tbuckley/cabot-search huggingface dataset:
Anticollagen type II antibodies are associated with an acute onset rheumatoid arthritis phenotype and prognosticate lower degree of inflammation during 5 years follow-up
Authors: Vivek Anand Manivel, Mohammed Mullazehi, Leonid Padyukov, Helga Westerlind, Lars Klareskog, Lars Alfredsson, Saedis Saevarsdottir, Johan Rönnelid
Journal: Annals of the Rheumatic Diseases (2017)

Antifibrillar collagen type II (anti-CII) antibody-positive patients with rheumatoid arthritis (RA) have early but not late signs of increased inflammation and joint erosions. We wanted to replicate this in a large RA cohort, and to relate to human leukocyte antigen (HLA)-DRB1* alleles.Anti-CII and anti-cyclic citrullinated peptide (CCP)2 were measured at baseline in 773 patients with RA from the Swedish Epidemiological Investigation in Rheumatoid Arthritis (EIRA) study with clinical follow-up data from the Swedish Rheumatology Quality Register (SRQ) registry, and 1476 with HLA-DRB1* information. Comparisons were done concerning C reactive protein (CRP), erythrocyte sedimentation rate (ESR), tender joint count (TJC), swollen joint count (SJC), Disease Activity Score encompassing 28 joints based on ESR (DAS28), DAS28CRP, pain-Visual Analogue Scale (VAS), global-VAS and Health Assessment Questionnaire Score (HAQ) at eight occasions during 5 years, and association with HLA-DRB1* alleles.Anti-CII associated with elevated CRP, ESR, SJC, DAS28 and DAS28CRP at diagnosis and up to 6 months, whereas anti-CCP2 associated with SJC and DAS28 from 6 months to 5 years, but not earlier. The anti-CII-associated phenotype was strong, and predominated in anti-CII/anti-CCP2 double-positive patients. Anti-CII was associated with improvements in CRP, ESR, SJC, TJC and DAS28, whereas anti-CCP2 was associated with deteriorations in SJC and DAS28 over time. Anti-CII-positive patients achieved European League Against Rheumatism good or moderate response more often than negative patients. Anti-CII was positively associated with HLA-DRB1*01 and HLA-DRB1*03, with significant interaction, and double-positive individuals had >14 times higher mean anti-CII levels than HLA double negatives. Whereas smoking was associated with elevated anti-CCP2 levels, smokers had lower anti-CII levels.Anti-CII seropositive RA represents a distinct phenotype, in many respects representing the converse to the clinical, genetic and smoking associations described for anticitrullinated protein peptide autoantibodies. Although not diagnostically useful, early anti-CII determinations predict favourable inflammatory outcome in RA.
Regulatory mechanisms, prophylaxis and treatment of vascular leakage following severe trauma and shock
Authors: Chen-Yang Duan, Jie Zhang, Hui-Ling Wu, Tao Li, Liang-Ming Liu
Journal: Military Medical Research (2017)

Vascular leakage, or increased vascular permeability, is a common but important pathological process for various critical diseases, including severe trauma, shock, sepsis, and multiple organ dysfunction syndrome (MODS), and has become one of the most important causes of death for intensive care units (ICU) patients. Currently, although there has been some progress in knowledge of the pathogenesis of these vascular disorders, the detailed mechanisms remain unclear, and effective prophylaxis and treatment are still lacking. In this study, we aimed to provide a review of the literature regarding the regulatory mechanisms and prophylaxis as well as the treatment of vascular leakage in critical diseases such as severe trauma and shock, which could be beneficial for the overall clinical treatment of vascular leakage disorders.
Circulating myeloid-derived suppressor cells in pediatric solid tumor patients.
Authors: John M. Goldberg, Abdel-Aziz Zidan, Rabia Siddiqi, Myriam Zayas, Camille D. Brown, Lourdes Forster, David A. Ludwig, Alberto J. Montero, C Marcela Diaz-Montero
Journal: Journal of Clinical Oncology (2012)

