tbuckley/cabot-search huggingface dataset:
Effect of CX-4945, a selective bioavailable small molecule inhibitor of protein kinase CK2, on gemcitabine antitumor activity in A2780 ovarian cancer.
Authors: K. L. Anderes, N. Streiner, M. Omori, N. Huser, C. Ho, A. Siddiqui-Jain, J. Bliesath, S. O'Brien, D. Drygin, W. G. Rice
Journal: Journal of Clinical Oncology (2010)

e13522 Background: The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance occurs against every effective anticancer drug and can develop by numerous mechanisms including activation of DNA repair mechanisms. X-ray repair cross-complementing protein 1 (XRCC1) is one of the most important DNA repair genes and is required for efficient single strand break/base excision repair. XRCC1 is positively regulated by CK2, a highly conserved, constitutively active serine/threonine protein kinase that is implicated in critical cellular processes and is a key participant in the cellular response to DNA damage. CK2 activity and expression levels are elevated in many cancers of diverse genetic background and have been linked to disease progression and poor prognosis. CK2 overexpression may enhance DNA repair in cancer cells via activation of XRCC1 thereby mediating MDR. CX-4945 is a potent, selective small molecule inhibitor of CK2 with single agent activity in xenografts. Methods: We investigated the role of CK2 in DNA repair using CX-4945 in combination with gemcitabine in the A2780 model of ovarian cancer. Effects on cell cycle, cell viability, molecular markers and antitumor activity were assessed. Results: CX-4945 effectively abrogated gemcitabine-induced S-phase cell cycle arrest and resulted in synergistic killing of A2780 cells. CX-4945 inhibited phosphorylation of XRCC1 at CK2 specific phosphorylation sites (Thr488, Ser518, and Thr519/523). In A2780 xenografts combination gemcitabine + CX-4945 was well tolerated and showed significant delay in time to endpoint of 11 days and 6/10 regressions versus no regressions with gemcitabine alone. Conclusions: Inhibition of CK2 by CX-4945 enhances the antitumor activity of gemcitabine via disruption of cell cycle checkpoints and DNA repair signaling triggered by gemcitabine-induced DNA damage. CK2 inhibitors represent an important element of combination chemotherapy strategy due to the roles of CK2 in DNA repair and chemoresistance. A phase I clinical trial of CX-4945 in patients with advanced solid tumors or multiple myeloma is currently in progress. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cylene Pharmaceuticals Cylene Pharmaceuticals
Anionic surfactants and commercial detergents decrease tight junction barrier integrity in human keratinocytes
Authors: Mu Xian, Paulina Wawrzyniak, Beate Rückert, Su Duan, Yifan Meng, Milena Sokolowska, Anna Globinska, Luo Zhang, Mübeccel Akdis, Cezmi A. Akdis
Journal: Journal of Allergy and Clinical Immunology (2016)
Association of Lymph Node Status With Survival in Patients After Liver Resection for Hilar Cholangiocarcinoma in an Italian Multicenter Analysis
Authors: Felice Giuliante, Francesco Ardito, Alfredo Guglielmi, Luca Aldrighetti, Alessandro Ferrero, Fulvio Calise, Stefano M. Giulini, Elio Jovine, Claudio Breccia, Agostino M. De Rose, Antonio D. Pinna, Gennaro Nuzzo
Journal: JAMA Surgery (2016)

