tbuckley/cabot-search huggingface dataset:
Fetal Thyroid Function, Birth Weight, and <i>in Utero</i> Exposure to Fine Particle Air Pollution: A Birth Cohort Study
Authors: Bram G. Janssen, Nelly D. Saenen, Harry A. Roels, Narjes Madhloum, Wilfried Gyselaers, Wouter Lefebvre, Joris Penders, Charlotte Vanpoucke, Karen Vrijens, Tim S. Nawrot
Journal: Environmental Health Perspectives (2016)

Thyroid hormones are critical for fetal development and growth. Whether prenatal exposure to fine particle air pollution (≤ 2.5 μm; PM2.5) affects fetal thyroid function and what the impact is on birth weight in normal healthy pregnancies have not been studied yet.We studied the impact of third-trimester PM2.5 exposure on fetal and maternal thyroid hormones and their mediating role on birth weight.We measured the levels of free thyroid hormones (FT3, FT4) and thyroid-stimulating hormone (TSH) in cord blood (n = 499) and maternal blood (n = 431) collected after delivery from mother-child pairs enrolled between February 2010 and June 2014 in the ENVIRONAGE birth cohort with catchment area in the province of Limburg, Belgium.An interquartile range (IQR) increment (8.2 μg/m3) in third-trimester PM2.5 exposure was inversely associated with cord blood TSH levels (-11.6%; 95% CI: -21.8, -0.1) and the FT4/FT3 ratio (-62.7%; 95% CI: -91.6, -33.8). A 10th-90th percentile decrease in cord blood FT4 levels was associated with a 56 g decrease in mean birth weight (95% CI: -90, -23). Assuming causality, we estimated that cord blood FT4 mediated 21% (-19 g; 95% CI: -37, -1) of the estimated effect of an IQR increment in third-trimester PM2.5 exposure on birth weight. Third-trimester PM2.5 exposure was inversely but not significantly associated with maternal blood FT4 levels collected 1 day after delivery (-4.0%, 95% CI: -8.0, 0.2 for an IQR increment in third-trimester PM2.5).In our study population of normal healthy pregnancies, third-trimester exposure to PM2.5 air pollution was associated with differences in fetal thyroid hormone levels that may contribute to reduced birth weight. Additional research is needed to confirm our findings in other populations and to evaluate potential consequences later in life.
Comparison of folate derivate levels in mucosa and tumor tissue in the course of antifolate treatment with pemetrexed.
Authors: B. Gustavsson, E. Odin, G. Kurlberg, T. Swartling, G. Carlsson, H. Björkqvist, P. Kälebo, M. Holmqvist, A. Thareau Vaury, C. Stoffregen
Journal: Journal of Clinical Oncology (2010)

