G. Maki, D. G. Thomas, D. Reinke, J. K. Wathen, S. Patel, D. A. Priebat, P. A. Meyers, R. S. Benjamin, L. H. Baker
Journal: Journal of Clinical Oncology (2006)

9515 Background: Aggressive fibromatosis (desmoid tumors, AF) are uncommon, locally aggressive, connective tissue neoplasms. Existing literature on systemic treatment of AF is sparse and consists mostly of case reports and small case-series. Based on previous observation of regression of AF treated with IM and tumoral expression of IM targets, SARC (Sarcoma Alliance for Research through Collaboration) included the treatment of AF onto a multi-institution phase II trial of IM in sarcoma. Here we report early clinical and laboratory results of the AF group. Methods: Eligible patients had histologically proven AF, unresectable or difficult to resect without considerable functional impairment. Patients were treated with IM 300 mg po BID (BSA≥1.5m 2 ). The primary endpoint was complete (CR) or partial response(PR) at two months or stable disease (SD) or better at four months. Tumor DNA was extracted from available formalin fixed paraffin embedded tissue specimens and analyzed via allelic PCR and genomic DNA sequence analysis for specific point mutations in PDGFRα exons 12/14/18, PDGFRβ exons 12/18, KIT exons 9/11/13/17, and bRAF. Results: 51 patients were enrolled from 10/02 to 12/05 at 5 institutions, with 45 patients currently evaluable. The median age is 37 (range 14–67), and median number of prior therapies is 1 (range 0–3). 36 patients (80%) reached the primary endpoint of CR/PR at 2 months or SD or better at 4 months. The median time to treatment failure is 6.8 months (95% C.I. 5.8–17.1). Thus far, the maximum change in the largest dimension of the tumor ranged from a 21% increase to a 45% decrease. In 22 available tumor specimens, deletions within PDGFRαE12 and E18 were noted in 1 and 3 patients, respectively, while a wildtype genotype was found in other regions. Conclusions: IM has activity in AF, the mechanism of which remains unclear. While this is the largest reported phase II trial of AF, further improvement in evaluating clinical efficacy in this disease is clearly necessary. We plan an analysis of the maximum change in largest tumor dimension for each patient, which will be particularly beneficial in AF as responses often occur late. We have not as yet identified a laboratory predictor of clinical benefit. Further investigation of other potential targets in fresh tissue is warranted. [Table: see text]
Abstract 2918: Peptide probe-based in vivo imaging of apoptosis and early decision on stomach tumor response to treatment
Authors: Fatima Khan, Smriti Gurung, Hyun-Kyung Jung, Moon-Chang Baek, Yong Woo Choi, In San Kim, Byung Heon Lee
Journal: Cancer Research (2015)

Abstract Early decision on tumor response after anti-cancer treatment is still an unmet medical need. Here we exploited ApoPep-1 peptide that binds to histone H1 exposed on apoptotic cell surface as a probe and investigated whether in vivo imaging of apoptosis using near-infrared fluorescence dye-labeled linear and cyclic (disulfide-bonded) form of ApoPep-1 at an early stage after treatment could enable us predict tumor response to the treatment later. Treatment of SNU16 stomach tumor cells with cistplatin and cetuximab alone significantly induced apoptosis of the cells, while combination of cisplatin and cetuximab more efficiently induced apoptosis, as detected by staining with linear and cyclic form of ApoPep1. However, the differences among groups were more remarkable when detected with cyclic form of ApoPep-1 compared to the linear counterpart. In tumor-bearing mice, apoptosis imaging was performed at the first and second week after the initiation of treatment, and tumor sizes and weights were measured 3 weeks after treatment. In vivo fluorescence imaging signals by the homing of ApoPep-1 to tumor was most remarkable in the group injected with cyclic form of ApoPep-1 at the first week after combined treatment with cisplatin plus cetuximab. There were no significant differences in tumor sizes and weights between groups injected with linear and cyclic form of ApoPep-1. Correlation analysis revealed that imaging signals 1 week after treatment with cisplatin and cetuximab in combination were most closely related with tumor volume changes (r2 = 0.934). These results demonstrate that in vivo apoptosis imaging using the cyclic form of Apopep-1 is a sensitive and predictive tool for early decision on stomach tumor response after anti-cancer treatment. Citation Format: Fatima Khan, Smriti Gurung, Hyun-Kyung Jung, Moon-Chang Baek, Yong Woo Choi, In San Kim, Byung Heon Lee. Peptide probe-based in vivo imaging of apoptosis and early decision on stomach tumor response to treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2918. doi:10.1158/1538-7445.AM2015-2918
Direct LAMP assay from clinical sample for carbapenem resistant A. baumannii
Authors: Shigeto Hamaguchi, Norihisa Yamamoto, Yukihiro Akeda, Pitak Santanirand, Anusak Kerdsin, Masafumi Seki, Wantana Phang, Kumthorn Malathum, Kazunori Oishi, Kazunori Tomono
Journal: European Respiratory Journal (2014)