The prognostic value of lymph node (LN) assessment after liver resection for hilar cholangiocarcinoma (HC) is still controversial, and the number of LNs required to be removed to obtain adequate staging is not well defined.To evaluate the LN status in patients after liver resection for HC and to clarify which prognostic factor (the number of positive LNs or the LN ratio [LNR]) was most accurate for staging and what minimum number of retrieved LNs was required for adequate staging.Retrospective multicenter study of patients who underwent resection for HC between January 1, 1992, and December 31, 2007, at 8 hepatobiliary Italian centers. The last follow-up was assessed in July 2014.Differences in overall survival (OS) according to the LN status were analyzed. The OS results were defined as actual because all included patients completed a 5-year follow-up.One-hundred seventy-five patients with 1133 retrieved LNs were analyzed. The mean (SD) age of the cohort was 63 (10) years, and 42.9% (75 of 175) were female. The median number of LNs examined per patient was 6.5. Forty percent (70 of 175) had LN metastasis. An LNR exceeding 0.20 was associated with significantly lower 5-year OS than an LNR of 0.20 or less (10.6% vs 24.4%; odds ratio, 2.434; 95% CI, 1.020-5.810; P = .04). On multivariable analysis, the LNR was the only independent prognostic factor for OS but was influenced by the total number of retrieved LNs. The LNR was greater than 0.20 in all patients (30 of 30) with 1 to 4 retrieved LNs and in 52.5% (21 of 40) of patients with at least 5 retrieved LNs. Five-year OS in patients with 1 to 5 retrieved LNs was significantly lower than that in those with 6 to 7 retrieved LNs and those with at least 8 retrieved LNs (34.2%, 64.5%, and 62.7%, respectively; P = .047). Five-year OS did not significantly improve when the number of retrieved LNs was greater than 6. These results were confirmed in a receiver operating characteristic curve analysis performed among N0R0 patients, in whom 5 retrieved LNs was the most accurate cutoff to predict 5-year actual OS (area under the curve, 0.624; P = .004).An LNR exceeding 0.20 was the only independent prognostic factor for OS in N1 patients after liver resection for HC. However, the LNR was influenced by the total number of retrieved LNs, and removal of more than 5 LNs was the minimum number of LNs required for adequate staging.
Common Malignancies With Uncommon Sites of Presentation
Authors: D. Bruce Panasuk, Thomas L. Bauer, Allen L. Davies, Charles Schneider, Cynthia Flynn
Journal: Journal of Clinical Oncology (2003)

Article Tools DIAGNOSIS IN ONCOLOGY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2003.03.149 Journal of Clinical Oncology - published online before print November 1, 2016 PMID: 14645436 Common Malignancies With Uncommon Sites of Presentation CASE 1. ANTERIOR MEDIASTINAL RHABDOMYOSARCOMA D. Bruce PanasukxD. Bruce PanasukSearch for articles by this author , Thomas L. BauerxThomas L. BauerSearch for articles by this author , Allen L. DaviesxAllen L. DaviesSearch for articles by this author , Charles SchneiderxCharles SchneiderSearch for articles by this author , Cynthia FlynnxCynthia FlynnSearch for articles by this author Show More Helen F. Graham Cancer Center, Christiana Care Health Services, Newark, DE https://doi.org/10.1200/JCO.2003.03.149 First Page Full Text PDF Figures and Tables © 2003 by American Society of Clinical Oncology
Adjuvant temozolamide given with radiation concomitantly or sequentially in a Jordanian tertiary cancer center.
Authors: S. A. Hashem, A. Almousa, A. F. Al-Rashdan, A. Nour, M. Sughayer, A. Alsharbaji, M. Al-Hussaini, A. H. Addasi
Journal: Journal of Clinical Oncology (2010)

