tbuckley/cabot-search huggingface dataset:
The anti-metastatic effect of the chemopreventive polyphenol Curcumin - in vitro and in vivo studies on the molecular mechanisms
Authors: Beatrice Bachmeier, Cristina Iancu, Isabelle Mohrenz, Valentina Mirisola, Erwin Schleicher, Andreas Nerlich, Ulrich Pfeffer
Journal: Cancer Research (2008)

3834  Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. Here we propose the plant derived Curcumin for cancer chemoprevention since it inhibits the formation of breast cancer metastases. Curcumin reduces the activity of Nuclear Factor kappa B (NFκB), an inflammation and cell survival related transcription factor, though this cannot be the only reason for the anti-metastatic effect.  We undertook a dual approach and examined the effects of Curcumin (i) in vitro on the human breast cancer cell line MDA-MB-231 and (ii) in vivo in a mouse metastasis model. We show that Curcumin strongly induces apoptosis in MDA-MB-231 cells in correlation with diminished activation of NFκB. Moreover it reduces the expression of matrix metalloproteinases (MMPs) due to transcriptional down-regulation of NFκB and AP-1. Consequently the breast cancer cells had a decreased invasive capacity as evidenced by Matrigel assays.  Application of Curcumin in vivo in a model of immunodeficient mice resulted in a significantly lower number of lung metastases after intracardiac injection of MDA-MB-231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases.  To get a complete picture of the effects of Curcumin on breast cancer cells we used microarray gene expression analyses. Among the 62 genes whose expression was significantly altered, we found the two inflammatory cytokines CXCL1 and -2 to be down-regulated. Further validation of our microarray results by qRT-PCR, Western blots, and ELISA revealed that Curcumin impairs the expression of CXCL1 and 2. Using siRNA techniques we revealed that reduction of CXCL1 and -2 mRNA levels is NFκB dependent and requires intact IκBα expression. Moreover CXCL1 and -2 silencing leads to down-regulation of several metastasis promoting genes among which we found the cytokine receptor CXCR4. We therefore suggest that the decrease of CXCL1 and -2 mediated by Curcumin is involved in the inhibition of metastasis. Moreover, our data show that Curcumin exerts anti-proliferative and pro-apoptotic activities and thereby reduces the metastatic dissemination of tumor cells  most probably through down-regulation of NFκB dependent transcription.  Altogether we provide evidence that dietary chemoprevention of metastases appears feasible.
Limited success of Durasphere for the treatment of urinary incontinence following radical prostatectomy (RP)
Authors: F. P. Secin, K. S. Eilber
Journal: Journal of Clinical Oncology (2004)

4711 Background: Durasphere is a permanent bulking agent used for the treatment of stress urinary incontinence (SUI). To our knowledge there is no data available regarding its efficacy for the treatment of SUI after RP. The purpose of this study is to describe our initial experience with Durasphere in the treatment of SUI following RP. Methods: The medical records of eight patients who were treated with Durasphere for SUI after RP between 1/1/03 to 1/10/03 were retrospectively reviewed according to IRB guidelines. Patient age, preoperative urinary continence, time from RP to treatment, number of pads, operative reports and responses to treatment were reviewed. Results: Eight patients aged 50 to 71 (mean age 63.2) with SUI after RP were treated with Durasphere. The average time from RP to treatment was 4 years (range 1.3 to 11). No patient had urinary incontinence preoperatively. The average number of pads used preoperatively was 3 (range 1 to 6). The median number of syringes of Durasphere used intraoperatively was 5 (range 4 to 7). Optimal coaptation following injection of Durasphere was obtained in only three patients. At a mean follow-up of 5.3 months (range 2 to 10 months), no patient was completely dry. Five patients (62.5%) opted for other surigcal treatment of their incontinence The remaining three patients were satisfied with the postoperative result. Two patients decreased daily pad use from 6 to 3 while the third patient continued to use 1 pad per day. Conclusions: Durasphere does not consistently provide successful outcomes for SUI after RP. Its poor success rate is most likely secondary to decreased tissue compliance of the bladder neck after RP which limits its bulking ability. No significant financial relationships to disclose.
Glyceraldehyde‐3‐phosphate dehydrogenase promotes liver tumorigenesis by modulating phosphoglycerate dehydrogenase
Authors: Shanshan Liu, Yu Sun, Ming Jiang, Yangkai Li, Ye Tian, Weili Xue, Ninghe Ding, Yue Sun, Cheng Cheng, Jianshuang Li, Xiaoping Miao, Xinran Liu, Ling Zheng, Kun Huang
Journal: Hepatology (2017)