10612 Background: THF (tetrahydrofolate), methyl-THF and methylene-THF are cornerstones for viability of mucosa with different functions in the cell cycle. Understanding the tumor growth and the role of reduced folates is essential in the understanding of mechanisms that occur during chemotherapy with pemetrexed and folate supplementation. Methods: 37 patients (pts) with operable nonmetastatic rectal adenocarcinoma were enrolled. Pemetrexed 500 mg/m2 was administered every 3 weeks, during 3 cycles with standard comedication (vitamin B12, folic acid, and dexamethasone). Biopsies of tumor and adjacent mucosa were taken before the patient received vitamin supplementation, after supplementation but before antifolate therapy and at surgery. A LC-MS/MS method was used for the determination of THF, methylene-THF and methyl-THF levels. Results: See Table. All levels of the three folate derivates increased significantly after the start of the supplementation, in mucosa as well as in tumor tissue. Mean THF and methylene-THF levels were significantly higher in tumor compared with mucosa at baseline, after folate supplementation and at surgery after 3 cycles of pemetrexed. Conclusions: In a population of 37 pts with rectal cancer, there was a strong and consistent significant difference observed for reduced folates between tumor and mucosa. High tumor tissue levels of reduced folates need further exploration to better understand the biological basis to optimize the treatment in rectal cancer and in other tumor entities. Baseline After supplementation At surgery THF a 463/584 620/901 704/906 b 123 (294) 292 (408) 202 (459) c p = 0.006 p ≤ 0.001 p = 0.012 d 36/37 35/35 37/37 Methyl-THF a 352/436 640/903 639/1065 b 84 (227) 263 (352) 426 (585) c p = 0.051 p ≤ 0.001 p ≤ 0.001 d 37/37 36/36 37/37 Methylene-THF a 830/1,018 1,405/2,067 1,302/1,871 b 188 (718) 662 (1,272) 568 (1,352) c p = 0.018 p ≤ 0.001 p = 0.004 d 37/37 36/36 37/37 a = mean levels mucosa/tumor (M/T) (pmol/g); b = Difference T/M, mean (SD); c = p value*; d= number of pts, M/T. * Wilcoxon signed rank test was used for pairwise comparison T-M, testing whether mean difference is zero. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly
What is an Optimal Rate of Early Revascularization After ST-elevation Myocardial Infarction? Insights from the GUSTO-V Trial
Authors: PW Armstrong, WC Chang, P Kaul, D Ardinisso, PE Aylward, FW BSr, A Betriu, C Bode, Guetta, PG Steg, Frans Van de Werf, AM Lincoff
Journal: Circulation (2003)
Treatment of otitis media by transtympanic delivery of antibiotics
Authors: Rong Yang, Vishakha Sabharwal, Obiajulu S. Okonkwo, Nadya Shlykova, Rong Tong, Lily Yun Lin, Weiping Wang, Shutao Guo, John J. Rosowski, Stephen I. Pelton, Daniel S. Kohane
Journal: Science Translational Medicine (2016)

A hydrogel drug delivery system allowed controlled, local delivery of ciprofloxacin across the tympanic membrane to treat acute otitis media in chinchillas.
Patterns of chemotherapy (CT) use in a population-based US-wide cohort of patients (pts) with metastatic pancreatic cancer (MPC).
Authors: Thomas Adam Abrams, Gary Meyer, Julie Moloney, Jeffrey A. Meyerhardt, Brian M. Wolpin, Deborah Schrag, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2014)

4131 Background: Few population studies have examined the frequencies and durations of specific CT treatment regimens in MPC. Methods: We assessed 3,796 consecutive MPC pts who received CT between Jan 2005 and Aug 2013 at academic, private and community hospital-based practices participating in a US-wide CT order entry system that captures pt, provider and treatment data. Multivariate analyses of prospectively recorded pt and provider characteristics identified predictors of specific therapeutic approaches. Results: Among all pts, median age was 70; 55% male. In 1st-line CT, 48% of pts received gemcitabine (GEM) monotherapy, 16% received a GEM-based doublet (incl. GEM + nab-paclitaxel [NAB-P]), 9% received fluoropyrimidine (FU) + oxaliplatin (OX) + irinotecan (FOLFIRINOX), 9% received FU monotherapy, and 5% received FU + OX (FOLFOX). The remaining 13% received other regimens. GEM monotherapy use peaked at 58% in 2009 but declined to 28% in 2013. FOLFIRINOX use emerged in 2010 with 4% usage and peaked at 23% in 2012. Since 2012, GEM + NAB-P use has risen substantially, representing 20% of first-line therapy in 2013. GEM + cisplatin use declined steadily from 2010 (9%) to 2013 (3%). Pts under age 60 and those treated at academic centers were more likely to receive first-line FOLFIRINOX and less likely to receive GEM monotherapy (both p<0.05). Mean duration of all 1st-line treatments was 87 days. 31% of all pts received 2nd-line treatment, 13% third-line, and 5% fourth-line. Second-line CTs included GEM monotherapy (28%), FOLFOX (14%), FOLFIRINOX (7%) and GEM + NAB-P (6%). 37% of pts who received second-line GEM + NAB-P received 1st-line FOLFIRINOX. Conclusions: This population-based study provides insight into US MPC treatment patterns. Treatments vary significantly according to patient and practice characteristics. MPC first-line CT treatment trends (2005-2013). 2005-2009 2010-2011 2012 2013† # Pts 1,694 1,111 604 387 GEM (%) 57.6 48.1 33.0 28.4 GEM doublet‡ (%) 16.1 8.6 11.4 9.3 GEM + NAB-P (%) 0.2 2.1 4.0 20.4 FOLFOX (%) 2.3 5.8 8.9 2.3 FOLFIRINOX (%) 0.1 11.8 23.3 20.7 FU (%) 9.5 9.0 8.4 11.9 Other (%) 14.2 14.6 11.0 7.0 †Through Aug 31 (data through Dec 31, 2013 will be presented at the meeting). ‡Not including GEM + NAB-P.
Deregulation of Micrornas Results in Overexpression of Oncogenic Transcription Factors Involved in Pathogenesis of CLL.
Authors: Christian P Pallasch, Susanne Hagist, Michaela Patz, Alexandra Schulz, Svenja Debey, Daniela Eggle, Joachim L Schultze, Michael Hallek, Clemens-Martin Wendtner
Journal: Blood (2008)
Cholesterol Embolization after Transcatheter Aortic-Valve Replacement
Authors: Lu Devy, Florence Brunet-Possenti
Journal: New England Journal of Medicine (2016)