9565 Background: Cure rates have reached a plateau for many pediatric solid tumors. Identifying new therapeutic targets, biomarkers of response and prognostic indicators should improve clinical outcomes. Accumulation of myeloid derived suppressor cells (MDSCs) is an important mechanism of tumor mediated immune evasion. Increased levels of MDSCs in adult cancer patients correlate with a worse prognosis, and decrease in levels with treatment is associated with benefit. Little is known about MDSCs in childhood, or in children with cancer. This pilot measured levels of MDSCs in pediatric patients with cancer and healthy children. Methods: We enrolled subjects using an Institutional Review Board approved protocol after obtaining informed consent. Blood was obtained from 14 children with newly diagnosed or recurrent solid tumors at start of therapy. In 10 of these patients, levels were also drawn after therapy. Blood was obtained once from 6 healthy children in a primary care office. Samples were obtained concurrently with complete blood counts. MDSCs were measured on fresh whole blood and were defined as Lin-1+/HLADR-/CD 33+/CD11b+/ by flow. Total MDSC numbers were then calculated. Results: The mean total number of MDSCs was 596 cells/ul at diagnosis for the 14 children with cancer and 170 cells/ul for the 6 healthy children (t(18) = 3.02, p = .0073). For the 10 children with cancer who had repeat values measured after treatment, MDSCs decreased in 4 and increased in 6. The mean initial MDSC count for these children was 494 cells/ul, and the mean post treatment count was 1716 cells/ul (t(9) = 1.81, p = .1036). Larger change scores tended to be associated with children treated with alkylator therapy followed by G-CSF. The results for percent MDSC in white cells mirrored those of total number. Conclusions: Circulating MDSCs were higher in pediatric cancer patients than healthy controls. Cancer treatment did not reliably reduce MDSC levels. After some treatments, the levels increased, potentially increasing immune tolerance. Further research is needed to determine if circulating MDSCs are a reliable predictive or prognostic marker in pediatric cancer, and whether they represent a potential target for therapeutic intervention.
Computer-aided lung cancer screening with CT: A clinically usable nodule detection and assessment system.
Authors: Pechin Lo, Matthew S. Brown, Jonathan Goldin, Eran Barnoy, Hyun J. Kim, Michael F. McNitt-Gray, Denise R. Aberle
Journal: Journal of Clinical Oncology (2013)

7562 Background: The National Lung Screening Trial (NLST) recently demonstrated that lung cancer screening with low-dose CT reduces mortality. Current protocols use 4–8 mm nodules as positive screens. While there are some computer-aided nodule detection (CAD) systems currently available, they are rarely used in clinical practice because they generate too many false positives and lack reliable measurement tools. The purpose of this work is to develop a new CAD system to overcome these limitations and evaluate it against an expert panel of radiologists. Methods: The CAD system developed for lung nodule detection and measurement incorporates computer vision techniques including intensity thresholding, Euclidean Distance Transformation, and watershed segmentation. Rules pertaining to volume and shape were applied to automatically discriminate between nodules and bronchovascular anatomy. CAD system performance was assessed using 108 consecutive cases from the publically available Lung Imaging Database Consortium (LIDC), in which four radiologists reviewed each case. CT slice thickness ranged from 0.6–3.0 mm. Nodules were included that were: (a) ≥ 4mm, and (b) marked by a majority of the LIDC readers, and (c) ≥ 4 x CT slice thickness (to ensure adequate spatial resolution). Results: 44 of 108 subjects had one or more nodules meeting criteria. Median CAD sensitivity per subject for these 44 cases is reported for all nodules ≥ 4mm and the subset of nodules ≥ 8mm. The false positive (FP) rate per subject is reported for all 108 cases. The overall concordance correlation coefficient (CCC) between the CAD volume of each nodule and the LIDC reference volume was measured. Conclusions: Based on clinical CT screening protocols, a CAD system has been developed with high nodule sensitivity and a much lower false positive rate than previously reported systems. Automated volume measurements show strong agreement with the reference standard, providing a comprehensive detection and assessment workflow for lung cancer screening. [Table: see text]
Outcomes of second allogeneic hematopoietic stem cell transplantation (SCT) for patients with acute lymphoblastic leukemia (ALL).
Authors: LM Poon, Roland Bassett, Gabriela Rondon, Laura L Worth, Laurence Cooper, Uday R. Popat, Yago Nieto, Marcos J.G. De Lima, Richard E. Champlin, Partow Kebriaei
Journal: Journal of Clinical Oncology (2012)

