tbuckley/cabot-search huggingface dataset:
Abstract LB-36: JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: A rationale for co-targeting these pathways in metastatic breast cancer.
Authors: Adrian Britschgi, Rita Andraos, Heike Brinkhaus, Inna Klebba, Masato Murakami, Vincent Romanet, Urs Müller, Thomas Radimerski, Mohamed Bentires-Alj
Journal: Cancer Research (2013)

Abstract Hyperactive PI3K/mTOR signaling is prevalent in the majority of human malignancies (1) and its inhibition exhibits potent antitumor activity in a wide spectrum of solid cancers. Unfortunately, single-agent targeted cancer therapy is usually short-lived and thwarted by different resistance mechanisms (2). Here, we report the discovery of a JAK2/STAT5-evoked positive feedback loop that causes adaptive resistance to dual PI3K/mTOR inhibition. Mechanistically, PI3K/mTOR inhibition increased IRS1-dependent activation of JAK2/STAT5 and secretion of IL-8 in several cell lines and primary triple-negative breast tumors. Genetic or pharmacological inhibition of JAK2 abrogated this vicious feedback loop. Combined PI3K/mTOR and JAK2 inhibition synergistically reduced cancer cell viability in vitro as well as tumor growth in vivo, and decreased tumor seeding and metastasis due to its impact on the IL-8 receptor CXCR1+ tumor-initiating subpopulation of cells. We further found that combined PI3K/mTOR and JAK2 inhibition increased event-free as a well as overall survival of tumor bearing animals. This study reveals a new link between growth factor signaling, JAK/STAT activation, cytokine secretion and metastasis. Our results provide a rationale for combined targeting of the PI3K/mTOR and JAK2/STAT5 pathways in triple-negative breast cancer, a particularly aggressive and currently incurable disease. Citation Format: Adrian Britschgi, Rita Andraos, Heike Brinkhaus, Inna Klebba, Masato Murakami, Vincent Romanet, Urs Müller, Thomas Radimerski, Mohamed Bentires-Alj. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: A rationale for co-targeting these pathways in metastatic breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-36. doi:10.1158/1538-7445.AM2013-LB-36
INCREASED PERFUSION DUE TO VASCULAR NORMALIZATION IMPROVES OXYGENATION AND SURVIVAL IN GLIOBLASTOMA PATIENTS TREATED WITH CEDIRANIB WITH OR WITHOUT CHEMORADIATION
Authors: T. T. Batchelor, E. R. Gerstner, K. E. Emblem, D. G. Duda, J. Kalpathy-Cramer, M. Snuderl, M. Ancukiewicz, P. Polaskova, M. C. Pinho, D. Jennings, S. R. Plotkin, A. S. Chi, A. F. Eichler, J. Dietrich, F. H. Hochberg, C. Lu-Emerson, A. J. Iafrate, S. P. Ivy, B. Rosen, J. S. Loeffler, P. Y. Wen, A. G. Sorensen, R. K. Jain
Journal: Neuro-Oncology (2014)

BACKGROUND: (blind field). METHODS: We evaluated MRI markers in 84 GBM patients enrolled in phase 2 trials (NCT00305656, NCT00662506) to investigate the mechanisms of tumor response to anti-VEGF treatment. Forty newly diagnosed GBM (nGBM) patients were treated with the oral pan-VEGFR inhibitor, cediranib, in combination with radiation and temozolomide. Fourteen nGBM patients were treated with radiation and temozolomide alone. Thirty recurrent GBM (rGBM) patients were treated with cediranib alone. All patients underwent serial brain MRI scans at uniform time points. RESULTS: In both the nGBM and rGBM cohorts treated with cediranib, increased tumor perfusion was observed in 20/40 and 7/30 patients, respectively. In contrast, in the nGBM cohort not treated with cediranib increased tumor perfusion was observed in 1/14 patients. Increased tumor perfusion was associated with improved overall survival in nGBM (p = 0.040) and rGBM (p = 0.009) patients. Moreover, increased perfusion was associated with improved tumor oxygenation status in patients the nGBM patients treated with cediranib and chemoradiation. These findings are consistent with a recent report in rGBM patients treated with bevacizumab. CONCLUSIONS: Anti-VEGF therapy confers clinical benefit to GBM patients by normalization of tumor vessels. We hypothesize that the subset of GBM subjects who experience increased perfusion and improved tumor oxygenation status after anti-VEGF therapy will derive optimal benefit from concurrent chemoradiation and innate anti-tumor immune mechanisms. MRI techniques may enable early identification of GBM patients most likely to benefit from this expensive, and potentially toxic, class of anti-cancer drugs. SECONDARY CATEGORY: Imaging.