Up‐regulated glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) is observed in multiple cancers with unclear mechanism. Using GAPDH transgenic mouse and a mouse model of diethylnitrosamine‐induced hepatocellular carcinoma (HCC), here we show that GAPDH overexpression aggravated tumor development by activating cell proliferation and inflammation. In cultured hepatic cells, overexpression of GAPDH or a catalytic domain‐deleted GAPDH (GAPDH ΔCD ) affected metabolism, up‐regulated phosphoglycerate dehydrogenase (PHGDH), increased histone methylation levels, and promoted proliferation. Consistently, inhibition of GAPDH by short hairpin RNA reprogrammed metabolism down‐regulated PHGDH and histone methylation, and inhibited proliferation. The xenograft study suggested that HepG2 cells overexpressing GAPDH or GAPDH ΔCD similarly promoted tumor development, whereas knockdown PHGDH in GAPDH overexpressing cells significantly inhibited tumor development. In liver sections of HCC patients, increased GAPDH staining was found to be positively correlated with PHGDH and histone methylation staining. Conclusion: GAPDH increases histone methylation levels by up‐regulating PHGDH, promoting diversion from glycolysis to serine biosynthesis, and consequently accelerating HCC development. (H epatology 2017;66:631–645).
Gemcitabine/carboplatin (GC) vs. carboplatin (C) in platinum sensitive recurrent ovarian cancer (OVCA). Results of a Gynecologic Cancer Intergroup randomized phase III trial of the AGO OVAR, the NCIC CTG and the EORTC GCG
Authors: J. Pfisterer, M. Plante, I. Vergote, A. Du Bois, U. Wagner, H. Hirte, A. J. Lacave, A. Stähle, R. Kimmig, E. Eisenhauer
Journal: Journal of Clinical Oncology (2004)

