tbuckley/cabot-search huggingface dataset:
Infiltrating Macrophages Induce ERα Expression through an IL17A-mediated Epigenetic Mechanism to Sensitize Endometrial Cancer Cells to Estrogen
Authors: Chengcheng Ning, Bingying Xie, Lin Zhang, Chunsheng Li, Weiwei Shan, Bingyi Yang, Xuezhen Luo, Chao Gu, Qizhi He, Hongyan Jin, Xiaojun Chen, Zhenbo Zhang, Youji Feng
Journal: Cancer Research (2016)

Abstract Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68+CD163+ macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERα), but not ERβ. Mechanistic investigations revealed that CD68+CD163+ macrophages secreted cytokines, such as IL17A, that upregulated ERα expression through TET1-mediated epigenetic modulation of the ERα gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERα expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting. Cancer Res; 76(6); 1354–66. ©2016 AACR.
Automated 5-plex fluorescent immunohistochemistry with tyramide signal amplification using antibodies from the same species
Authors: Wenjun Zhang, Antony Hubbard, Tobin Jones, Srabani Bhaumik, Adriana Racolta, Mark Lefever, Karl Garsha, Nicholas Cummins, Franklin Ventura, Lei Tang
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Immunohistochemical (IHC) detection of multiple antigens on the same tissue section represents a major unmet technological need in research and clinical diagnostics. While primary antibodies from different species have been used with differently labeled species-specific secondary
P-197 Number of CD68(+) macrophages and FasL expression in colon mucosa of patients with inflammatory bowel disease as prognostic factors of colon carcinogenesis
Authors: A. Santimov, A. Kolobov, V. Karev, O. Kolobova, M. Kostik, M. Dubko, O. Kalashnikova, V. Masalova, L. Snegireva, N. Volkova, A. Khvatov, M. Belogurova, V. Chasnyk
Journal: Annals of Oncology (2015)
A phase I, open-label, nonrandomized trial of OPB-31121, a STAT3 inhibitor, in patients with advanced solid tumors.
Authors: D. Oh, S. Han, T. M. Kim, S. Lee, T. Kim, D. S. Heo, Y. Bang
Journal: Journal of Clinical Oncology (2010)

e13056 Background: STAT pathway is activated in many solid tumors. OPB-31121 is an orally administered STAT3 inhibitor. We conducted a phase I study to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics of OPB-31121 in patients with advanced refractory solid tumors. Methods: A standard 3 + 3 dose-escalation design was used with a 28-day cycle. The tested dose level was 100 mg, 200 mg, 400 mg, 600 mg, and 800 mg/day. Results: Twenty-one patients were enrolled. Median age was 58 (19-74) and 15 patients were male. The tumors of patients were gastric cancer (5), colorectal cancer (7), esophageal cancer (2), hepatocellular carcinoma (1), pancreatic cancer (1), lung cancer (1), neuroectodermal cancer (1), melanoma (1), parotid gland cancer (1), and cervix cancer (1). The patient number enrolled in each dose cohort was 100 mg (4), 200 mg (3), 400 mg (3), 600 mg (7), 800 mg (4), respectively. The most common toxicities of all grades were nausea (Gr 1:11, Gr 2: 5, Gr 3:0, Gr 4:0), vomiting (Gr 1: 9, Gr 2: 4, Gr 3: 1, Gr 4:0), diarrhea (Gr 1: 10, Gr 2: 3, Gr 3:2, Gr 4:0), fatigue (Gr 1:2, Gr 2: 1, Gr 3:0, Gr 4:0), anorexia (Gr 1:2, Gr 2: 2, Gr 3:0, Gr 4:0). These toxicities were predominantly grade 1 or grade 2. The dose-limiting toxicities (DLT) were grade 3 vomiting at 600 mg and grade 3 diarrhea at 800 mg. The MTD has not been determined yet. Cmax and AUC of OPB-31121 and metabolites increased with increasing doses of OPB-31121. Among 17 response-evaluable patients, 8 had the stable disease (disease control rate 47.1%). Disease stabilization more than 12 months was observed in a gastric cancer patient. Conclusions: OPB-31121 was well-tolerated and the DLT were grade 3 vomiting and diarrhea. The MTD has not been determined yet and the preliminary promising antitumor activity needs further validation in phase II studies. No significant financial relationships to disclose.
FISHing for lung cancer: Promising findings using multi-targeted interphase fluorescence in situ hybridization (FISH) for lung cancer detection in sputum
Authors: W. A. Franklin, T. Byers, H. J. Wolf, S. Braudich, F. R. Hirsch, Y. E. Miller, R. L. Keith, T. C. Kennedy, S. Belinsky, M. Varella-Garcia
Journal: Journal of Clinical Oncology (2007)