Abstract 4886: Caffeine normalizes breast stromal fibroblasts and suppresses their pro-carcinogenic effects.
Authors: Mysoon M. Al Ansari, Abdelilah Aboussekhra
Journal: Cancer Research (2013)

Abstract Breast cancer is the leading cause of morbidity and second-leading cause of death in women worldwide. Breast stromal fibroblasts, the most abundant and the most reactive cells of the tumor stroma, actively promote tumor growth, invasion, migration, angiogenesis and metastasis through elevated secretion of several factors including SDF1, MMP-2 and vascular endothelial growth factor A (VEGF-A). These secretions are under the control of several tumor suppressor genes such as p16, p53 and CAV-1, which were fond to be down-regulated in most active fibroblasts. Therefore, our major aim in this study was to study the potential use of caffeine to up-regulate these tumor suppressor genes and hence reduces the secretion of these cancer-promoting factors. We have shown that low doses of caffeine up-regulate the tumor suppressor proteins p16, p21, p53 and CAV-1 in breast stromal fibroblasts. Consequently, the expression and secretion of MMP-2 and VEGF-A was reduced following caffeine treatment. Moreover, caffeine reduced the expression of SDF-1, TGF-β and α-SMA, three important markers of active fibroblast, suggesting that caffeine has the ability of “normalizing” stromal fibroblasts. To further confirm this, we have shown that caffeine suppresses stromal fibroblast-related enhancement of invasion/migration of breast cancer cells. Importantly, this effect was mediated through caffeine-dependent inactivation of the two major invasion/migration protein kinases Akt and Erk, through up-regulating PTEN in breast stromal fibroblasts. Furthermore, caffeine suppressed the expression/secretion of VEGF-A in breast stromal fibroblasts and their paracrine enhancement of angiogenesis in vitro. This effect was mediated through inhibition of the VEGF-A activator HIF-1α. Therefore, we have clearly shown here that caffeine, a natural and pharmacologically safe product, has the potential to normalize breast stromal fibroblasts and consequently suppresses their paracrine procarcinogenic effects. Citation Format: Mysoon M. Al Ansari, Abdelilah Aboussekhra. Caffeine normalizes breast stromal fibroblasts and suppresses their pro-carcinogenic effects. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4886. doi:10.1158/1538-7445.AM2013-4886
AB0754 Psoriatic Arthritis (PSA): an Indian Perspective:
Authors: N.D. Nahar, N. Kulkarni, M. Saluja, A. Venugopalan, A. Chopra
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Psoriatic arthritis is a major rheumatological problem. The heterogenous phenotype spectrum spans from RA like to a typical AS. There are few descriptions from India <h3>Objectives</h3> To evaluate the clinical phenotype &amp; immunology pattern of a patients with psoriatic arthritis. <h3>Methods</h3> We conducted a retrospective study to define the clinical profile of psoriatic arthritis in patients attending Centre for Rheumatic Diseases (CRD), Pune clinic. Standard of care, case record forms are used to enter patient profile &amp; medications. Investigations are carried out in dedicated lab. Data was extracted from referral database maintained from 1996 onwards. We cover study period from JAN 2001 to JUN 2013. Blood samples of 154, 354, and 136 patients respectively were analyzed for HLA B27 (PCR with sequence specific Primer), RF (Nephelometry, cut off 40 IU/ml) and anti-CCP (2nd generation ELISA, cut off 5 RU/ml). Clinical events during follow up were also analyzed (data not shown). Similarly we will present results of lipid profile &amp; comorbidity especially cardiovascular. ABBREVIATIONS- IA: Inflammatory arthritis, RA: Rheumatoid arthritis, AS: Ankylosing spondylitis <h3>Results</h3> Psoriatic arthritis was classified in 1.1% of total patients case records (n=39756). 491 patients records of psoriatic arthritis were analyzed. Mean age of Presentation was 43 yrs (range 14yr-79yr). 61.1% subjects were males. In 72.3% patients, skin psoriasis preceded arthritis by a median interval 48 months, arthritis preceded skin lesion in 12.2%, occurred simultaneously in 9.3%. Dominant articular patterns were observed were polyarticular 50.1%, spondyloarthritis (Axial) 24.4%, oligoarticular 35.6%, distal interphalangeal joint arthritis (DIP alone) 2.4%. The table below shows selected patients characteristics. <h3>Conclusions</h3> This study describes a large series of Psoriatic arthritis from India followed for several years. Overall profile was similar to classical reports but there are interesting differences of articular pattern &amp; DIP disease in particular. Higher frequency of dactylitis &amp; nail involvement was observed. Seropositive RF polyarthritis was intriguingly uncommon. Overall, the frequency of HLA B27 &amp; RF is rather low while frequency of anti CCP is consistent with literature. <h3>References</h3> Taylor W et al Arthritis &amp; Rheumatism 2006; 54(8):2665-73 <h3>Acknowledgements</h3> Arthritis Research &amp; Care Foundation – Center for Rheumatic Diseases <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3203
Metastasis from Thyroid Carcinoma
Authors: Abhay K Kattepur, Kodaganur S Gopinath
Journal: New England Journal of Medicine (2014)

A 50-year-old woman presented with a painless lesion deep in the nail of the left little finger, which she had first noted 2 months earlier. There was no history of associated trauma or pruritus. The physical examination revealed a firm 2-cm lesion with a scab in the center.
