tbuckley/cabot-search huggingface dataset:
Specialist-Led Diabetes Registries and Prevalence of Poor Glycemic Control in Type 2 Diabetes: The Diabetes Registry Outcomes Project for A1C Reduction (DROP A1C)
Authors: Ronnie Aronson, Naomi Orzech, Chenglin Ye, Ruth E. Brown, Ronald Goldenberg, Vivien Brown
Journal: Diabetes Care (2016)

To highlight the utility of a large patient registry to identify functionally refractory patients (persistent HbA1c ≥75 mmol/mol [9.0%]) with type 2 diabetes, identify their barriers to glycemic control, and implement barrier-specific care path strategies to improve glycemic control.A working group developed a structured tool to optimize the collection of information on barriers to glycemic control and designed structured care paths to address each barrier. Participants were identified from a large Canadian registry and were assigned to a certified diabetes educator (CDE) as their case manager for a 12-month period to coordinate assessment of their barriers and to implement appropriate care path strategies. The primary outcome measure was the mean change in HbA1c from baseline at 12 months.Overall, 3,662 refractory patients were initially identified of whom 1,379 were eligible for inclusion and 155 enrolled. The most common barrier categories participants identified were psychological/support (93%), socioeconomic (87%), and accessibility (82%), with high concordance (75-94%) between participant and CDE. No specific barriers were predictive of hyperglycemia. After implementation of barrier-specific care paths, the mean reduction in HbA1c at 12 months was 17 mmol/mol (1.5%; P < 0.01 vs. baseline) versus only 5 mmol/mol (0.5%) in the source cohort (n = 966) who continued with standard care. The incidence of severe hypoglycemia did not change significantly during the study.In registry-identified hyperglycemic patients with type 2 diabetes, the use of barrier-specific care paths significantly improved glycemic control in otherwise refractory patients with persistently elevated HbA1c. Further studies using this strategy in other practice settings are warranted.
Do Bicycle Helmets Protect, and Should They Be Mandatory?-Reply
Authors: Diane C. Thompson
Journal: JAMA (1997)

In Reply.  —Drs Bayliss and Goldman express philosophical positions against mandatory helmet laws. Their arguments do not stand up to scientific scrutiny. Furthermore, they both demonstrate a misunderstanding of the validity of well-conducted case-control studies. 1 All the cyclists in our studies had experienced a bicycle crash, thus all could potentially have sustained a head injury. Therefore, the major potential confounding factors to be evaluated are the crash forces experienced by both case and control groups (speed, surface, motor vehicle involvement) so that the protective effect of helmets can be estimated. Our study took such an approach.  We agree that bicycling is beneficial to the environment and to personal physical health. This is all the more reason to publish studies that offer bicyclists a way to avoid their most serious hazard, head injury. Contrary to Bayliss' statement, fatality risk studies that compare bicycle travel with motor vehicle and motorcycle travel using the
La résistance bactérienne aux antibiotiques en France : une priorité en santé publique
Authors: H Aubry Damon, J Carlet, P Courvalin, J C Desenclos, J Drucker, D Guillemot, V Jarlier, B Régnier, B Schlemmer
Journal: Eurosurveillance (2000)

Depuis quelques annees, on assiste en France a une dissemination de la resistance aux antibiotiques interessant aussi bien les infections a l'hopital que celles acquises en ville malgre de nombreuses recommandations pour lutter contre ce phenomene. En 1999, a l’initiative de l’Institut de Veille Sanitaire (InVS), une expertise collective a ete lancee, suivie d’une large consultation des experts concernes par le probleme de la resistance aux antibiotiques. A l’issue de cette consultation, des propositions pour un plan national d'actions pour la maitrise de la resistance aux antibiotiques ont ete transmises au Ministere de la Sante.
Upfront CLL treatment with single agent obinutuzumab.
Authors: Eliana Lois Kozin, Stephen Edward Forbes Spurgeon
Journal: Journal of Clinical Oncology (2015)