7567 Background: Lung CT imaging shows promise for early lung cancer detection, but may be insensitive for central lesions and will create a need for complementary biomarkers to guide clinical decisions. Methods: We have been conducting a prospective study to assess the performance of various biomarkers in sputum to detect lung cancer. Within a cohort of 3,269 people at high risk for lung cancer (over 30 pack-years of cigarette use and chronic obstructive lung disease) we have conducted a nested case-control study to assay stored samples from 85 incident lung cancer cases and 73 controls for cytologic morphology, DNA methylation, and multi-targeted FISH assays (LAVysion, Vysis/Abbott Molecular). The FISH assay targeted DNA sequences from centromere 6, 5p15.2, 7p12 (EGFR), and 8q24 (cMYC). Cytology was classified as abnormal if moderate or greater atypia was observed, methylation was abnormal if three or more of 8 selected genes were methylated, and FISH was abnormal if two or more scored cells were observed to contain chromosomal aneuploidy indicated by signal gain for at least two targets or signal gain for one and signal loss for two or more targets. Results: Among all subjects, regardless of the time between sputum collection and diagnosis, FISH was abnormal in 49/87 cases (56%) and 5/73 controls (7%) (odds ratio (OR) = 17.5, 95% CI = 6.4 to 47.8). Considering only the cases for which sputum had been collected within 18 months before the lung cancer diagnosis, FISH was abnormal in 37/49 cases (75%) and in 3/38 controls (8%) (OR = 36.0, 95% CI = 9.4 to 138). For this same time period, cytological atypia was abnormal in 37% of cases and 22% of controls (OR = 2.1, 95% CI = 0.8 to 5.3) and methylation was abnormal in 64% of cases and 36% of controls (OR = 4.5, 95% CI = 1.0 to 19.8). Conclusions: The LAVysion FISH assay is more sensitive than other currently available sputum tests for the prediction of invasive carcinoma in subjects and is highly specific with a low frequency of false positive and false negative results. The results suggest that chromosomal aneuploidy and by extrapolation, missegregation, are features of advanced premalignancy and should identify patients who are proximate to clinically overt lung cancer. [Table: see text]
Critique of a hypothesis of dominance and sexual behavior
Authors: R C Friedman
Journal: American Journal of Psychiatry (1975)

The author critically evaluates the article "Dominance and Sexual Behavior: A Hypothesis," which appeared in this journal last year and hypothesized that "male dominance facilitates male-female copulatory behavior while female dominance inhibits it." He concludes that such unitary-cause hypotheses of complex behaviors may be reductionistic and therefore less helpful than intended.
Comparison of Ex Vivo and In Vivo Dermoscopy in Dermatopathologic Evaluation of Skin Tumors
Authors: Marc Haspeslagh, Katrien Vossaert, Sven Lanssens, Michael Noë, Isabelle Hoorens, Ines Chevolet, Ine De Wispelaere, Nele Degryse, Fabio Facchetti, Lieve Brochez
Journal: JAMA Dermatology (2016)