5005 Background: Most patients (pts) with OVCA relapse. ICON 4 - AGO OVAR 2.2 results suggest combination C-based therapy may be superior to single agent C. GC is a feasible less neurotoxic regimen and thus of interest to evaluate in this setting. Methods: In this phase III trial pts with platinum sensitive recurrent OVCA (≥ 6 months after the end of primary therapy) were randomized to receive C (AUC 4 d1) plus G (1000 mg/m2 d1 and 8) or C (AUC 5 d1) every 3 weeks. The primary objective compared progression free survival (PFS) in both arms. Secondary objectives were response rate (RR) and duration, overall survival (OS), toxicity and quality of life (QoL). Results: From 09/99 and 04/02, 356 pts (178 GC, 178 C) were randomized. Both study arms were well balanced for baseline disease characteristics. Median number of cycles was 6 for GC (0–10) and C (0–9). The weekly dose intensity was 98.2% for C (C arm) and 96.2% for C and 75.6% (92.8% for d 1 and 63.4% for d8) for G (GC arm). Grade 3/4 hematologic toxicities were significant higher in the GC arm (anemia 27.4% of pts. vs. 8.0%, neutropenia 70.3% vs. 12.0%, thrombocytopenia 34.9% vs. 11.4%). G-CSF or GM-CSF was more often used in GC (23.6% of pts. vs. 10.1%) as well as red cell transfusions (37.1% vs. 14.6%). Clinical sequelae were similar between arms: febrile neutropenia (1.1% GC vs. 0% C) and infections (0.6% for both arms). Grade 3/4 non-hematologic toxicities were infrequent in both arms (< 5%), especially for sensory neuropathy (1.1% GC vs. 1.7% C). Overall RR for GC was 47.2% (95% CI: 39.9–54.5%) and 30.9% (95% CI: 24.1–37.7) for C (p= 0.0016). GC pts reported significantly faster palliation of abdominal symptoms as well as significantly improved global QoL. With a median follow up of 13 months, median PFS was 8.6 mo (95%CI: 8.0–9.7) for GC and 5.8 mo (95% CI: 5.2–7.1) for C (HR 0.72 [95% CI: 0.57–0.90], p= 0.0038, e= 311). OS data are immature and this study was not powered to detect differences in OS. Conclusion: The combination of G plus C improves PFS and QoL in platinum sensitive recurrent OVCA patients with acceptable toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb; Eli Lilly Bristol-Myers Squibb; Eli Lilly Eli Lilly
Patient engagement on claims-registry reports of cost and quality.
Authors: Karma L. Kreizenbeck, Catherine R. Fedorenko, Julia Rose Walker, Mikael Anne Greenwood-Hickman, Laura Panattoni, Sarah Barger, Keith D. Eaton, Janet Freeman-Daily, Diane Mapes, Margaret Leigh Pate, Courtney J. Preusse, Gary H. Lyman, Scott David Ramsey
Journal: Journal of Clinical Oncology (2017)

159 Background: Moving cancer care towards a value framework requires patients, providers, and payers to weigh cost, quality, and outcomes in decision-making. Many efforts are underway to help providers and payers make value decisions, but little has been developed for patients. Our regional value in cancer care effort used a claims-registry database to develop quality and cost reports aiming to provide actionable data to all stakeholders. Methods: Reports were generated using cancer registry records for Western WA from 2007-2015 linked with claims from two regional commercial insurers. Patients were presented quality reports on regionally prioritized metrics and the 2012 ASCO Choosing Wisely guidelines on breast cancer surveillance and EOL care. Patients also reviewed cost reports for episodes of care (diagnosis, treatment, end-of-life (EOL)) and out-of-pocket (OOP) cost estimates. Feedback stemmed from 1) stakeholder meetings over a 2-year period, 2) working groups of patients, payers and providers, and 3) an annual regional meeting on value in cancer care. Results: In total, 13 patients provided feedback at one or more outreach event. See table. Conclusions: Reports from a claims-registry database may not support the information needs of patients for care decision-making or representing “value”. Patients desired understanding more about patients “like them” for decision-making. [Table: see text]
First phase I trial of a steroid sulfatase inhibitor in breast cancer
Authors: S. J. Stanway, A. Purohit, L. Woo, S. Sufi, N. Dobbs, M. Elliott, B. Potter, M. Reed, R. C. Coombes
Journal: Journal of Clinical Oncology (2004)

