tbuckley/cabot-search huggingface dataset:
When to Adjust for Potentially Confounding Variables
Authors: Johannes M. Lehner
Journal: JAMA Internal Medicine (2017)

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Dulce Digital: An mHealth SMS-Based Intervention Improves Glycemic Control in Hispanics With Type 2 Diabetes
Authors: Addie L. Fortmann, Linda C. Gallo, Maria Isabel Garcia, Mariam Taleb, Johanna A. Euyoque, Taylor Clark, Jessica Skidmore, Monica Ruiz, Sapna Dharkar-Surber, James Schultz, Athena Philis-Tsimikas
Journal: Diabetes Care (2017)

OBJECTIVE Type 2 diabetes is growing in epidemic proportions and disproportionately affects lower-income, diverse communities. Text messaging may provide one of the most rapid methods to overcome the “digital divide” to improve care. RESEARCH DESIGN AND METHODS A randomized, nonblinded, parallel-groups clinical trial design allocated N = 126 low-income, Hispanic participants with poorly controlled type 2 diabetes to receive the Dulce Digital intervention or usual care (UC). Dulce Digital participants received up to three motivational, educational, and/or call-to-action text messages per day over 6 months. The primary outcome was HbA1c; lipids, blood pressure, and BMI were secondary outcomes. Satisfaction and acceptability were evaluated via focus groups and self-report survey items. RESULTS The majority of patients were middle-aged (mean age 48.43 years, SD 9.80), female (75%), born in Mexico (91%), and uninsured (75%) and reported less than a ninth-grade education level (73%) and mean baseline HbA1c 9.5% (80 mmol/mol), SD 1.3, and fasting plasma glucose 187.17 mg/dL, SD 64.75. A statistically significant time-by-group interaction effect indicated that the Dulce Digital group achieved a significantly greater reduction in HbA1c over time compared with UC (P = 0.03). No statistically significant effects were observed for secondary clinical indicators. The number of blood glucose values texted in by participants was a statistically significant predictor of month 6 HbA1c (P &amp;lt; 0.05). Satisfaction and acceptability ratings for the Dulce Digital intervention were high. CONCLUSIONS Use of a simple, low-cost text messaging program was found to be highly acceptable in this sample of high-risk, Hispanic individuals with type 2 diabetes and resulted in greater improvement in glycemic control compared with UC.
Better research flattens the J shaped curve
Authors: Fiona Godlee
Journal: BMJ (2017)

As you reach for your post-election glass of wine this weekend, or perhaps even something stronger, spare a thought for your brain. You may have been told that alcohol, when consumed in moderation, protects against dementia—an example of the workings of the famous “J shaped curve.” Sadly, as with cardiovascular health, the reported benefits of light to moderate drinking on brain health are now looking decidedly shaky.

This week Anya Topiwala and colleagues report their follow-up study of a cohort of 550 civil servants whose alcohol intake and cognitive function were repeatedly assessed …
Association between insulin-like growth factor-1 receptor (IGF1R) expression in circulating tumor cells (CTCs) and prognosis in patients with metastatic breast cancer (MBC).
Authors: Alessandra Gennari, Rita Zamarchi, Dino Amadori, Andrea De Censi, Oriana Nanni, Alessandra Bologna, Luigi Cavanna, Lorenzo Gianni, Laura Scaltriti, Elisabetta Rossi, Antonella Facchinetti, Davide Corradengo, Flavia Foca, Paolo Bruzzi
Journal: Journal of Clinical Oncology (2017)