SAT0116 Being underweight is associated with high disease activity and increased risk for hospitalization in patients with rheumatoid arthritis
Authors: T. Matsui, J. Nishino, Y. Kuga, H. Tsuno, A. Hashimoto, S. Tohma
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The influence of body mass index (BMI) on disease activity or risk for complication in patients with rheumatoid arthritis (RA) is unclear. <h3>Objectives</h3> To investigate the influences of BMI on disease activity, risk for hospitalization, and joint destruction in patients with RA using data of NinJa (National Database of Rheumatic Diseases by iR-net in Japan) in 2010. <h3>Methods</h3> A total of 3,255 RA patients (2,631 women and 624 men; mean age, 63.1 yr; disease duration, 13.1 yr; height/body weight/BMI, 153.2 cm/50.9 kg/21.7 kg/m<sup>2</sup> in women and 165.7 cm/61.6 kg/22.4k g/m<sup>2</sup>in men) were included in the analyses. They were categorized by BMI as follows; Group A (underweight): &lt;18.5 kg/m<sup>2</sup>, Group B (normal): 18.5-24.9 kg/m<sup>2</sup>, Group C (overweight): 25.0-29.9 kg/m<sup>2</sup>, Group D (obese): ≥30.0 kg/m<sup>2</sup>, and their composite disease activity indices (DAS28-ESR), their components and other markers (TJC, SJC, PtGA, PtPain, PhGA, mHAQ, CRP, ESR), incidence of hospitalization in 2010, and past history of joint arthroplasty were compared in a gender-specific manner. <h3>Results</h3> Women were younger (62.9 yr), had longer disease duration (14.0 yr), and higher SDAI scores (9.0) than men (65.2 yr, 9.6 yr, and 8.8). The mean SDAI scores were highest in Group A in both women and men. SDAI scores decreased gradually from Group A to D in men. Similarly, in women the scores decreased from A to C, but increased again in Group D (mean SDAI: Group A: 12.2, B: 8.9, C: 6.9, D: 4.0 in men, and A: 11.2, B: 8.6, C: 8.5, D: 10.6 in women). Mean numbers or values of each component showed almost similar trends to SDAI scores. In both women and men, incidence rate of hospitalization was highest in Group A (23.3% in women and 25.5% in men) and the following was in Group D (20.7% and 25.0%), but decreased in Group C (16.1% and 19.7%) and D (17.6% and 17.8%). Similar trends were observed in the rate of past history of joint arthroplasty. <h3>Conclusions</h3> Being underweight appears to be associated with high disease activity and risk for hospitalization in patients with RA. <h3>Disclosure of Interest</h3> None Declared
SAT0127 Long-Term Safety and Efficacy Following the Administration of Multiple Rituximab Cycles in Rheumatoid Arthritis (RA) Patients: The Multicenter, Prospective Launch Study
Authors: L. Settas, A. Andrianakos, S. Aslanidis, P. Boura, M. Katsounaros, D. Vassilopoulos, P. Athanassiou, K. Tempos, G. Skarantavos, C. Antoniadis, L. Sakkas, A. P. Andonopoulos, V. Galanopoulou, F. Solioti, K. Boki, E. Vritzali, P. P. Sfikakis
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> About one third of RA patients do not initially respond to treatment with an anti-TNF agent whereas a similar rate demonstrates lack of efficacy over time. Rituximab/Mabthera administration (temporary B-lymphocyte depletion) is one of the therapeutic options for them. <h3>Objectives</h3> The LAUNCH prospective study aimed at the evaluation of long-term efficacy and safety data following rituximab administration in standard clinical practice <h3>Methods</h3> 17 Rheumatology sites in Greece enrolled 234 adult patients (63.0±12.4 years, 79.5% women) with severe RA and an inadequate response or non-tolerance to anti-TNF treatment. Rituximab (1gr) was administered IV on days 1 and 14 of each cycle, repeated every 6-12 months, for up to 7 cycles. Of these patients 41.2% and 56.2% had received