e12548 Background: Based on the 2004 Stupp's trial, treatment with concomitant and adjuvant temozolomide and radiotherapy (RT/TMZ) improved the median and 2-year survival for patients with glioblastoma multiforme (GBM). In 2009, Stupp showed continued survival benefit at 5 years. Our institution adopted the concomitant RT/TMZ regimen as the standard of care for patients with favorable prognostic profile (age ≤ 50, Karnofsky Performance Status [KPS] ≥ 70%). Patients with unfavorable profile (age > 50, KPS < 70) were offered the RT/TMZ in a sequential fashion. The importance of the concomitant versus sequential part of the treatment, however, was still questionable. Methods: Retrospective chart review of 78 patients with histologically confirmed GBM, who had been diagnosed and treated at KHCC, from January 2003 to December 2008, with RT/TMZ regimens. Results: A total of 78 patients were eligible, 54 patients received RT/TMZ concomitantly, and 24 patients sequentially. Median age was 50 years. Male to female ratio was 2.4:1 and 8.9 % had gross tumor resection (GTR). At a median follow-up of 12 months (range: 1.2-62 months) the median survival for the whole cohort was 12 months. Median survival rate was 13.4 months (range 11.9-19.2 months) and 10.6 months (range 8.3-19.5 months) for the concomitant and sequential group, respectively. The unadjusted survival for RT/TMZ sequencing was not statistically significant (p = 0.19), but were statistically significantly better among patients with KPS ≥ 70%, age ≤ 50, RT dose ≥ 54 Gy, and those who had GTR. Other variables; tumor size and gender were also found to be statistically significant, but after using the stepwise Cox Hazard model, the KPS was the most significant factor impacting survival. The Hazard ratio (HR) for KPS ≥ 70% was 2.4 (95% CI [1.6, 3.6]) comparing KPS < 70% (p < 0.001). Conclusions: Our results demonstrated that median survival for both approaches is statistically comparable, regardless of prognostic features. This observation might be premature, since this study was not designed to detect clinically significant differences in a prospective setting, which may necessitate conducting a prospective randomized trial. No significant financial relationships to disclose.
P0865 : The use of sofosbuvir based regimens amongst treatment naive and experienced patients with advanced fibrosis/cirrhosis: Real world results from a difficult to treat cohort
Authors: D. Sutherland, S. Datta, E.H. Forrest, R. Fox, M. Heydtmann, M. Priest, P.R. Mills, J. Morris, A.J. Stanley, S.T. Barclay
Journal: Journal of Hepatology (2015)
P0903 : Slow HCV kinetics following sofosbuvir + ribavirin administration in real-life setting of liver transplant recipients with severe recurrent hepatitis C
Authors: V. Cento, M.F. Donato, I. Lenci, M. Rendina, M. Milana, V.C. Di Maio, S. Monico, M. Aragri, R. Alfieri, A. Abedrabbo, D. Sforza, M. Manuelli, L. Mameli, M.C. Sorbo, R. Canu, M.L. Ponti, C. Chialà, F. Malinverno, S. Marenco, L. Milanesi, A. Picciotto, G. Rossi, A. Di Leo, G. Tisone, F. Zamboni, R. Ganga, M. Colombo, C.F. Perno, M. Angelico, F. Ceccherini-Silberstein
Journal: Journal of Hepatology (2015)
Identifying concussion: when guidelines collide with real-world implementation—is a formal medical diagnosis necessary in every case once a proper protocol is implemented?
Authors: Pierre Frémont
Journal: British Journal of Sports Medicine (2016)

Several countries, such as Canada, are in the process of defining strategies to address the public health problem of sport-related concussions. One of the challenges is to develop strategies that can apply at the earlier levels where the timely availability of qualified healthcare resources is limited.

Here, I respectfully challenge the notion that every athlete with suspected concussion should have a medical consultation to confirm the diagnosis.

Specifically, I question the added value of the systematic requirement for a medical diagnosis in a sport or school-based environment, when a suspected case of concussion without any ‘red flag’ (as per the concussion recognition tool)1 is identified and a proper concussion management protocol is initiated.