1086 Background: CTCs are strongly associated with prognosis in MBC. In a recent metanalysis on 1944 patients, a CTC count &gt; 5/7.5 ml was associated with a 2-fold increased risk of progression and death. Little evidence is available on the prognostic role of phenotypic CTC assessment, however. In this study, nested in a randomized clinical trial of Ist line chemotherapy ± metformin, we evaluated the prognostic role of IGF1R expression in CTCs, given its potential growth promoting effect. Methods: CTCs were isolated from blood samples of enrolled patients; an automated sample preparation and analysis system (CellSearch) was customized for detecting IGF1R positive CTCs. The prognostic role of total CTCs, IGF1R positive (+ve) and negative (-ve) CTCs was assessed by fitting different PFS and OS multivariate Cox’s models.Results: CTC evaluation at baseline was performed in 72 of 126 patients, of whom 30 (42%) had CTCs ≥5/7,5ml and 41 (57%) had at least one IGF1R+ve CTC. In univariate analysis the prognostic role of total CTCs was confirmed: PFS ( &lt; 5 vs ≥5) HR = 1.69, 95%CI 1.01-2.69, p 0.042 and OS HR = 2.80, 95%CI 1.47-5.30, p 0.002).However, when total CTCs were split in IGF1R+ve and IGF1R–ve, a striking difference was seen in the prognostic effect of these cell types.While no association was detected between an increasing number of IGF1R+ve CTCs and PFS or OS (p = 0.56 and p = 0.99), the number of IGF1R-ve CTCs ( &lt; 4 vs ≥4) was strongly associated with an increased risk of progression and death: HR 1.93 (95%CI 1.15-3.23, p 0.013) and 3.65 (95%CI 1.88-7.09, p 0.001). In multivariate analysis, adjusted for metformin, the prognostic role of the number of IGF1R-ve CTCs was confirmed, while no residual prognostic role of total CTCs or number of IGF1R+ve cells was found (p = 0.55 and p = 0.64 for PFS; p = 0.86 in both cases for OS). Conclusions: In our study, the loss of IGF1R expression in CTCs exhibited a significant adverse prognostic effect, whereas no significant effect of total CTCs and IGF1R+ve CTCs was observed. This finding supports the biological characterization of CTCs as a critical step for further definition of their prognostic significance.
Phase Ib Study of Lumretuzumab Plus Cetuximab or Erlotinib in Solid Tumor Patients and Evaluation of HER3 and Heregulin as Potential Biomarkers of Clinical Activity
Authors: Didier Meulendijks, Wolfgang Jacob, Emile E. Voest, Morten Mau-Sorensen, Maria Martinez-Garcia, Alvaro Taus, Tania Fleitas, Andres Cervantes, Martijn P. Lolkema, Marlies H.G. Langenberg, Maja J. De Jonge, Stefan Sleijfer, Ji-Youn Han, Antonio Calles, Enriqueta Felip, Sang-We Kim, Jan H.M. Schellens, Sabine Wilson, Marlene Thomas, Maurizio Ceppi, Georgina Meneses-Lorente, Ian James, Suzana Vega-Harring, Rajiv Dua, Maitram Nguyen, Lori Steiner, Celine Adessi, Francesca Michielin, Birgit Bossenmaier, Martin Weisser, Ulrik N. Lassen
Journal: Clinical Cancer Research (2017)

Abstract Purpose: This study investigated the safety, clinical activity, and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas. Experimental Design: The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2,000 mg plus cetuximab or erlotinib according to standard posology, respectively. The effect of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of squamous non–small cell lung cancer (sqNSCLC) patients treated with lumretuzumab and erlotinib. Results: Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and two DLTs in the erlotinib part were reported. The most frequent adverse events were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with a numerically higher disease control rate but not ORR. Conclusions: The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable, but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels. Clin Cancer Res; 23(18); 5406–15. ©2017 AACR.
Neoadjuvant treatment of HER2 positive breast cancer with concomitant nonpegylated liposomal doxorubicin (NPLD), docetaxel and dual blockade with trastuzumab and pertuzumab: A retrospective analysis of pCR and cardiac safety.
Authors: Daniel Egle, Christine Brunner, Theresa Czech, Thomas Jaeger, Alois Lang, Christopher Hager, Clemens Poisl, Birgit Volgger, Christian Marth
Journal: Journal of Clinical Oncology (2017)