one, or more, anti-TNF agent(s), respectively. Adverse events, DAS28, and the quality of life evaluation indices (Euroqol) were collected every 2 to 6 months for 5 years according to each site's standard clinical practice <h3>Results</h3> During 496 patient/years, 28 adverse events /100 pt-yrs (including9.9 serious adverse events and 7.7 serious infectious per 100pt-yrs, respectively) were observed. Of the total number of adverse events a 46.7% was not related to rituximab. The mean number of adverse events per patient remained stable during repeated treatment cycles. Disease activity at baseline (mean±SD DAS28 of 5.36±1.40) was significantly reduced in cycles 1,2, 3, 4, 5, and 6 by 1.34, 2.12, 2.25, 2,56, 2.42 and 2.79, respectively (p&lt;0.01). Compared to baseline, significant improvement in quality of life was also observed in all cycles (p&lt;0.01) <h3>Conclusions</h3> Rituximab administration in clinical practice for up to 5 years demonstrated an acceptable safety profile which was maintained over time. Likewise, maintenance and/or improvement of efficacy with repeated treatment cycles in patients with severe RA not responding to anti-TNF were evident <h3>Disclosure of Interest</h3> L. Settas: None Declared, A. Andrianakos: None Declared, S. Aslanidis: None Declared, P. Boura: None Declared, M. Katsounaros: None Declared, D. Vassilopoulos: None Declared, P. Athanassiou: None Declared, K. Tempos: None Declared, G. Skarantavos: None Declared, C. Antoniadis : None Declared, L. Sakkas: None Declared, A. Andonopoulos: None Declared, V. Galanopoulou: None Declared, F. Solioti: None Declared, K. Boki: None Declared, E. Vritzali Employee of: Roche Hellas SA, P. Sfikakis: None Declared
A Randomized Trial of Low-Cost Mesh in Groin Hernia Repair
Authors: Jenny Löfgren, Pär Nordin, Charles Ibingira, Alphonsus Matovu, Edward Galiwango, Andreas Wladis
Journal: New England Journal of Medicine (2016)

The most effective method for repair of a groin hernia involves the use of a synthetic mesh, but this type of mesh is unaffordable for many patients in low- and middle-income countries. Sterilized mosquito meshes have been used as a lower-cost alternative but have not been rigorously studied.
Discrepancies in Brain Perfusion SPECT Findings Between Tc-99m HMPAO and Tc-99m ECD: Evaluation Using Dynamic SPECT in Patients With Hyperemia
Authors: N Miyazawa, K Koizumi, S Mitsuka, H Nukui
Journal: Clinical Nuclear Medicine (1998)

Discrepancies have been reported between the findings of Tc-99m HMPAO and Tc-99m ECD brain perfusion SPECT imaging. This study investigated the discrepancies in the accumulation of these tracers using dynamic SPECT to detect the super early phase of distribution. Thirteen patients with luxury perfusion or high flow states were studied with both dynamic and standard SPECT using Tc-99m HMPAO and Tc-99m ECD within 1-3 days. Standard SPECT showed discrepancies in 6 of 13 patients. Patients with meningioma and cerebral thrombosis had increased accumulation of Tc-99m HMPAO and decreased uptake of Tc-99m ECD. Patients with arteriovenous malformation, subarachnoid hemorrhage, and cavernous angioma had decreased accumulation of both tracers, but to different degrees. Dynamic SPECT showed increased or normal accumulation (i.e., essentially no discrepancy) in the first few minutes. However, Tc-99m HMPAO had a longer retention time than Tc-99m ECD in the ensuing 5-10 minutes. Dynamic SPECT revealed a similar accumulation pattern but different washout rates for the two tracers. Tc-99m HMPAO might be a more suitable tracer to detect high flow states or luxury perfusion because the findings on standard SPECT were more in agreement with those of dynamic SPECT using this tracer.