645 Background: 667-Coumate is the first steroid sulfatase (STS) inhibitor to enter clinical trials. STS has a crucial role in regulating the formation of steroids with potent estrogenic properties, such as estrone and androstenediol. Methods: Eligible patients (pts) are postmenopausal women with locally advanced or metastatic hormone receptor positive breast cancer. Treatment consists of a test dose followed by 3 two-weekly cycles. Each cycle consists of daily dosing for 5 days followed by 9 days off treatment. Dose levels of 5mg, 20mg and 80mg (6 pts at each) were planned. Primary endpoints are to establish the oral dose of 667-Coumate needed to suppress STS by over 90% in peripheral blood lymphocytes (PBL) and to investigate the tolerability profile of 667-Coumate. Secondary endpoints include measurement of the pharmacokinetic and endocrine parameters, determination of the oral dose of 667-Coumate needed to inhibit intra-tumoral sulfatase and documentation of anti-tumor activity. PBL STS was measured using (6,7-3H) E1S as the substrate. Results: Six pts have been treated at the 5mg dose level. The mean percentage inhibition (+/-SD, N=4) of PBL STS was 96.6% (+/-3.4%) 24 hours post the first dose of 667-Coumate and was 98% (+/-0.8%) 8 hours post dose on Day 5 Cycle 1, Intra-tumoral sulfatase (assessed on Day 5, Cycle 1) was inhibited to 99.6% and 78.4% for pts 4 and 5, respectively. The following mild related adverse events were reported (CTC grade; pts): headache (2;1 pt), mood depression (1;2 pts), taste disturbance post treatment (1;5 pts). The primary endpoint has been met in the first 4 pts at the 5mg dose level. Pt 1 had stable disease clinically, an improvement in breast pain and received a further 6 cycles of treatment. Conclusions: We have successfully demonstrated the ability to inhibit STS activity with a potent oral inhibitor without any serious drug-related adverse events. This study was sponsored by Cancer Research UK and supported by Sterix Ltd. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sterix Ltd. Sterix Ltd. Sterix Ltd. Sterix Ltd.
Sargramostim in combination with irinotecan (I), 5-fluorouracil (F), and leucovorin (L) for metastatic colorectal cancer (CRC): Second interim results of PROGRESS trial
Authors: R. F. Taylor, M. A. Rovito, M. Kleinman, T. Gray, G. R. Jones, M. J. Gilbert
Journal: Journal of Clinical Oncology (2004)

3663 Background: Weekly/biweekly irinotecan-based regimens improve survival in CRC patients but are associated with significant myelosuppressive toxicities. In the PROGRESS trial, sargramostim (Leukine®, GM-CSF) was added to two commonly used regimens to study its ability to reduce toxicities and allow increased chemotherapy dose delivery thereby delaying disease progression. Methods: Weekly: Day 1: 125 mg/m2 I, 500 mg/m2 F, 20 mg/m2 L. Sargramostim 250 μg/m2 on Days 2–6. Cycles consist of 4 weekly courses + 2 weeks rest for up to 48 weeks. Biweekly: Day 1: 180 mg/m2 I, 1000 mg/m2 F, 200 mg/m2 L. Day 2: 400 mg/m2 F bolus, followed by 600 mg/m2 F infusion over 22 hr; 200 mg/m2 L. Sargramostim 250 μg/m2 on Days 4–13 for up to 48 weeks. The primary endpoint is progression-free survival (PFS) at 24 weeks (using χ2 test and null hypothesis that PFS ≤ 55%). Results: Eighty-one patients were enrolled, and 64 were evaluable for PFS. Of these, 51 (80%) had liver involvement, 20 (31%) had lung involvement, and 24 (38%) had prior F therapy. At 24 weeks, 38 patients (59%) had no disease progression, 26 (41%) had progressed, and 9 (14%) had died. Median time to progression was 215 days. Mean dose intensity was 83% of the planned I and F doses. Grade 3/4 events included diarrhea (28%), neutropenia (23%), deep vein thrombophlebitis (16%), dehydration (9%), asthenia (6%), vomiting (6%), and 4 infections (6%, 2 fever and 2 pneumonia). Only 1 patient had Grade 3 bone pain (Cycle 1). Conclusions: The addition of sargramostim to weekly/biweekly irinotecan-based regimens for CRC supports planned dose delivery by decreasing neutropenia and severe infections, and may improve PFS. Sargramostim is generally well tolerated with weekly and biweekly IFL regimens, and should be considered with other short-cycle chemotherapy regimens. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Berlex, Inc.
Does supportive-expressive group therapy for metastatic breast cancer patients lower health care services resource utilization
Authors: J. Lemieux, H. Chappell, A. Topp, P. J. Goodwin
Journal: Journal of Clinical Oncology (2004)