An 88-year-old man with a history of MI for which he had required quadruple coronary-artery bypass grafting presented with mottled purple discoloration of the toes. One month earlier, he had undergone transapical transcatheter aortic-valve replacement.
Correlation of prevalence of CD68<sup>+</sup> macrophages within tumor-draining lymph node basins and overall survival in stage III melanoma patients.
Authors: G. Lizee, M. A. Whittington, J. Chen, V. R. Greene, S. Liu, R. L. Bassett, J. Khalili, V. Prieto, L. G. Radvanyi, P. Hwu, E. A. Grimm, J. E. Gershenwald
Journal: Journal of Clinical Oncology (2010)

e21034 Background: Although it is well-established that melanomas can elicit immune responses, they more often produce factors that adversely impact or block antitumor immunity. Suppressive immune cells such as Foxp3+ regulatory T cells (Treg) and tumor-infiltrating macrophages have been implicated as poor prognostic indicators in other cancer etiologies, but their prognostic value in melanoma has remained unclear. Methods: We performed an immunohistochemical (IHC) analysis of 62 melanoma tumors comprising a spectra of disease stages to assess tumor infiltration by T cells (CD3+, CD4+, CD8+ and Foxp3+ subsets), B cells (CD19+), and macrophages (CD68+). To assess the potential negative impact of tumors on regional immunity, we also analyzed a set of uninvolved regional lymph nodes (LN) harvested from sentinel node positive basins of 28 stage III melanoma patients. All immune markers were correlated with overall survival by univariate Cox regression analyses. Results: Overall, relatively few Foxp3+ T cells or B cells infiltrated melanoma tumors. In contrast, CD68+ macrophages were found to be abundant at all disease stages, typically comprising 5% to 20% of all cells within the tumor parenchyma. Although no significant associations were found with any immune markers in melanoma tumors, Cox regression analysis demonstrated a significant adverse association between the percentage of CD68+ macrophages in uninvolved regional LNs and overall survival (HR=1.93 per 5% increase in CD68+ cells, 95% CI (1.17, 3.18), p=0.01). Kaplan-Meier analyses revealed that stage III patients harboring >15% CD68+ cells in uninvolved regional LNs had a median survival of 2.6 yr vs. 7.7 yr for patients with <15% CD68+ cells. Conclusions: These results suggest that melanoma involvement of regional LNs can adversely impact the immune microenvironment of adjacent uninvolved regional LNs, possibly by facilitating regional immune suppression mediated by CD68+ cells. Pharmacological targeting of tumor-associated CD68+ macrophages may favorably impact survival outcomes for patients with stage III melanoma. No significant financial relationships to disclose.
NCI 9448: Phase I study of trametinib in combination with chemoradiation for KRAS-mutant non-small cell lung cancer.
Authors: Steven H. Lin, Isabel Mok, David Leos, Manolo G Pasia, Peter F. Thall, Heather Y. Lin, Meng XU Welliver, Miguel Angel Villalona-Calero, James C. Yao, Funda Meric-Bernstam, Ritsuko Komaki, Helen X. Chen, George R. Blumenschein
Journal: Journal of Clinical Oncology (2015)