Use of a Cumulative Exposure Index to Estimate the Impact of Tap Water Lead Concentration on Blood Lead Levels in 1- to 5-Year-Old Children (Montréal, Canada)
Authors: Gerard Ngueta, Belkacem Abdous, Robert Tardif, Julie St-Laurent, Patrick Levallois
Journal: Environmental Health Perspectives (2015)

Drinking water is recognized as a source of lead (Pb) exposure. However, questions remain about the impact of chronic exposure to lead-contaminated water on internal dose.Our goal was to estimate the relation between a cumulative water Pb exposure index (CWLEI) and blood Pb levels (BPb) in children 1-5 years of ages.Between 10 September 2009 and 27 March 2010, individual characteristics and water consumption data were obtained from 298 children. Venous blood samples were collected (one per child) and a total of five 1-L samples of water per home were drawn from the kitchen tap. A second round of water collection was performed between 22 June 2011 and 6 September 2011 on a subsample of houses. Pb analyses used inductively coupled plasma mass spectroscopy. Multiple linear regressions were used to estimate the association between CWLEI and BPb.Each 1-unit increase in CWLEI multiplies the expected value of BPb by 1.10 (95% CI: 1.06, 1.15) after adjustment for confounders. Mean BPb was significantly higher in children in the upper third and fourth quartiles of CWLEI (0.7-1.9 and ≥ 1.9 μg/kg of body weight) compared with the first (< 0.2 μg/kg) after adjusting for confounders (19%; 95% CI: 0, 42% and 39%; 95% CI: 15, 67%, respectively). The trends analysis yielded a p-value < 0.0001 after adjusting for confounders suggesting a dose-response relationship between percentiles of CWLEI and BPb.In children 1-5 years of age, BPb was significantly associated with water lead concentration with an increase starting at a cumulative lead exposure of ≥ 0.7 μg Pb/kg of body weight. In this age group, an increase of 1 μg/L in water lead would result in an increase of 35% of BPb after 150 days of exposure.
Abstract P1-12-07: Neo-Adjuvant Exemestane in Post Menopausal Estrogen and/or Progesterone Receptor Positive Breast Cancer: A Randomized Phase II Trial To Investigate Optimal Duration (4 Month Versus 6 Month) of Preoperative Endocrine Therapy (PTEX46 Trial)
Authors: T Hojo, T Kinoshita, N Wada, S Imoto, N Tamura, T Nagao, M Ando, N Katsumata, Y. Fujiwara
Journal: Cancer Research (2010)

Abstract Background: Since the 1990s, primary endocrine therapy has been considered the gold standard in the adjuvant and metastatic treatment settings for estrogen and/or progesterone receptor (ER and/or PgR) positive breast cancer. This therapy has also been shown to be effective as neo-adjuvant endocrine therapy in these indications. In recent years, the focus of clinical interest has shifted to the third-generation aromatase inhibitors from tamoxifen. The optimal treatment duration time and causal relationship between neo-adjuvant endocrine therapy and survival, however, are not clear. We therefore conducted the present study to investigate the potential benefits of neo-adjuvant exemestane (E) therapy with the goal of identifying the optimal treatment duration (4 months versus 6 months). Methods: Conducted at three hospitals in Japan, this study was a multicenter, randomized phase II trial of pre-operative E treatment in postmenopausal women with untreated primary breast cancer. Fifty postmenopausal women with ER positive and/or PgR positive invasive breast cancer were randomly assigned to E (25 mg/day) for 4 months (4 mo) or E (25 mg/day) for 6 months (6 mo). All patient data were collected by UMIN and were analyzed by the National Cancer Center in Japan. Tumor regression (by clinical examination, ultrasound, and MRI), pathological response, shift towards breast-conserving surgery, and safety assessments were the main outcome measures. Results: Of the 50 patients that enrolled, 28 patients had undergone surgery. The mean ages in the 4 mo and 6 mo treatment groups were 66.7 years and 66.8 years, respectively. No significant differences in the patient characteristics were found in the two groups. The response rates (partial or complete responses) by clinical examination in the 4 mo and 6 mo groups were 37.5% and 50%, respectively. Pathological responses (minimal response or better) were found in 13.3% and 41.7% of patients and a partial mastectomy was performed in 50.0% and 58.3% of patients after 4 mo and 6 mo, respectively. Conclusion: To date, the results of this study demonstrate that treatment with E for 6 mo was more efficacious than treatment with E for 4 mo. Further work is in progress to obtain data from additional patients and to identify the optimal duration of neo-adjuvant E. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-12-07.