e12061 Background: Neoadjuvant treatment in HER2 overexpressing early breast cancer (EBC) has increased considerably. The Neosphere study, in which dual blockade of HER2 was combined with docetaxel resulted in favorable pCR rates. The addition of anthracyclines could play an important role in enhancing the effectiveness. The use of NPLD might be valuable in combination with HER2 targeted therapies. Safety and efficacy of NPLD, taxotere and trastuzumab was reported in the ABSCG 32 study. There is only little data about the cardiac safety and efficacy in combination with dual HER2 blockade. We report pCR-rate and cardiac safety of a single arm, retrospective, multicenter analysis of neoadj. treatment for HER2+ EBC. Methods: In this study 98 women with HER2+ EBC were investigated in 4 oncological departments in Austria. All patients were treated with NPLD (50 mg/m²), docetaxel (75 mg/m²) concurrent with trastuzumab and pertuzumab in standard dosage for 6 cycles as neoadjuvant therapy. All patients were free of cardiovascular disease and had a left ventricular ejection fraction (LVEF) of ≥50%. Cardiac function was measured by LVEF. All patients underwent surgery after neoadjuvant chemotherapy. The absence of any residual invasive cancer in the breast and axilla was defined as pathological complete response (pCR). Median follow up was 1.7 years. Results: Median age was 49 years. pCR rate was 73%. In this cohort a negative estrogen-and progesteron receptor was predictive for pCR (p&lt;0.001). These patients achieved pCR in 89%. No patient progressed during treatment. Only one patient(1%) suffered symptomatic heart failure after surgery. Conclusions: We observed a considerably high rate of pCR in HER2-positive EBC treated with a combination of NPLD, docetaxel, trastuzumab and pertuzumab. Hormone receptor negativity was highly predictive for pCR. The addition of NPLD entails a very favorable cardiotoxicity profile. This regimen is a safe and highly effective treatment option in patients with HER-2 positive EBC.
Volume-based parameters on FDG-PET/CT as early predictors of disease recurrence in postmastectomy breast cancer patients with one to three positive axillary lymph nodes without adjuvant radiotherapy.
Authors: Naomi Nakajima, Masaaki Kataoka, Atsushi Nishikawa, Yoshifumi Sugawara, Shinya Sakai, Shozo Ohsumi, Sachiko Kiyoto, Teruhito Mochizuki
Journal: Journal of Clinical Oncology (2013)

1124 Background: The indication for postmastectomy radiotherapy (PMRT) in patients with 1-3 lymph node metastases in the axilla have been controversial, despite the recommendation that PMRT should be applied. In the current study, we focused our study on volume-based parameters of pretreatment FDG-PET/CT, with the aim of investigating a measurement that could help identify high-risk populations for recurrence. Methods: We retrospectively analyzed 88 patients of breast cancer treated with modified radical mastectomy and were found to have 1-3 metastatic axillary lymph nodes between 2006 and 2010. All of them were studied with FDG-PET/CT for initial staging. We evaluated the relationship between clinicopathologic factors or PET parameters including the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and recurrence. MTV and TLG of the primary tumor and metastatic lymph node were measured by using semi-automatically delineated volume of interest (VOI) with an isocontour threshold of 40 % of the SUVmax. The optimal cutoffs of PET parameters were determined by ROC curve analysis. Results: The median follow up duration was 39 months. Median MTV was 21.1and median TLG was 42.7. Recurrence was observed in 10 patients. The area under the ROC curve of MTV and TLG for DFS was 0.82 and 0.85, respectively. In Cox univariate analysis, estrogen receptor status (HR = 6.8, p = 0.003), triple negativity (HR = 10.4, p = 0.0008), SUVmax (HR = 71.1, p = 0.001), MTV (HR = 130.3, p &lt; 0.0001), and TLG (HR = 234.1, p = 0.0001) were significantly related to disease free survival (DFS). The estimated 3-year DFS rates were 96.4 % for the lower MTV group (&lt; 31.8) and 71.4% for the higher MTV group (≥ 31.8, p = 0.0005). The estimated 3-year DFS rates were 95.8 % for the lower TLG group (&lt; 109.6) and 50.0 % for the higher TLG group (≥ 109.6, p &lt; 0.0001). On multivariate analysis, TLG was an independent prognostic factor of DFS (HR = 8.5, p = 0.005). Conclusions: Volume-based parameters on FDG-PET/CT were significant predictors of DFS in postmastectomy breast cancer patients with 1-3 metastatic axillary lymph nodes.
First line antiangiogenics for advanced renal cell carcinoma: A systematic review and network meta-analysis comparing efficacy and toxicities.
Authors: Emmanuelle Kempf, Benoit Rousseau, Gaelle Desamericq, Emilie Boissier, Charlotte Joly, Carolina Saldana, Marie Chaubet-Houdu, Laurent Salomon, Alexandre de la Taille, Christophe Tournigand
Journal: Journal of Clinical Oncology (2015)