TPS7585 Background: Concurrent chemoradiotherapy is the standard management approach for unresectable, non-metastatic locally advanced non-small cell lung cancer (NSCLC). However, progress has been slow in making substantial improvements in the outcomes of these patients. Preclinical data suggests that adding molecular targeted drugs affecting specific pathways could enhance radiation effects, and Kras mutated NSCLC may be particularly susceptible for MEK1/2 inhibition for radiation sensitization. This trial tests the safety of combining trametinib (GSK1120212), a potent MEK1/2 inhibitor, with standard carboplatin and paclitaxel chemoradiotherapy, for the treatment of locally advanced NSCLC. Methods: This is a multi-center, NCI UM1-sponsored, phase I clinical trial. Patients with unresectable stage II-III NSCLC with Kras mutation who can receive concurrent carboplatin (AUC 2.0) and paclitaxel (50 mg/m2) with once-daily trametinib and 60 Gy radiotherapy delivered in 30 fractions are eligible. Two additional cycles of consolidation chemotherapy (carboplatin AUC 6.0 and paclitaxel 200 mg/m2) are given after completing concurrent chemoradiotherapy. Trametinib is delivered at the starting dose level of 1.0 mg, and Time-to-Event-Continuous Reassessment Method (TiTE-CRM) is used for dose escalation at 4 levels (0.5, 1.0, 1.5, and 2.0 mg). CTCAE v4.0 is used to determine dose-limiting toxicity (DLT), with the Pr(tox) within 70 days at 0.6 for general DLTs, and 0.3 for severe DLTs. Primary objective of the trial is to determine the maximum tolerated dose (MTD) and safety of trametinib as measured by rate of grade 3 or worse non-hematologic toxicities attributed to chemoradiation within 70 days of start of therapy, as well as pharmacokinetic studies. Secondary objectives include response rate, overall survival, patterns of recurrence, dose delay and percentage of dose delivered, and biomarker exploratory endpoints. The maximum number of patients is 30. Conduct to Date: The trial was activated October 28, 2013 at MD Anderson, and recently at Ohio State University. So far 7 patients have enrolled on study. Clinical trial information NCT01912625. Clinical trial information: NCT01912625.
Identification of prognostic genomic markers in patients with localized clear cell renal cell carcinoma (ccRCC).
Authors: B. I. Rini, M. Zhou, H. Aydin, P. Elson, T. Maddala, D. Knezevic, L. Parodi, R. M. Bukowski, W. F. Novotny, J. W. Cowens
Journal: Journal of Clinical Oncology (2010)