<h3>Importance</h3> Ex vivo dermoscopy (EVD) can be a valuable tool in routine diagnostic dermatopathologic evaluation. <h3>Objectives</h3> To compare in vivo dermoscopy (IVD) and EVD and to provide guidance for routine dermatopathologic evaluations. <h3>Design, Setting, and Participants</h3> This observational study collected 101 consecutive IVD and EVD images of skin tumors from a private dermatology practice from March 1 to September 30, 2013. Four observers (3 dermatologists and 1 dermatopathologist) blinded to the histopathologic diagnoses independently scored and compared the colors, structures, and vessels of EVD images with those of the corresponding IVD images. Data were analyzed from January 1 to March 31, 2014. <h3>Main Outcomes and Measures</h3> Concordance between the EVD and IVD images and gain or loss of colors, structures, and vessels on EVD relative to IVD images. <h3>Results</h3> The final analysis included 404 observations of 101 images. The EVD image was generally similar to the corresponding IVD image but clearly darker, with new areas of blue in 130 of 404 observations (32.2%) and white in 100 of 404 observations (24.8%) and loss of red in 283 of 404 observations (70.0%). Most structures were well preserved. New structureless areas were found in 78 of 404 observations of EVD images (19.3%), and new crystalline structures were detected in 68 of 404 observations of EVD images (16.8%). On EVD images, squames and crusts were lost in 56 of 404 observations (13.9%) and 43 of 404 observations (10.6%), respectively. Blood vessels were lost in 142 of 404 observations of EVD images (35.1%). <h3>Conclusions and Relevance</h3> The EVD image is an important new tool in dermatopathology and may give direction to targeted tissue processing and examination of skin tumors.
Effects of cessation of imatinib mesylate (IM) therapy in patients (pts) with IM-refractory gastrointestinal stromal tumors (GIST) as visualized by FDG-PET scanning
Authors: A. D. Van Den Abbeele, R. D. Badawi, J. Manola, J. A. Morgan, J. Desai, A. Kazanovicz, M. St. Armand, C. Baum, G. D. Demetri
Journal: Journal of Clinical Oncology (2004)

3012 Background: FDG-PET is a reliable and sensitive measure of metabolic activity in pts with GIST. Pts with GIST controlled by IM may develop resistance that can be localized to a single clonal outgrowth or limited oligoclonal sites of IM-refractory disease. As part of a clinical trial of SU11248, a novel multi-targeted kinase inhibitor, pts with IM-refractory GIST underwent FDG-PET scanning before and after cessation of IM therapy (prior to initiation of SU11248 dosing).Methods: 11 pts with GIST were treated with IM therapy for an average of 22 months (range 14–33 months) and subsequently developed objective progression of disease by bidimensional (Southwest Oncology Group) criteria. These pts underwent FDG-PET scanning 11 to 31 days before IM cessation, and 10 to 19 days thereafter, prior to SU11248 initiation. A total of 24 lesions were followed (1 to 4 lesions per pt), and the maximum standardized uptake value (SUV) and its logarithm were computed for each lesion. The significance of the differences between the distributions of log (SUV) before and after therapy cessation was determined using a two-tailed paired T-test. Lesions within the same pt were assumed to be independent. Results: The mean SUV prior to IM cessation was 5.5 (range 2.1–11.3). This increased to 8.8 (range 2.6–23.4) after cessation, and the difference between log (SUV) means before and after termination of IM therapy was highly significant (p=0.0005). The median change in SUV was a 35% increase (range: 31% reduction to 410% increase); 9/11 patients had at least 1 lesion with an SUV increase of > 25%.Conclusion: These data suggest that termination of IM therapy in pts with IM-refractory GIST results in a
<i>KRAS</i> mutation testing in patients with metastatic colorectal carcinoma: An 18-month experience emphasizing the risk of false-negative results.
Authors: F. Bibeau, H. Frugier, E. Crapez, P. Lamy, M. Ychou, F. Boissière-Michot
Journal: Journal of Clinical Oncology (2010)