e15586 Background: Four different antiangiogenic treatment are approved in first line advanced Renal Cell Carcinoma (RCC): sunitinib (Su), pazopanib (Pa), sorafenib (So) and bevacizumab (Be). Due to parallel development, most of them were not directly compared for efficacy and toxicities. The aim of the present study was to perform a network meta-analysis in order to compare each drug to the others for efficacy and safety outcome. Methods: As of the 31th of July 2014, two independent reviewers searched and collected data of randomized clinical trials (RCT) of first line assessing at least one approved antiangiogenic drug in advanced RCC (Su, Pa, So, Be). The study measured the following outcomes: response rate, progression-free survival (PFS), overall survival (OS), safety (CTCAE). We calculated a traditional weighted average meta-analysis and then conducted a network meta-analysis: we examined the network formed by treatments performing a linear mixed-effect model. Results: We screened 411 abstracts and selected 17 different articles corresponding to 9 RCT including 5,050 patients Treatment arms were: 3 Su, 2 Pa, 2 So, 1 Be, 3 Be+Interferon alpha (INF2A), 2 Placebo (Pl), 4 INF2A. Efficacy meta-analysis showed significantly improvement of PFS (HR = .6; IC95% .55-.65) and OS (HR = .87; IC95% .80-.95) compared to Pl or INF2A. Network meta-analysis showed: significantly better 6-month PFS for Su or Pa compared to So (OR = 1.6; IC95% 1.1-2.4 and 1.4; IC95% 1.0-2.1, respectively) or Be+IFN (OR = 1.4; IC95% 1.0-1.9 and 1.2; IC95% 0.9-1.8, respectively); no difference between antiangiogenics for drug-related toxicity discontinuation, all grade toxicity for hypertension, diarrhea, and weight loss (Su, Pa, So); significantly more treatment discontinuation with Be+IFN (vs Su, Pz, or So), less all grade fatigue for Pa vs (Su, So or Be+IFN), more all grade anemia for Su vs (Pa, So, or Be+IFN). Conclusions: This meta-analysis confirms benefits of first line antiangiogenic in advanced RCC both for PFS and OS. Network meta-analysis suggests better 6-month PFS for Su or Pa compared to Be+IFN or So, and different safety profiles that may help clinicians to better individualize treatment.
Association Between Prenatal Alcohol Exposure and Craniofacial Shape of Children at 12 Months of Age
Authors: Evelyne Muggli, Harold Matthews, Anthony Penington, Peter Claes, Colleen O’Leary, Della Forster, Susan Donath, Peter J. Anderson, Sharon Lewis, Cate Nagle, Jeffrey M. Craig, Susan M. White, Elizabeth J. Elliott, Jane Halliday
Journal: JAMA Pediatrics (2017)