4501 Background: Tumor gene expression may impact prognosis following surgery for early stage ccRCC. Genomic analysis may also aid in understanding disease biology. Methods: Patients with stage I-III ccRCC who underwent nephrectomy at CCF between 1985 and 2003 with archived paraffin-embedded nephrectomy samples were identified. Pathology and RCC recurrence status were re-reviewed and verified. Exclusions included inherited RCC, neo/adjuvant systemic therapy or <6 months follow-up. RNA was extracted from 6 × 10μ m dissected tumor sections and RNA expression quantified for 732 genes (including 5 reference) using RT-PCR. The primary endpoint was recurrence-free interval (RFI), defined as time from nephrectomy to first recurrence or death due to RCC. The study had 80% power (α=0.05) to identify genes associated with RFI (standardized hazard ratios (HR) ≥ 1.3). Results: 931 patients with complete clinical/pathology data and tissue blocks were evaluable. Patient characteristics: 63% male, median age 61, stage I (68%), II (10%) and III (22%), median follow-up of 5.6 yrs. Clinical/pathology covariates significantly associated with RFI included microscopic necrosis, Fuhrman grade, stage, tumor size and lymph node involvement (all p<0.001). 448 genes were significantly (p<0.05, unadj.; Cox models) associated with RFI and 300 genes were significantly (p<0.05, unadj.) associated with ≥4 of 5 covariates. In a multivariate model, 16 genes remained significantly and strongly associated with RFI after clinical/pathologic covariate and false discovery adjustments (HR 0.68–0.80). Among the 16 genes, increased expression was associated with lower risk of recurrence for angiogenesis-related (including EMCN and NOS3) and immune-related (including CCL5 and CXCL9) genes. Conclusions: This is the largest genomic study of localized ccRCC performed to date. Genomic factors strongly associated with risk of recurrence and clinical/pathologic covariates were identified. The magnitude of HRs are comparable to those of other clinically used prognostic markers, such as ER and HER2 in breast cancer. These results can be used to create a multi-gene algorithm to predict recurrence of ccRCC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genomic Health, Pfizer Genomic Health, Pfizer Genomic Health, Pfizer
Local excision after neoadjuvant chemoradiation for rectal cancer: Is it an acceptable treatment option?
Authors: B. Brenner, R. Brenner, O. Puirm, N. Peled, E. Idelevich, B. Nisenbaum, E. Fenig, A. Sulkes
Journal: Journal of Clinical Oncology (2010)

3646 Background: Neoadjuvant concurrent chemoradiation (CCRT) followed by radical surgery is standard in patients (pts) with locally advanced rectal cancer (LARC). Nevertheless, some pts undergo local excision (LE) only, for various reasons. The role of LE in this setting is currently unclear; the main concern regarding LE is the possible neglectance of involved regional lymph nodes (LNs). We therefore evaluated the correlation between pathologic T stage and LN involvement following CCRT and the outcome of pts with good histologic response, i.e. pathological complete response (pCR), undergoing LE. Methods: 340 eligible pts, who underwent neoadjuvant CCRT followed by surgery for LARC between 1/1997 and 12/2007, were included in the study. LARC was defined as T3-4Nx, TxN+ or distal (≤ 6 cm from the anus) T2N0. Radiotherapy was standard (50.4-54 Gy in fractions of 1.8 Gy) and chemotherapy consisted of several common fluoropyrimidine-based regimens. Results: The median age of the whole group was 67 years, 50% were males and 52% had distal tumors. 309 pts (91%) underwent radical surgery, 22 (6%) had LE only and 9 (3%) did not have surgery following CCRT. Of the 22 pts who had LE only, 15 had pT0, 3- microscopic residual disease (mRd), 3-pT1 and 1-pT2. With a median follow-up of 34 month, two pts died, one with mRd and one with T1. We compared the outcome of pT0 pts (n = 37) who underwent radical surgery (group I) with that of pT0 pts (n = 15) who had LE only (group II). With a median follow-up of 48 month, 4 pts in group I had a recurrence (3-local, 1-distant) and none in group II; one pt died in group I and none in group II. There was no significant difference in 5-year disease-free survival (88% vs. 100%), pelvic recurrence-free survival (92% vs. 100%) and overall survival (97% vs. 100%) between the groups. Conclusions: In this small cohort, pts who underwent LE following neoadjuvant CCRT had a relatively good outcome. In pts with pCR, radical surgery did not result in an improved outcome. Therefore, LE may be an acceptable option, at least for pts with mural pCR. No significant financial relationships to disclose.
Safety, clinical activity, and PD-L1 expression of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with metastatic urothelial carcinoma from the JAVELIN Solid Tumor phase Ib trial.
Authors: Andrea B. Apolo, Jeffrey R. Infante, Omid Hamid, Manish R. Patel, Ding Wang, Karen Kelly, Anthony E. Mega, Carolyn D. Britten, Alain C. Mita, Alain Ravaud, Jean-Marie Cuillerot, Anja von Heydebreck, James L. Gulley
Journal: Journal of Clinical Oncology (2016)