e18039 Background: Obinutuzumab is a type 2 anti-CD20 monoclonal antibody approved in combination with chlorambucil for the initial treatment of CLL. In a randomized study, treatment with chlorambucil plus obintuzumab resulted in superior response rates, progression free-survival (PFS), and MRD negativity compared to R-chlorambucil (ORR 78% vs 65%; PFS 26.7 vs. 15.2 months, MRD 21 vs. 7%). Given the potency of obinutuzumab, it is being utilized as a single agent. However, little is known about the outcomes of single agent obinutuzumab in the upfront setting. Methods: To assess the activity and toxicities of Obinutuzumab, we retrospectively reviewed the demographics, toxicities and outcomes for CLL patients (n = 14) treated with single agent obinutuzumab at OHSU from 11/7/13 to 2/2/15. Response was assessed as defined by the IWCLL 2008 guidelines. Patients did not get bone marrow biopsy for confirmation of response. Peripheral blood MRD testing (8 color flow cytometry) was evaluated 6 months after completing therapy. For a prospective protocol, pre-treatment peripheral samples were collected to test a panel of 76 known mutations (next generation sequencing). Results: The median time to initial treatment was 65 months (14-168 months). 11/14 (78%) patients had Rai stage 3 or 4 disease. Median age was 68 years (43-86). Cytogenetic or molecular abnormalities included trisomy 12 (21%), 11q del (14%), 13q del (28%), unmutated IgVh (14%). Median number of treatment cycles was 6 (3-6) with 78% of patients having completed all 6 cycles. As no bone marrow analysis was done to confirm complete response (CR), all patients were recorded as having PR-8 patients would have been classified as CR or CRi clinically. At a median follow up of 305 days (56-419) from initiation, no relapses or deaths have occurred. ORR was 100%. To date MRD results are available on 6 patients with 5 (83%) being MRD negative. Gr. 3-4 toxicities included: infusion reactions 28%, tumor lysis 7%, febrile neutropenia 21%, neutropenia 35%, pulmonary infection 7% and thrombocytopenia 14%. Conclusions: Obinutuzumab as a single agent was active and well tolerated. Although the sample size is small, rates of MRD negativity were high. Next generation sequencing to further evaluate disease characteristics are ongoing.
Abstract C04: In vivo upregulation of bone morphogenic protein 4 (BMP4) in esophageal cancer is through tumor-stroma crosstalk
Authors: Silvia Calpe, Matthew Read, Maria del Carmen Sancho-Serra, Danielle Straub, Nick Clemons, David Liu, Wayne Phillips, Kausilia K. Krishnadath
Journal: Cancer Research (2016)

Abstract Bone morphogenic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor-beta (TGFβ;) superfamily. Amongst them, BMP4 is becoming increasingly attractive due to its crucial role in the development of many cancers. Whereas in malignancies such as glioblastoma and myeloma high levels of BMP4 are associated with benign features, in gastrointestinal cancers BMP4 possesses tumorigenic capacities. In these cancers, BMP4 acts on tumor epithelial cells enhancing their pro-metastatic behavior and chemo-resistance. However, whether BMP4 is being secreted by the epithelial cells or by the stroma, has not been well established yet, in part due to a lack of specific anti-BMP4 antibodies. To elucidate the functional implications of the origin of BMP4 production, we made use of a novel esophageal adenocarcinoma (EAC) tumor xenograft model and a newly generated Llama-derived anti-BMP4 antibody. Using in vivo molecular imaging techniques we find that BMP4 expression in the tumor is increased after engraftment of BMP4 negative human EAC tumor cells into immunodeficient mice. Immunohistochemical studies of the engrafted tissue reveal both a mouse and a human origin of BMP4 protein, suggesting that both epithelial as well as stromal cells are involved in BMP4 secretion. This implies that whereas the stroma directly secretes BMP4; it also produces molecules that activate autocrine BMP4 production by the cancer epithelial cells. In vitro analysis such as co-cultures with different stromal cells, revealed the functional effects of stroma-derived BMP4 on tumor cells, and how our anti-BMP4 antibodies can inhibit these. Further, these studies also uncovered the stromal components that induce BMP4 secretion by the human epithelial cells. In sum, these studies suggest a pivotal role of the microenvironment in regulating both directly and indirectly BMP4 expression in a model of esophageal cancer. As BMP4 has also been shown to be responsible for tumor progression in other gastrointestinal cancers, stromal regulation of BMP4 production might not be restricted to EAC, and might be a common feature in gastrointestinal cancers. Finally, as our anti-BMP4 Llama-derived antibodies can inhibit these effects in vitro, they might represent a novel therapy in targeting stromal function and preventing metastasis. Citation Format: Silvia Calpe, Matthew Read, Maria del Carmen Sancho-Serra, Danielle Straub, Nick Clemons, David Liu, Wayne Phillips, Kausilia K. Krishnadath. In vivo upregulation of bone morphogenic protein 4 (BMP4) in esophageal cancer is through tumor-stroma crosstalk. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C04.
Comparative Rates of Serious Infections Among Patients With Systemic Lupus Erythematosus Receiving Immunosuppressive Medications
Authors: Candace H. Feldman, Francisco M. Marty, Wolfgang C. Winkelmayer, Hongshu Guan, Jessica M. Franklin, Daniel H. Solomon, Karen H. Costenbader, Seoyoung C. Kim
Journal: Arthritis & Rheumatology (2016)