Carbapenem-resistant  Acinetobacter baumannii  (CRAb) is one of the most important nosocomial pathogens and provokes various infections such as ventilator associated pneumonia (VAP) in ICU. For prevention of VAP by CRAb, rapid and sensitive diagnostic technique for this pathogen is indispensable.  The aim of this study is to evaluate how useful the CRAb LAMP (Loop-Mediated Isothermal Amplification) assay which we developed is in clinical practice, and to compare the detection rate between sample collection sites; bronchial aspirates and rectal swab.  Samples were collected from the intubated patient in the ICU of university hospital in Bangkok, Thailand. Our CRAb LAMP assay can use clinical specimens directly as the template of LAMP reaction and detects CRAb by amplifying blaOXA-23 gene, which is highly conserved among CRAb isolates in Thailand. The CRAb LAMP provides the result within 40 minutes from sample collection and can be used for active surveillance.  Our CRAb LAMP has high sensitivity (100% (31/31)) and high specificity (84.1% (74/88)) enough to apply to clinical setting. Furthermore when the results of CRAb LAMP in each site were compared, 92.5% of them were concordant each other. These results suggested that our CRAb LAMP effectively detect CRAb in bronchial aspirates. Moreover the CRAb LAMP from rectal swab is a useful method for detecting CRAb-positive patient and can be used as the active surveillance for CRAb, since collection of rectal swab is easier and accomplished in all cases.  To reduce the number of VAP patients, detection of CRAb is the first and necessary step. Our CRAb LAMP assay must be applied as a diagnostic test to detect carriages of CRAb.
US Preventive Services Task Force Recommendation Statement on Screening for Depression in Adults
Authors: Charles F. Reynolds, Ellen Frank
Journal: JAMA Psychiatry (2016)

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Indications for Globin Insulin
Authors: D. W. Pugh
Journal: BMJ (1950)