The Zurich consensus states that, following the identification of a suspected case of concussion, ‘The final determination regarding concussion diagnosis and/or fitness to play is a medical decision based on clinical judgement’.2 Also, the concussion recognition tool recommends that: ‘… in all cases of suspected concussion, the player is referred to a medical professional for diagnosis and guidance…’.1 However, the …
MGMT promotor methylation status and Ki-67 in correlation to survival and response to treatment with temozolamide and radiotherapy in newly diagnosed glioblastoma patients.
Authors: M. M. Abdel Wahab, L. R. Ezz El Arab, K. Abdel Karim, M. El Mahdy, M. A. Osman, A. El Shehaby, S. Abel Raouf
Journal: Journal of Clinical Oncology (2010)

e12504 Background: This study aims at investigating the correlation between O6-methylguanine DNA-methyl transferase (MGMT) promoter methylation with Ki-67 labeling index to the response, time to progression (TTP), and overall survival (OS) in newly diagnosed patients with glioblastoma (GBM) treated with temozolamide (TMZ) concomitant with and adjuvant to radiotherapy (RT). Methods: Thirty one patients received TMZ 75 mg/m2 plus RT 2 Gy/ treatment up to 60 Gy, followed by TMZ 175 mg/m2 for five days every 4 weeks for 12 doses. Methylation-specific PCR assay and Ki-67 expression were performed on the tissue blocks. The patients were followed by MRI while MR spectroscopy (MRS) was performed to confirm progression and accordingly bevacizumab 10 mg/kg every 2 weeks was added to 7 patients till further progression. Results: Twelve specimens (38.7%) had unmethylated MGMT, 19 (61.3%) were methylated, the cut off value of Ki-67 in relation to survival was 17%, where 15 specimens were < 17% (48.4%), and 16 were ≥ 17% (51.6%).The overall disease control rate (ODC) was 74.2%, as 2 patients had complete response (CR), 14 had partial response (PR), and 7 had stable disease (SD), while 8 patients (25.8%) had progressive disease (PD). The ODC was significantly higher among methylated patients and in those with Ki-67 < 17% (p = 0.0003). The median TTP was 12 months and the median OS was 20 months, methylated patients had a higher TTP of 13 months (range 8 to 18 months, CI 95% of 9.36 to 12.9), and OS of 24 months (range 12 to 31 months, CI 95% of 16.1 to 21.32), while the unmethylated patients had TTP of 6.5 months and OS of 12 months which was highly significant (p = 0.0001), patients with Ki-67 < 17% had a TTP of 16 months and OS of 24 months compared to 7 and 12.5 months respectively for the patients with Ki-67 ≥17. Conclusions: MGMT promotor methylation status and the Ki-67 status could serve as independent predictive and prognostic markers of response and survival , they also might identify a specific group of patients who could benefit from combining further therapeutic agents to the TMZ. No significant financial relationships to disclose.
Overweight, Obesity, and All-Cause Mortality
Authors: Jose Viña, Consuelo Borras, Mari Carmen Gomez-Cabrera
Journal: JAMA (2013)

Dr Flegal and colleagues1 concluded that grade 1 obesity was not associated with higher all-cause mortality and that overweight was associated with significantly lower all-cause mortality. Other studies have shown that obesity in different populations, such as elderly people and patients with cardiovascular diseases, is also paradoxically not associated with a higher but rather with a lower mortality risk.2 This has been termed the obesity paradox
A Comparison of Inhibitors for Thrombin, FXa, FXIa, and FXIIa in Whole Blood Coagulation and Fibrinolysis Using Thromboelastography
Authors: Zhu Chen, Weizhen Wu, Yiming Xu, Martin L Ogletree, Andrew S Plump, Michael Graziano, Liangsu Wang
Journal: Blood (2011)
Population pharmacokinetics and exposure-safety relationship of nanoliposomal irinotecan (MM-398, nal-IRI) in patients with solid tumors.
Authors: Wen Wee Ma, Ik-Joo Chung, Istvan Lang, Tibor Csõszi, Miklos Wenczl, Antonio Cubillo, Jen-Shi Chen, Mark Wong, Joon Oh Park, Jun Suk Kim, Kun-Ming Rau, Bohuslav Melichar, Javier Gallego, Martin Smakal, Jaeyeon Kim, Bruce Belanger, Eliel Bayever, Navreet Dhindsa, Istvan Molnar, Bambang Adiwijaya
Journal: Journal of Clinical Oncology (2015)