Children who receive a diagnosis of fetal alcohol spectrum disorder may have a characteristic facial appearance in addition to neurodevelopmental impairment. It is not well understood whether there is a gradient of facial characteristics of children who did not receive a diagnosis of fetal alcohol spectrum disorder but who were exposed to a range of common drinking patterns during pregnancy.To examine the association between dose, frequency, and timing of prenatal alcohol exposure and craniofacial phenotype in 12-month-old children.A prospective cohort study was performed from January 1, 2011, to December 30, 2014, among mothers recruited in the first trimester of pregnancy from low-risk, public maternity clinics in metropolitan Melbourne, Australia. A total of 415 white children were included in this analysis of 3-dimensional craniofacial images taken at 12 months of age. Analysis was performed with objective, holistic craniofacial phenotyping using dense surface models of the face and head. Partial least square regression models included covariates known to affect craniofacial shape.Low, moderate to high, or binge-level alcohol exposure in the first trimester or throughout pregnancy.Anatomical differences in global and regional craniofacial shape between children of women who abstained from alcohol during pregnancy and children with varying levels of prenatal alcohol exposure.Of the 415 children in the study (195 girls and 220 boys; mean [SD] age, 363.0 [8.3] days), a consistent association between craniofacial shape and prenatal alcohol exposure was observed at almost any level regardless of whether exposure occurred only in the first trimester or throughout pregnancy. Regions of difference were concentrated around the midface, nose, lips, and eyes. Directional visualization showed that these differences corresponded to general recession of the midface and superior displacement of the nose, especially the tip of the nose, indicating shortening of the nose and upturning of the nose tip. Differences were most pronounced between groups with no exposure and groups with low exposure in the first trimester (forehead), moderate to high exposure in the first trimester (eyes, midface, chin, and parietal region), and binge-level exposure in the first trimester (chin).Prenatal alcohol exposure, even at low levels, can influence craniofacial development. Although the clinical significance of these findings is yet to be determined, they support the conclusion that for women who are or may become pregnant, avoiding alcohol is the safest option.
Abstract NTOC-080: NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER
Authors: Paige Baldwin, Anders Ohman, Daniela Dinulescu, Srinivas Sridhar
Journal: Clinical Cancer Research (2017)

Abstract PURPOSE: PARP inhibitor therapy for ovarian cancer exploits the concept of synthetic lethality by taking advantage of defects in DNA damage repair pathways. Currently Olaparib is the only FDA-approved PARP inhibitor and is available as an oral dosage, which has plenty of advantages, but requires the drug to undergo first pass metabolism, inactivating a significant fraction of the dose. We have developed a nanoparticle delivery system to allow for local delivery of Olaparib directly to the intraperitoneal cavity. METHODS: NanoOlaparib was characterized in vitro in regards to size, charge, drug loading and release before testing on a panel of ovarian cancer cell lines, including KURAMOCHI, SKOV3, OVSAHO, JHOS2, PA1, COV318, 403 and 404, derived from tumors of Brca2-/-, Pten-/-, Tp53-/- mice, and 4306 and 4412, developed from conditional KrasLSL-G12D/+, Pten-/- mice, to elucidate sensitivity profiles and ensure comparable activity to the free drug. 404 cells, derived from Brca2-/-, Tp53-/-, Pten-/- genetically engineered mouse models, were utilized to develop an IP spread xenograft model to test NanoOlaparib in vivo. Animals were treated with NanoOlaparib or oral Olaparib daily for 4 weeks. Tumor burden was monitored weekly via bioluminescence imaging. RESULTS: NanoOlaparib shows comparable efficacy in vitro to free Olaparib. The murine cell lines were the most sensitive to the treatment regardless of BRCA status, suggesting that Pten deletions are just as susceptible to PARP inhibitor therapy as the BRCA mutations. The average fold change in bioluminescence for NanoOlaparib decreased, while it increased for oral Olaparib. The oral Olaparib animals had widely varied responses, with some animals' tumors shrinking and others never responding. All NanoOlaparib tumors shrank initially, however, severe toxicity was noted after 3 weeks of treatment. CONCLUSIONS: NanoOlaparib toxicity in vivo was observed with daily dosing likely due to the sustained release of the drug in comparison to the much more rapid clearance of the oral drug. While the NanoOlaparib was toxic, it provided a much more uniform response to the treatment than the oral Olaparib. It is clear that because this strategy provides 100% of the dose to the disease site with a sustained delivery it is no longer necessary to administer daily. This suggests that NanoOlaparib changes the pharmacokinetics to allow for a lower dose to be administered. A modified dosing regime is to be tested with the goal of lowering the toxicity while still maintaining therapeutic efficacy. Citation Format: Paige Baldwin, Anders Ohman, Daniela Dinulescu, Srinivas Sridhar. NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-080.