3572 Background: KRAS status is a prerequisite in patients with metastatic colorectal carcinoma (mCRC) candidate for treatment with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies. Indeed, KRAS mutations are associated with resistance to treatment. However, KRAS status determination may be very challenging when tumor cellularity is poor, notably after neoadjuvant radiotherapy and/or chemotherapy. We report our experience about the management of tumor samples for KRAS testing, emphasizing the potential pitfalls encountered. Methods: From May 2008 to November 2009, we tested 575 paraffin embedded samples for KRAS status. After rigorous selection of tumor area on a stained slide, tumor enrichment was performed using careful macrodissection. Samples were ranked in 2 classes: > 20% and < 20% of tumor cells (92% and 8% of tumor samples, respectively) before DNA extraction (QIAampDNA FFPE Tissue, QIAGEN). Bidirectional DNA sequencing for KRAS exon 2 was used for KRAS testing. Results: Overall, 97% of the tested samples were assessable for KRAS status. Testing failure was mainly related to DNA degradation (n = 12) precluding efficient amplification, or to exhausted tumor cells (n = 3). KRAS mutation was detected in 37% of the cases (74.5% on codon 12; 25.5% on codon 13), in agreement with the literature. However, the frequency of KRAS mutations was dependent on the relative amount of tumor cells: > 20%: 38,5%; < 20%: 22.5% (p = 0.044 Fisher's exact test). Conclusions: Our results confirmed that KRAS status can be efficiently assessed from archival paraffin-embedded tissue. This material allows an easy enrichment by selecting the tumor area with a morphologic control on histologic sections. We demonstrated that this step is highly critical as the incidence of detected KRAS mutations was dependent on the ratio of tumor cells in the studied sample. Poor cellularity raised the question of false-negative results. Consequently, in these particular samples, we suggest the use more sensitive assays and/or microdissection to enhance tumor purity. We also recommend a tumor pre-treatment biopsy dedicated to molecular diagnosis before any neoadjuvant treatment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Merck
The Prostate Cancer Clinical Trials Working Group (PCCTWG) consensus criteria for phase II clinical trials for castration-resistant prostate cancer
Authors: H. I. Scher, S. Halabi, I. Tannock, M. Morris, C. Higano, W. Kelly, C. Sternberg, M. Eisenberger, A. Martin, M. Hussain
Journal: Journal of Clinical Oncology (2007)

5057 Background: The clinical manifestations of castration-resistant metastatic prostate cancer pose challenges to the design of phase 2 trials. In 1999, PSAWG issued a consensus report to standardize phase 2 design and endpoint definitions. A reassessment is reported. Methods: At 4 meetings, and using electronic communication, PCCTWG is seeking consensus on the design and analysis of phase 2 trials that can inform decisions about proceeding to phase 3. Results: PCCTWG recognizes that trial objectives, and details of design and analysis depend on the agent under study. PCCTWG recommends: (i) A standard disease assessment that includes prior treatment history, bone scan, and CT of the chest, abdomen and pelvis; (ii) Revision of eligibility criteria to lower PSA thresholds and serum testosterone levels; (iii) Emphasis on time-to-event endpoints including clinical, biochemical (e.g. PSA) or radiologic progression, recognizing that molecular targeted agents may delay progression without influencing initial response. (iv) Independent reporting of biochemical, radiographic, and clinical outcomes, avoiding grouped categorizations of complete or partial response, or stable disease. (v) Treating for a minimum of 12 weeks before assessing disease status, as the onset of PSA declines are often delayed, verifying that an agent does not influence release of PSA from cells. (vi) RECIST criteria are appropriate for changes in measurable disease, separating nodal and visceral sites. (vii) Changes in bone scan should be reported as “new lesions” or “no new lesions”, confirming findings of progression on a second scan. (viii) Pain and analgesic intake should be assessed using validated scales. (ix) Due to inherent variability, randomization to experimental and control groups is preferred, and innovative designs, e.g. expanding selected arms of randomized phase 2 trials to phase 3. Conclusions: PCCTWG recommends increasing emphasis on time to event endpoints as decision aids in proceeding from phase 2 to phase 3 trials. The recommendations will evolve as data are generated from phase 3 studies on the ability of intermediate endpoints to predict for clinical benefit. Support: MSKCC SPORE (CA 92629), Prostate Cancer Foundation. No significant financial relationships to disclose.
Phase I trial of bortezomib in adults with recurrent malignant glioma
Authors: S. Phuphanich, J. Supko, K. A. Carson, S. A. Grossman, L. B. Nabors, T. Mikkelsen, G. Lesser, M. Rosenfeld, S. Desideri, J. Olson
Journal: Journal of Clinical Oncology (2006)