e13588 Background: MM-398 is a nanoliposomal irinotecan (nal-IRI). This study characterized the population PK and exposure–response with MM-398 in patients with solid tumors. Methods: Population PK analysis was performed for total irinotecan (IRI) and its active metabolite SN-38 in 353 patients administered MM-398 60-120 mg/m2 in 6 studies. Covariates include body size (BSA), hepatic and renal functions (UGT1A1*28 7/7, bilirubin, liver metastasis, AST, ALT, albumin, CrCl), demographics (sex, race, age), and external factors (co-treatment with 5-FU, manufacturing site). Exposure-safety (neutropenia, diarrhea, and anemia) relationships were evaluated from 6 studies. Predictions of incidence rates of AEs were obtained from exposure-safety and predicted exposure with a dose of 80mg/m2. Results: Population PK of IRI was described as a 2-compartmental model, and SN-38 as a 1-compartmental model. Significant covariates to IRI were race and BSA; covariates to SN-38 were baseline bilirubin and BSA. No other covariates were significant; association with UGT1A1*28 was not significant. Compared to 120 mg/m2 q3w, MM398 80 mg/m2 q2w had similar average (Cavg), and 1.5-fold lower Cmax for both IRI and SN-38. SN-38 Cmax was associated with incidence of G ≥ 3 neutropenia and anemia, and IRI Cmax was associated with incidence of G ≥ 3 diarrhea. Compared to Caucasians, Asians had 0.5-fold lower IRI Cmax, corresponding to 5% lower predicted G ≥ 3 diarrhea. In contrast, Asians had 1.5-fold higher SN-38 Cmax than Caucasians, corresponding to 7% higher predicted G ≥ 3 neutropenia. Compared to patients with bilirubin < 1 mg/dL, patients with bilirubin 1-2 mg/dL had 1.4-fold higher SN-38. Conclusions: MM-398 at a lower dose, given more frequently, was predicted to have similar Cavg and lower Cmax. IRI Cmax was associated with diarrhea and SN-38 Cmax was associated with neutropenia and anemia. Asians had lower IRI levels, but higher SN-38. Increasing baseline bilirubin was associated with higher SN-38 levels. Clinical trial information: NCT01494506.
Ethnic difference in chemoradiation-induced esophagitis in unresectable stage III non-small cell lung cancer (NSCLC).
Authors: Takefumi Komiya, Shana L. Palla, Fen Wang, Raymond P. Perez, Chao Hui Huang
Journal: Journal of Clinical Oncology (2014)

e18518 Background: Patients with unresectable stage III NSCLC are currently treated with platinum-containing concurrent chemoradiation. One of dose limiting toxicities is severe (grade 3 or higher) esophagitis (G3E). The difference among ethnic groups has never been investigated in detail. Methods: Prospective trials including treatment arm(s) of concurrent platinum-containing chemoradiation in unresectable stage III NSCLC were identified by Pub Med search. Eligible studies/arms must have reported the number cases with G3E that occurred during concurrent phase of chemoradiation. Phase I/dose escalation studies, neoadjuvant chemoradiation with intent of surgery, and non-platinum only arms were excluded. Clinical variables available in more than 50% of treatment arms were investigated if there is any correlation with G3E. Two-sided univariate and multivariate multi-level mixed-effects logistic regression models were used with a significant p-value <0.05. Results: A total of 116 treatment arms with 7,520 patients were identified. Information about the types of chemotherapy (single agent vs. multi-agent, cisplatin vs carboplatin, induction vs. no induction), radiation (once-daily (QD) vs. twice daily (BID), Dose >60Gy vs. ≤60Gy, Split course radiation + vs. -), year of enrollment (starting in 1998 and later vs. before 1998), and study location (corresponding author’s location in Asian vs. non-Asian countries) were available as variables for correlation analysis. Univariate analysis demonstrated that Asian/Non-Asian, Multi-/Single-Agent therapy, BID/QID, Dose, and Split are all individually predictive of G3E. Of note, treatment arms conducted in Asia had significantly lower incidence of G3E (170/2,534, 6.7%, Odds Ratio 0.289) than in other nations (1,025/4,986, 20.6%). In the multivariable model, Asian/Non-Asian, Multi-/Single-Agent and Split are jointly significant predictors after adjusting for all possible factors. Conclusions: This publication based meta-analysis suggests that G3E occurs less frequently in Asian population as compared to non-Asian population treated with chemoradiation. Further research is required to verify the result.
Tampons and Toxic Shock Syndrome
Authors: Barbara S. Hulka
Journal: JAMA (1982)