When globin insulin was introduced over six years ago it was hoped that a single daily injection of this type of insulin would control most diabetics.Mosenthal (1944) reported on a series of 50 ambulant diabetics treated with globin insulin (G.I.) and showed that as a rule G.I. produces a fall in blood sugar within two hours of injection.This effect is intermediate between that of soluble insulin (S.I.) and zinc protamine insulin (Z.P.I.).The action-lasts for 12 to 16 hours and sometimes 24 hours, depending on the size of dose and other factors.Eaton (1944) reported on a series of 41 diabetics treated with G.I. who had failed to do well on other types of insulin.He showed that a combination of Z.P.I. and S.I. produces a lower fasting blood sugar than G.I., but that in suitable cases G.I. gave results more nearly physiological than did any other single type of insulin, and that its action closely resembled that of mixed doses of Z.P.I. and S.I. containing over 50% of the latter.These favourable reports encouraged other clinicians to use G.I. Wauchope (1948) reported enthusiastically on a series of 366 diabetics treated with G.I. as out-patients thus: " All types of patient do as well on a single dose of globin insulin each day as on other kinds of insulin, singly or in combination."This has not been quite the experience at the diabetic clinics of the London Hospital, and I was prompted, therefore, to review the records of diabetic patients who had been treated with G.I. since its introduc- tion in 1943.In that year a large number of patients attending the London Hospital were changed from a twice- daily dose of S.I., or a single combined dose of S.I. and Z.P.I., to a single daily dose of G.I.This dose was usually two-thirds of the previous total dose of other insulins.In addition, a small number of new diabetics were treated with G.I. from the start.Out of a total of approximately 1,800 diabetics treated between 1943 and 1948, 360 were given G.I.In 55 of these, control of the diabetes proved unsatisfactory, so that a change to some other kind of insulin had to be made.It is of interest to note at this point that during the same period over 750 patients were being maintained satisfac- torily on a twice-daily dose of S.I. or a combined daily dose of Z.P.I. and S.I.
Role of Transforming Growth Factor-beta Signaling in Cancer
Authors: M. P. de Caestecker
Journal: JNCI Journal of the National Cancer Institute (2000)

Signaling from transforming growth factor-beta (TGF-beta) through its unique transmembrane receptor serine-threonine kinases plays a complex role in carcinogenesis, having both tumor suppressor and oncogenic activities. Tumor cells often escape from the antiproliferative effects of TGF-beta by mutational inactivation or dysregulated expression of components in its signaling pathway. Decreased receptor function and altered ratios of the TGF-beta type I and type II receptors found in many tumor cells compromise the tumor suppressor activities of TGF-beta and enable its oncogenic functions. Recent identification of a family of intracellular mediators, the Smads, has provided new paradigms for understanding mechanisms of subversion of TGF-beta signaling by tumor cells. In addition, several proteins recently have been identified that can modulate the Smad-signaling pathway and may also be targets for mutation in cancer. Other pathways such as various mitogen-activated protein kinase cascades also contribute substantially to TGF-beta signaling. Understanding the interplay between these signaling cascades as well as the complex patterns of cross-talk with other signaling pathways is an important area of investigation that will ultimately contribute to understanding of the bifunctional tumor suppressor/oncogene role of TGF-beta in carcinogenesis.
Identifying the potential long-term survivors among breast cancer patients with distant metastasis
Authors: E.S. Lee, S.Y. Jung, J.Y. Kim, J.J. Kim, T.K. Yoo, Y.G. Kim, K.S. Lee, E.S. Lee, E.K. Kim, J.W. Min, W. Han, D.Y. Noh, H.G. Moon
Journal: Annals of Oncology (2016)
Resected pancreatic cancer: A proposal for a prognostic score
Authors: S. Dell’oro, P. Passoni, G. Balzano, E. Bonetto, F. Scaltrini, A. Zerbi, C. Staudacher, E. Villa, V. Di Carlo, M. Reni
Journal: Journal of Clinical Oncology (2005)