6052 Background: Metastatic breast cancer is associated with psychological distress, which, in other diseases has been associated with higher health care resource utilization. We hypothesized that a psychosocial intervention in metastatic breast cancer will reduce health care resource utilization. Methods: Goodwin et al. reported results of a randomized controlled trial of supportive expressive group support in metastatic breast cancer (NEJM 2001;345:1719–1726). The intervention did not impact survival or quality of life (EORTC QLQ-C30) but it improved total mood disturbance (Profile of Mood States -POMS, range −32 to 200) and perception of pain (10 cm VAS). Resource utilization data were collected prospectively (data from 3 of the largest centers were used). Costing was done at 2 tertiary care U of Toronto hospitals in $2001 (Canadian) using the perspective of the health care system. A cost-minimization analysis was conducted as the primary analysis; secondarily, a cost-effectiveness analysis (CEA) was conducted for mood and perception of pain to identify costs associated with an improvement equal to 10% of the range of the scale (23.2 POMS, 1.0 cm pain VAS), an effect size considered clinically significant. Results: Average health care utilization costs for the intervention group were $25,537 +/- $21,059 and for the control group $22,461 +/- $18,686 (p = 0.43). A sensitivity analysis, of +/- 20% of hospitalization and chemotherapy costs (the two largest costs) resulted in no significant differences between groups. The CEA for POMS showed the intervention group incurred incremental costs of $6,205 per 23.2 points POMS improvement; the incremental cost per 1.0 cm VAS increase in perception of pain was $3076. Conclusions: Supportive-expressive group therapy in metastatic breast cancer does not lower health care resource utilization. Costs associated with clinically significant beneficial effects on mood and perception of pain were acceptable. No significant financial relationships to disclose.
Bisphosphonates and esophageal cancer: A RADAR report.
Authors: Beatrice J. Edwards, Beatrice Nardone, Dennis W Raisch, June M. Mckoy, Steven M Belknap, Jaimee S Holbrook, Vishvas Garg, Xian Shen, Victoria Godinez-Puig, Steven M Trifilio, Romala Emmanuel, Dennis P. West, Steven T. Rosen
Journal: Journal of Clinical Oncology (2012)

4063 Background: In 2009, the US Food and Drug Administration (FDA) reported on 23 patients who had developed distal esophageal cancer, with alendronate (ALN) within 2 years of initiation of therapy. Similarly, 31 cases of esophageal cancer were reported from Europe and Japan. Esophagitis has been associated with oral BPs. Erosive esophagitis and persistent mucosal abnormalities have been noted with crystalline material (similar to ground ALN). Our objective was to assess the FDA Adverse event reporting system (FDA AERS) for a safety signal. Methods: The FDA Adverse Event Reporting System (AERS) database was searched using terms related to esophageal cancer combined with all drug names for bisphosphonates (search period:1996-2010). Disproportionality ratios were calculated: Proportional reporting ratio (PRR) and Empiric Bayes Geometric Mean (EBGM) determining that the esophageal cancer cases were more common with bisphosphonates than with other drugs in the database. Results: We identified 128 cases of bisphosphonate-associated esophageal cancer; 114 (89%) female and 14 male (11%), mean age 72 ± 12 yrs; the drugs included alendronate (n=96, 75%), risedronate sodium (n=14, 11%), ibandronic acid (n=10, 7.8%), zoledronic acid (n=7, 5.4%) and pamidronate (n=1, 1%). Barrett’s esophagus was listed in 3 cases of esophageal carcinoma. A significant safety signal was found only for alendronate with a PRR= 6.4 (95% C.I. 5.29, 7.730; p=0.001), EBGM = 6.3 (95% C.I. 5.1, 7.6 p=0.001). Conclusions: Our analysis of FDA AERS identifies a larger number of cases of esophageal cancer than previously described, and a significant safety signal with alendronate use. Avoidance of oral bisphosphonates in patients with Barrett’s esophagus, and persistent mucosal abnormalities is recommended. Increased awareness and vigilance is needed for patients receiving oral bisphosphonate therapy.
<i>Staphylococcus aureus</i> enterotoxin sensitization is associated with allergic poly‐sensitization and allergic multimorbidity in adolescents
Authors: M. Sørensen, C. Klingenberg, M. Wickman, J. U. E. Sollid, A‐S. Furberg, C. Bachert, J. Bousquet
Journal: Allergy (2017)