1567 Background: Bortezomib is a selective inhibitor of the proteasome that has been approved for the treatment of multiple myeloma and has also shown promising evidence of clinical activity against solid tumors. This study was undertaken to determine the maximum tolerated dose (MTD), toxicity profile, and biologic activity of bortezomib for the treatment of recurrent malignant glioma (MG). Methods: Eligible patients (pts) had supratentorial progressive MG upon radiotherapy and ≤ 1 prior regimen of chemotherapy. Dose escalation was conducted separately for pts taking enzyme inducing antiseizure drugs (EIASD+) and for those not (EIASD-). Bortezomib was given by bolus iv injection on weeks 1 and 2 of each 3 week cycle of therapy. The starting dose in both groups was 0.9 mg/m 2 . Cohorts of at least 3 patients were evaluated at each dose level. 20S proteasome activity was determined in whole blood lysates before and at 1 and 24 h after the first dose. Results: Fifty-nine evaluable pts (41 male/18 female) with a median age of 51 years and median KPS of 90% have been enrolled. All but 2 pts had received 1 prior chemotherapy regimen. In the EIASD- group, the weekly dose was escalated from 0.9 to 1.9 mg/m 2 through 3 intermediate dose levels, with 1.7 mg/m 2 established as the MTD. DLT experienced by 2 of 6 pts in the 1.90 mg/m 2 dose level were grade 3 thrombocytopenia and grade 3 fatigue plus neurosensory toxicities. In the EIASD+ group, the dose has been escalated to 2.3 mg/m 2 without the occurrence of any DLT. Ten additional EIASD- pts were treated at 1.7 mg/m 2 , with the most common adverse events being thrombocytopenia and peripheral neuropathy. The extent of proteasome inhibition in whole blood increased in a dose-dependent manner in both treatment groups. Mean proteasome inhibition in EIASD+ pts 1 h after receiving 2.1 mg/m 2 of bortezomib (77 ± 12%) was similar to the 1.7 mg/m 2 dose in EIASD- pts (79 ± 6%). Conclusions: The MTD for the weekly x 2 schedule of bortezomib in EIASD- patients, 1.7 mg/m 2 , is higher than the approved dose of 1.3 mg/m 2 for the treatment of multiple myeloma. The enhanced tolerability of the drug when given together with EIASDs, for which the MTD is at least 2.1 mg/m 2 , is consistent with the diminished inhibition of 20S proteasome activity in these pts. No significant financial relationships to disclose.
Abstract 18099: Renal Sympathetic Denervation Increases Renal Artery Blood Flow: a Serial MRI Study in Resistant Hypertension
Authors: Sinny Delacroix, Ramesh G Chokka, Shweta Sahay, Adam J Nelson, Joanne Nimmo, Dennis T Wong, Adil Rajwani, Angelo Carbone, Elizabeth O Lau, Cary Hata, Peter Chen, Karen S Teo, Stephen G Worthley
Journal: Circulation (2014)

Background: Pre-clinical studies to date have demonstrated potential improvements in renal blood flow after renal sympathetic denervation, however such effects are yet to be confirmed in patients with resistant hypertension. We assessed the effects of renal sympathetic denervation in these patients on renal artery blood flow and diameter at multiple time points. Methods and results: Patients (n = 15) with systolic blood pressures ≤ 160mmHg despite taking ≥ 3 antihypertensive medications concurrently at maximum tolerated dose were recruited into this single centre, prospective, non-blinded study. MRI indices included renal blood flow and renal artery diameters at baseline, 1 month and 6 months. In addition to significant decreases in blood pressures (p &lt; 0.05) renal blood flow (total volume per cardiac cycle) increased 20% from (6.9 ± 2 mls) at baseline to (8.7 ± 2 mls; p=0.001) at one month and (8.0 ± 2mls; p=0.01) six months post procedure. There was a significant decrease in renal artery diameters from (6.8 ± 2 mm) at baseline to (6.2 ± 1 mm; p&lt;0.03) at 1 month post procedure and this decrease was associated with increases of maximum velocity of blood flow from (73 ± 19 cm/sec) at baseline to (78 ± 19 cm/sec) at one month post procedure and notably, both parameters revert to 6.9 ± 2 mm and 72 ± 18 cm/sec respectively. Thus, this study is the first to provide evidence of an early reduction in renal artery diameters (potentially due to oedema and inflammation) post intervention that has resolved by 6 months. Conclusion: Renal sympathetic denervation improves renal physiology as evidenced by significant improvements in renal blood flow. Additionally, this study for the first time identifies a transient decrease in renal artery diameters immediately after procedure and further demonstrates that these changes revert to baseline values six months post procedure.