Objective While infection burden is high among patients with systemic lupus erythematosus (SLE), there is uncertainty about whether infection rates differ by immunosuppressive drug regimens. We undertook this study to compare infection rates among SLE patients newly initiating immunosuppressive therapy with mycophenolate mofetil (MMF), azathioprine (AZA), or cyclophosphamide (CYC). Methods Within the Medicaid Analytic eXtract database (2000–2010; 29 most populated US states), we identified adults with SLE starting MMF, AZA, or CYC treatment. We estimated propensity scores for receipt of MMF versus AZA and MMF versus CYC based on sociodemographic, comorbidity, and medication use information. After 1:1 propensity score matching, we estimated incidence rates of serious infections up to 6 and 12 months after drug initiation and used Cox regression to estimate hazard ratios (HRs) of first infection and death, with 95% confidence intervals (95% CIs). We performed primary intent‐to‐treat (ITT) and secondary as‐treated analyses. Results We studied 1,350 propensity score–matched pairs of MMF and AZA initiators and 674 propensity score–matched pairs of MMF and CYC initiators. In 6‐month ITT analyses, the incidence rate per 100 person‐years for first serious hospitalized infection was 14.6 in MMF users and 15.2 in AZA users (HR of MMF versus AZA 0.99 [95% CI 0.74–1.32]). Comparing MMF to CYC, the incidence rate per 100 person‐years for first serious infection was 24.1 in MMF users and 24.6 in CYC users (HR 0.95 [95% CI 0.69–1.32]). There were no differences in mortality in either comparison. As‐treated analyses yielded similar results. Conclusion In a nationwide longitudinal study of Medicaid SLE patients at high risk of infection, rates of serious infection and mortality did not differ among new users of MMF, AZA, or CYC.
Prospective Randomized Trial Comparing Titanium Clips to Bipolar Coagulation in Sealing Lymphatic Vessels During Pelvic Lymph Node Dissection at the Time of Robot-assisted Radical Prostatectomy
Authors: Pietro Grande, Giovanni Battista Di Pierro, Livio Mordasini, Matteo Ferrari, Christoph Würnschimmel, Hansjörg Danuser, Agostino Mattei
Journal: European Urology (2016)
Final overall survival (OS) analysis with modeling of crossover impact in the phase III GRID trial of regorafenib vs placebo in advanced gastrointestinal stromal tumors (GIST).
Authors: George D. Demetri, Peter Reichardt, Yoon-Koo Kang, Jean-Yves Blay, Heikki Joensuu, Klaus Schaefer, Andrea Wagner, Paolo Giovanni Casali, Christian Kappeler
Journal: Journal of Clinical Oncology (2016)

156 Background: GRID showed that regorafenib (REG) improves progression-free survival (PFS; primary endpoint) vs placebo (PBO) in patients (pts) with advanced GIST after failure of at least imatinib and sunitinib (HR 0.27; 1-sided p &lt; 0.0001). An interim OS analysis at the time of the primary PFS analysis showed a positive trend (HR 0.77; p = 0.199) despite 85% of PBO pts crossing over to REG. An exploratory analysis modeling the impact of crossover on OS suggested a benefit for REG. We present exploratory analyses of OS comparing crossover correction results at different times, including at the planned final OS analysis. Methods: Data cut-off dates for OS analyses were 26 Jan 2012 (final PFS analysis), 31 Jan 2014, and 8 Jun 2015 (final OS analysis). The impact of crossover on OS was modeled using 2 randomization-based methods: rank preserving structural failure time (RPSFT) and iterative parameter estimation (IPE), both considered best choice among correction analytics. Hazard ratios (HRs) and 95% CIs were derived using the Cox model. Results: Pts were randomized (2:1) to REG (n = 133) or PBO (n = 66). Data maturity in terms of deaths of randomized pts was 23%, 70%, and 81%. At data cut-off for the final OS analysis, a total of 162 deaths occurred: REG 109 (82%) and PBO 53 (80%); 7 pts remained on treatment. Compared to the 2012 OS analysis, continued crossover treatment further diluted the treatment effect, evidenced by the increasing HR in the ITT analysis at later times (Table). Conclusions: IPE correction provides more stable estimated median times and HRs than RPSFT. These exploratory analyses modeling the impact of crossover to active drug suggest that REG has a greater OS benefit than noted in the ITT analysis. Such sensitivity analytics are needed to understand fully the benefits of active drugs in crossover trials. Clinical trial information: NCT01271712. [Table: see text]
Prevalence of autoimmune comorbidities in patients with metastatic melanoma in the US.
Authors: Qiufei Ma, Mark Shilkrut, Minming Li, Beth L. Barber, Zhongyun Zhao
Journal: Journal of Clinical Oncology (2016)