4108 Background: Survival after curative surgery for pancreatic adenocarcinoma (PA) is poor and postoperative management is controversial. The identification of prognostic factors may favor interpretation of results from phase II trials, selection of promising therapeutic strategies, and definition of stratification criteria for phase III trials. Methods: A series of 239 patients, curatively resected in a single center for PA between June 1985 and June 2002, was analyzed. The prognostic role of patient- and PA- related variables was estimated by univariate (log-rank test) and multivariate analyses (Cox proportional hazard model), stratifying patients for the year of diagnosis and chemotherapy regimen received. Significance levels were adjusted for multiple group comparisons (Bonferroni method). Results: Post-surgical performance status (PS) >1, stage > IIA, grading > 2, tumor size > 2,9 cm, and pre-surgical CA19.9 value > 5 upper limit of normal were significantly and independently associated with a worse survival (p<0.005), while gender, age, nodal status, resection margins, and site of disease were not. Results were confirmed by the Cox model. Each variable was assigned a value of either 0, if favorable, or 1, if unfavorable. The values were then added together to generate a score and three risk groups were individuated: low, intermediate and high risk for score 0–1, 2–3 and 4–5, respectively. Risk group attribution was possible for 216 (90%) patients due to missing data. Overall survival was significantly different (p<0.0003) across groups: median, 2-yr, and 5-yr overall survival for 55 patients in low-risk group were 28, 58%, and 22%; for 130 patients in intermediate-risk group were 17, 32%, and 6%; and for 31 patients in high-risk group were 9, 10% and 0%. Conclusions: Post-surgical PS, stage, tumor grade and size, and pre-surgical CA19.9 value were independent predictors of survival in patients with PA submitted to curative surgery. A prognostic score including these five variables was able to distinguish three different risk groups with significantly different survival. The proposed risk stratification and its relevance in therapeutic decision deserve to be validated in further studies. No significant financial relationships to disclose.
Abstract 10859: Walnut-enriched Diet Reduces Fasting Non-HDL-cholesterol in Healthy Caucasian Subjects
Authors: Liya Wu, Katja Piotrowski, Tiina Rau, Elisa Waldmann, Uli C Broedl, Christos Mantzoros, Klaus G Parhofer
Journal: Circulation (2012)

Background: Epidemiological studies indicate that regular walnut consumption reduces the risk of coronary heart disease (CHD). We therefore evaluated the effect of walnut consumption on fasting and...
Phase I and Pharmacokinetic Study of Ecteinascidin-743, a New Marine Compound, Administered as a 24-hour Continuous Infusion in Patients With Solid Tumors
Authors: A. Taamma, J. L. Misset, M. Riofrio, C. Guzman, E. Brain, L. Lopez Lazaro, H. Rosing, J. M. Jimeno, E. Cvitkovic
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To define the maximum-tolerated dose (MTD) and the phase II recommended dose (RD) of ecteinascidin-743 (ET-743) given as a 24-hour continuous infusion every 3 weeks to patients with treatment-refractory solid tumors. PATIENTS AND METHODS: Fifty-two patients received a total of 158 cycles of ET-743 at one of nine dose levels (DLs) ranging from 50 to 1,800 μg/m 2 . RESULTS: The MTD was defined as 1,800 μg/m 2 (DL 9), and the phase II RD was 1,500 μg/m 2 (DL 8) for moderately pretreated patients with performance status (PS) 0 to 1 and good hepatobiliary function. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were severe at the MTD (1,800 μg/m 2 ) in 94% and 25% of cycles, respectively. At the RD (1,500 μg/m 2 ), neutropenia and thrombocytopenia were present in 33% and 10% of cycles, respectively. Transient acute elevated transaminase levels occurred in almost all cycles and was severe in 38% of cycles. Severe toxicities and DLTs were observed in patients with poor PS or abnormal liver function or who had received a large number of previous chemotherapy regimens. Antitumor activity was observed at the three highest DLs, including three partial responses (breast cancer, osteosarcoma, and liposarcoma), and four patients (all with progressing soft tissue sarcomas) had stable disease lasting ≥ 3 months. Pharmacokinetic studies were performed on all patients for at least the first cycle, giving a linear pharmacokinetic profile; this showed a relationship between area under the curve (AUC) and transaminitis grade and a clear correlation between AUC and severe hematologic toxicity likelihood. CONCLUSION: The RD for a 24-hour continuous intravenous infusion of ET-743 is 1,500 μg/m 2 , with the most prevalent DLTs being hematologic. Patients with minor baseline hepatobiliary function abnormalities have a higher likelihood of severe hematologic toxicities and AUC-related DLTs, requiring dose adjustments or delays.