Toxic shock syndrome (TSS) is an uncommon condition characterized by rash, fever, hypotension, desquamation of skin, and multisystem involvement. It occurs most commonly in menstruating women, estimated to afflict 9/100,000 per year, but it has been reported in nonmenstruating women and men as well. Toxin(s) producing strains of<i>Staphylococcus aureus</i>have been cultured from some body site in almost all cases. The<i>Staphylococcus</i>is presumed to be etiologic, although identical strains have been cultured from normal persons. The question raised by the two articles in the current issue ofThe Journal(pp 835 and 840) is whether tampon use enhances the risk of TSS among menstruating women who are vaginal carriers of S aureus. And if so, do Rely<sup>®</sup>brand tampons in particular further enhance this risk? (Rely brand tampons were voluntarily removed from the market on Sept 22, 1980, by the manufacturer, Procter and Gamble.) The two articles
An international multicenter phase III study of chemoradiotherapy versus chemoradiotherapy plus hyperthermia for locally advanced cervical cancer.
Authors: Baukje Flameling, Terje Nordberg, Oliver Ott, Rolf D. Issels, Peter Wust, J Crezee, Lars Lindner, Lukas Stalpers, Olav Mella, Astrid Keijser, R Fietkau, Josefine Rauch, A.H. Zwinderman, A.M. Westermann
Journal: Journal of Clinical Oncology (2016)

e17023 Background: Standard treatment of locally advanced cervical carcinoma consists of concurrent radiotherapy (including brachytherapy) and chemotherapy (weekly cisplatin 40 mg/m2), or chemoradiotherapy (CRT). Locoregional hyperthermia (HT) improves results of both radiotherapy and chemotherapy. After feasibility was demonstrated, an international multicenter randomized study of CRT ± hyperthermia was conducted. Methods: Patients with histologically confirmed advanced cervical cancer were randomized to CRT or CRT - HT. Weekly HT was applied concurrent with cisplatin. Primary endpoints were progression-free and overall survival. A total of 400 patients was needed to demonstrate a 15% PFS and OS advantage for triple therapy over chemoradiation, but the study was closed in 2010 because of insufficient patient accrual. We present the analysis of 99 randomized patients that were evaluable. Results: Between 2003 and 2010, 99 eligible Dutch, Norwegian and German patients were randomized to CRT (n = 50) or CRT-HT (n = 49). Patient characteristics (age, ECOG, FIGO) were well balanced between both groups and not statistically different. Patients were generally able to complete the protocol treatment of chemoradiotherapy. The median number of cisplatin courses was 6 in both groups, and in the triple group a median number of 5 treatments of hyperthermia were delivered. No unexpected toxicity occurred in either group. Complete responses were seen in 86% (42/49) of the patients in the CRT-HT group versus 76% (38/50) for CRT alone (p = 0.54). Five-year DFS (61.0 vs 58.7%) and 5-year OS (66.0 vs 70.7%) (p = 0.65, and p = 0.80) were not statistically different between both groups. Conclusions: In this underpowered study, no statistically significant improvement in treatment outcome by addition of hyperthermia to chemoradiotherapy could be demonstrated. Clinical trial information: NCT00085631.