Abstract Background Staphylococcus aureus ( S. aureus) carriage and sensitization to S. aureus enterotoxins ( SE s) have been associated with allergic diseases. From the Tromsø Study Fit Futures 2, we have previously shown an association between S. aureus carriage and severe allergic disease and allergic multimorbidity. However, the role of S. aureus carriage and SE sensitization on allergic multimorbidity and allergic sensitization is unclear. Objective To study associations of both nasal S. aureus carriage and SE sensitization to allergic disease and allergic sensitization. Methods A cross‐sectional study of a school‐based cohort in late adolescence (aged 18‐19 years: The Tromsø Study Fit Futures 2). Self‐reported allergic diseases were assessed using the Mechanisms of the Development of ALL ergy questionnaire (Me DALL ). Participants were tested for nasal S. aureus carriage, serum total IgE and specific IgE to SE s, and food and inhalant allergens. Results A total of 868 participants were studied. Sensitization to at least one food or inhalant allergen was found in 319 of 765 (41.7%), and to at least one SE in 173 of 656 (26.2%) participants. SE sensitization, but not S. aureus carriage, was associated with poly‐sensitization to food and inhalant allergens. SE ‐sensitized participants had higher median specific IgE to inhalant allergens (41.4 kU A /L, IQR 10.1‐118.4) compared to non‐ SE ‐sensitized participants (18.0 kU A /L, IQR 5.5‐48.6, P =.004), but not to food allergens. SE sensitization was associated with allergic multimorbidity. Conclusion Sensitization to SE s may play a role in the development of allergen poly‐sensitization and allergic multimorbidity.
Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial
Authors: Eugenio Paci, Donella Puliti, Andrea Lopes Pegna, Laura Carrozzi, Giulia Picozzi, Fabio Falaschi, Francesco Pistelli, Ferruccio Aquilini, Cristina Ocello, Marco Zappa, Francesca M Carozzi, Mario Mascalchi
Journal: Thorax (2017)

<h3>Background</h3> ITALUNG is contributing to the European evaluation of low-dose CT (LDCT) screening for lung cancer (LC). <h3>Methods</h3> Eligible subjects aged 55–69 years, smokers or ex-smokers (at least 20 pack-years in the last 10 years), were randomised to receive an annual invitation for LDCT screening for 4 years (active group) or to usual care (control group). All participants were followed up for vital status and cause of death (at the end of 2014) and LC incidence (at the end of 2013). Pathological and clinical information was collected from the Tuscan Cancer Registry data. <h3>Results</h3> 1613 subjects were randomly assigned to the active group and 1593 to the control group. At the end of the follow-up period 67 LC cases were diagnosed in the active group and 71 in the control group (rate ratio (RR)=0.93; 95% CI 0.67 to 1.30). A greater proportion of stage I LC was observed in the active group (36% vs 11%, p&lt;0.001). Non-significant reductions of 17% (RR=0.83; 95% CI 0.67 to 1.03) for overall mortality and 30% (RR=0.70; 95% CI 0.47 to 1.03) for LC-specific mortality were estimated. <h3>Conclusions</h3> Despite the lack of statistical significance, the ITALUNG trial outcomes suggest that LDCT screening could reduce LC and overall mortality. Moreover, the comparison of the number of LC cases diagnosed in the two groups does not show overdiagnosis after an adequate follow-up period. A pooled analysis of all European screening trials is advocated to assess the benefit-to-harm ratio of LDCT screening and its implementation in public health settings. <h3>Trial registration number</h3> Results, NCT02777996.