367 Background: Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in multiple clinical trials. We report safety and clinical activity of avelumab as a second-line therapy in patients (pts) with metastatic urothelial carcinoma (mUC) based on level of PD-L1 expression (NCT01772004). Methods: Pts with mUC unselected for PD-L1 expression received avelumab at 10 mg/kg Q2W by IV infusion until confirmed progression, unacceptable toxicity, or any criterion for withdrawal occurred. Tumors were assessed every 6 wks (RECIST 1.1). Best overall response rate (ORR) and progression-free survival (PFS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. PD-L1 expression was assessed by immunohistochemistry. Results: As of 19 Mar 2015, 44 pts (30 men, 14 women) with mUC were treated with avelumab (median 13 wks [range 2-28]) and followed for a median of 3.5 mo (range 3.0-5.0). Median age was 68y (range 30-84), ECOG performance status was 0 (43.2%) or 1 (56.8%), and pts had received a median of 2 prior therapies (range 1- ≥ 4). Treatment-related treatment-emergent AEs (TR-TEAEs) of any grade occurred in 26 pts (59.1%); those occurring ≥ 10% were grade 1/2 infusion-related reactions (8 [18.2%]) and fatigue (7 [15.9%]). One pt had grade 3 asthenia. There were no treatment-related deaths. ORR was 15.9% (7 pts; 95% CI: 6.6, 30.1) with 1 CR and 6 PRs; 6 responses were ongoing at data cutoff. Stable disease (SD) was observed in 19 pts (42.3%) and disease-control rate (CR+PR+SD) was 59.1%. PD-L1 expression was evaluable in 32 pts. Using a ≥ 5% cutoff (10/32 [31.3%] were PD-L1+), ORR was 40.0% in PD-L1+ pts (4/10) vs 9.1% in PD-L1– pts (2/22; p= 0.060). PFS rate at 12 wks was 70.0% (95% CI: 32.9, 89.2) in PD-L1+ pts vs 45.5% (95% CI 22.7, 65.8) in PD-L1− pts. Conclusions: Avelumabshowed an acceptable safety profile and had clinical activity in pts with mUC. There was a trend towards higher ORR and prolonged PFS rate at 12 wks in pts with PD-L1+ mUC. Further analyses of PD-L1 expression and clinical activity of avelumab in UC are ongoing. *Proposed INN. Clinical trial information: NCT01772004.
Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis
Authors: Jörg H. W. Distler, Carol Feghali‐Bostwick, Alina Soare, Yoshihide Asano, Oliver Distler, David J. Abraham
Journal: Arthritis & Rheumatology (2016)

Although fibrosis is becoming increasingly recognized as a major cause of morbidity and mortality in modern societies, targeted anti fibrotic therapies are still not approved for most fibrotic disorders.However, intense research over the last decade has improved our understanding of the underlying pathogenesis of fibrotic diseases.We now appreciate fibrosis as the consequence of a persistent tissue repair responses, which, in contrast to normal wound healing, fails to be effectively terminated.Profibrotic mediators released from infiltrating leukocytes, activated endothelial cells and degranulated platelets may predominantly drive fibroblast activation and collagen release in early stages, whereas endogenous activation of fibroblasts due epigenetic modifications and biomechanical or physical factors such as stiffening of the extracellular matrix and hypoxia may play pivotal role for disease progression in later stages.In the present review, we discuss novel insights into the pathogenesis of fibrotic diseases using systemic sclerosis (SSc) as example for an idiopathic, multisystem disorder.We set a strong translational focus and predominantly discuss approaches with very high potential for rapid transfer from bench to bedside.We highlight the molecular basis for ongoing clinical trials in SSc and also provide an outlook on upcoming trials.
Motexafin Gadolinium (MGd) Has Clinical Activity in Relapsed/Refractory Low Grade Lymphomas (LG) and Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).
Authors: Brad S. Kahl, Ranjana Advani, Neil Kay, Izidore S. Lossos, Andrew Evens, Leo Gordon, Richard A. Miller, See-Chun Phan
Journal: Blood (2005)