9529 Background: Immunotherapies have advanced the treatment of metastatic melanoma (MM); however they are associated with frequent immune-related toxicities. As a result, patients with pre-existing autoimmune conditions were commonly excluded from clinical trials studying immunotherapies in metastatic melanoma. Since limited information is available on pre-existing autoimmune comorbidities in “real-world” patients with MM, we sought to estimate prevalence of autoimmune comorbidities and the change over time in this population. Methods: Definitions of autoimmune disorders included in this study were obtained from the American Autoimmune-Related Diseases Association. Prevalence of autoimmune disorders and time trend over a period of 10 years from 2004 to 2014 were estimated in patients with newly diagnosed mm as well as in patients with newly diagnosed non-MM, and in the general population. Prevalence rates and trends were compared among these 3 populations to delineate the potential role of disease vis-à-vis time on prevalence trends. Data were obtained from MarketScan, a large US claims database. Logistic regression analyses were performed to evaluate the relationship between risk factors and pre-existing autoimmune disorders in MM. Results: A list of 147 autoimmune disorders was examined in this study. Among 12,028 patients with newly-diagnosed MM, the prevalence rate for autoimmune disorders increased 1.7-fold from 17.1% in 2004 to 28.3% in 2014 (P < 0.001). The prevalence rates were lower in patients with non-MM (11.7% in 2004 to 19.8% in 2014) and in the general population (7.9% in 2004 to 9.2% in 2014), but the rates increased 1.7- and 1.2-fold over time, respectively. Additionally, female, bone or gastrointestinal metastasis, and high comorbid disease burden were found to be associated with higher risk of autoimmune disorders. Conclusions: Prevalence of autoimmune comorbidities is high and increases over time in patients with newly diagnosed metastatic melanoma. Comorbid autoimmune disorders should be taken into consideration when treatment decisions are made.
Clinical Characteristics and Outcome of 104 Patients with Gastric Diffuse B-Cell Non-Hodgkin Lymphoma (DLBCL) a Multicenter Study
Authors: Marcia T Delamain, Eliana Cristina Martins Miranda, Maria Gomes da Silva, Joana Desterro, Merli Francesco, Carlos Chiattone, Stefano Luminari, Katia BB Pagnano, Carmino Antonio De Souza, Massimo Federico
Journal: Blood (2015)
Actinic keratosis-related signs predictive of squamous cell carcinoma in renal transplant recipients: a nested case-control study
Authors: Z. Jiyad, P. O'Rourke, H.P. Soyer, A.C. Green
Journal: British Journal of Dermatology (2016)

Squamous cell carcinoma (SCC) and intraepidermal carcinoma (IEC) commonly arise in actinically damaged skin.To identify clinical features of actinic change that correlate with an increased risk of SCC or IEC in the short-to-medium term as guidance for prioritizing field treatment.In a nested case-control study, cases were renal transplant recipients who developed an incident SCC or IEC within 18 months following baseline examination and photography. Controls without SCC or IEC were matched to cases on age, sex and duration of immunosuppression. Predefined skin sites on the head, neck and upper limbs were examined using baseline photographs to assess objectively the following features of actinic damage: presence of actinic keratosis (AK) patch (defined as AK > 1 cm2 ), number of AK patches, number of AKs and area affected by AK. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using McNemar's test to identify differences in SCC/IEC risk combined and SCC risk alone between case and control skin sites.Thirty-nine cases were matched to 39 controls. Significant associations with the presence of an AK patch, number of AK patches, number of AKs and area affected by AKs were identified. The presence of an AK patch conferred an 18-fold increased risk of SCC (OR 18·00, 95% CI 2·84-750) and more than a sixfold increased risk of SCC/IEC combined (OR 6·60, 95% CI 2·56-21·66).AK patches are predictive of SCC/IEC development within 18 months. This can be used to guide site selection for field treatment in patients with widespread actinic damage.
Evaluation of pre- and post-treatment related to outcome in advanced non-small cell lung cancer (NSCLC) patients treated with split course concurrent chemoradiotherapy (CRT) followed by resection: A single-institution series of 49 patients.
Authors: B. T. Gielda, J. C. Marsh, T. W. Zusag, A. J. Khan, M. J. Liptay, S. Basu, P. Faber, M. J. Fidler, R. A. Abrams, P. D. Bonomi
Journal: Journal of Clinical Oncology (2010)

e17510 Background: Preoperative CRT is a conventional treatment for operable, locally advanced, NSCLC. Pathologic response has been recognized as a predictor of outcome, and we reviewed 10 year's experience at RUMC with preoperative split course CRT to identify other factors that may be associated with outcome. Methods: All patients treated with preoperative split course CRT between 1/1999 and 12/2008 were analyzed. The split course consisted of three consecutive 21 days cycles, with RT delivered on days 1-5 and 8-10, carboplatin AUC 4 delivered on day 1, and paclitaxel 100 mg/m2 delivered on days 1,8 (a small number of patients received etoposide). Endpoints were overall survival (OS) and disease-free survival (DFS). Factors analyzed were: stage, age, gender, performance status, pre-tx weight loss >5%, histology, albumin, hemoglobin, RT technique, RT delay, pathologic complete response/pathologic nodal clearance (pCR and pN0 versus not), and weight change during CRT. Univariate analysis was performed to identify correlation between factors and outcomes. Cox multivariate analysis was performed on factors found to be significant on univariate analysis. Results: 49 patients were analyzed, stage IIIA-IV. Univariate analysis revealed stage (p<0.01) and percent weight change during treatment (p<0.01) to be significantly correlated with both DFS and OS. On multivariate analysis stage (HR 2.4 95%CI 1.18-4.90 p=0.02) and percent weight change (HR 0.79 95%CI 0.67-0.93 p<0.01) were significantly associated with OS. DFS was likewise correlated with stage (HR 1.99 95%CI 1.09-3.65 p=0.03) and percent weight change (HR 0.86 95%CI 0.76-0.97 p=0.02). Those with pN0 or pCR demonstrated a trend toward improved OS/DFS that did not attain statistical significance. Conclusions: While validation is necessary, the positive relationship between weight gain during CRT and OS/DFS suggests this easily measured parameter may reflect treatment tolerability and efficacy. It could be useful, in conjunction with pathologic response, in selecting preoperative regimens for further study. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Lilly Bristol-Myers Squibb
Neddylation E2 UBE2F Promotes the Survival of Lung Cancer Cells by Activating CRL5 to Degrade NOXA via the K11 Linkage
Authors: Weihua Zhou, Jie Xu, Haomin Li, Ming Xu, Zhijian J. Chen, Wenyi Wei, Zhenqiang Pan, Yi Sun
Journal: Clinical Cancer Research (2016)

Purpose: Recent studies have shown that the process of protein neddylation was abnormally activated in several human cancers. However, it is unknown whether and how UBE2F, a less characterized neddylation E2, regulates lung cancer cell survival, and whether and how NOXA, a proapoptotic protein, is ubiquitylated and degraded by which E3 and via which ubiquitin linkage.Experimental Design: Methods of immunohistochemistry and immunoblotting were utilized to examine UBE2F protein expression. The biological functions of UBE2F were evaluated by in vitro cell culture and in vivo xenograft models. The in vivo complex formation among UBE2F-SAG-CUL5-NOXA was measured by a pulldown assay. Polyubiquitylation of NOXA was evaluated by in vivo and in vitro ubiquitylation assays.Results: UBE2F is overexpressed in non-small cell lung cancer (NSCLC) and predicts poor patient survival. While UBE2F overexpression promotes lung cancer growth both in vitro and in vivo, UBE2F knockdown selectively inhibits tumor growth. By promoting CUL5 neddylation, UBE2F/SAG/CUL5 tri-complex activates CRL5 (Cullin-RING-ligase-5) to ubiquitylate NOXA via a novel K11, but not K48, linkage for targeted proteasomal degradation. CRL5 inactivation or forced expression of K11R ubiquitin mutant caused NOXA accumulation to induce apoptosis, which is rescued by NOXA knockdown. Notably, NOXA knockdown rescues the UBE2F silencing effect, indicating a causal role of NOXA in this process. In lung cancer tissues, high levels of UBE2F and CUL5 correlate with a low level of NOXA and poor patient survival.Conclusions: By ubiquitylating and degrading NOXA through activating CRL5, UBE2F selectively promotes lung cancer cell survival and could, therefore, serve as a novel cancer target. Clin Cancer Res; 23(4); 1104-16. ©2016 AACR.