6540 Background: Disease relapse is the major cause of failure after allogeneic hematopoietic stem cell transplantation (SCT) for acute lymphoblastic leukemia (ALL). Treatment options for these patients (pts) are limited and only a second SCT provides a realistic chance for long term disease remission. Methods: We retrospectively analyzed the outcomes of 31 pts with ALL who relapsed following their first allogeneic SCT, and went on to receive a second allogeneic SCT. Univariate analysis was used to assess for risk factors which influenced treatment-related mortality (TRM), and progression free survival (PFS) following second SCT. Results: 31 pts were evaluable for response with 2 early deaths within 30 days of SCT. The median age of the pts was 26 years (range 7- 49), and the median duration between their first SCT (SCT1) to relapse was 9.5 months (range 2.2-32.6 months). 39% of pts were transplanted in active disease (n=12). The complete remission (CR) rate post SCT was 89%; 83% of pts transplanted with active disease attained CR. With a median follow-up of 3 years among survivors, PFS, and OS rates at 1 year were estimated at 23%. The TRM rate was 41% at 12 months. We did not identify any factors that impacted TRM through univariate analysis. We found a significant relationship between the time to progression following SCT 1 and PFS following SCT 2 (p=0.02, HR=0.93/month). Conclusions: In summary, a second transplant remains an effective method for achieving response in a highly refractory patient population. Pts with longer PFS following SCT1 have a better PFS following SCT2. While long-term survival is limited, a significant proportion of pts remain disease-free for up to one year following SCT2, providing a window of time to administer preventive interventions. Notably, our 4 long-term survivors, received novel therapies in the form of a single umbilical cord blood unit in addition to the PBSC to augment the immune response (n=2), a change in the stem cell source for the SCT from cord to mismatched adult unrelated (n=1), and post SCT maintenance therapy with 5-azacytidine (n=1), underscoring the need for a fundamental change with the methods for the second transplant to improve outcome.
Phase II tailored S-1 regimen study of first-line chemotherapy in elderly patients with advanced and recurrent non-small cell lung cancer.
Authors: Takayuki Shiroyama, Takashi Kijima, Kiyoshi Komuta, Suguru Yamamoto, Seigo Minami, Yoshitaka Ogata, Kouhei Okafuji, Fumio Imamura, Tomonori Hirashima, Isao Tachibana, Ichiro Kawase, Atsushi Kumanogoh
Journal: Journal of Clinical Oncology (2012)

e18141 Background: The aim of this study was to evaluate the efficacy and toxicity of a novel oral 5-fluorouracil (5-FU) formulation (S-1), administered according to a tailored dose regimen based on body surface area (BSA) and creatinine clearance (Ccr), in patients with advanced non-small-cell lung cancer who were 75 years or older. Pharmacokinetic analysis was also performed to evaluate the adequacy of the tailored S-1 dose. Methods: S-1 was administered orally for 28 days, followed by 14 days, in 23 patients who received a tailored dose of S-1, adjusted on the basis of individual creatinine clearance (Ccr) and body surface area (BSA). In 8 of the patients pharmacokinetic study were performed on the 5 times points on seventh day after S-1 administration. Results: Of the 23 patients enrolled in this study, 2 (8.7%) had a partial response and 14 (60.9%) had stable disease. The disease control rate was 69.6% (16/23) (95% confidence interval, 50.8-88.4%). Grade 3/4 hematologic and non-hematologic toxicities were minor. In the pharmacokinetic study group the maximum plasma concentration (Cmax) and the area under the plasma concentration curve (AUC) of 5-FU at all 5 times points after administration of the tailored S-1 dose regimen were similar to the values reported in a previous study describing cancer patients with normal renal function who received a standard dose of S-1 (80 mg/m 2 /day). Conclusions: Our results suggest that tailored S-1 monotherapy is safe and therapeutically useful as first-line treatment for elderly patients with advanced and recurrent non-small-cell lung cancer.
Evaluation of systemic inflammation-based prognostic scores in patients with advanced colorectal cancer receiving palliative pelvic radiotherapy (RT).
Authors: Ross Dolan, Nicholas James MacLeod, Stephen Thomas McSorley, Paul G. Horgan, Barry Laird, Donald C McMillan
Journal: Journal of Clinical Oncology (2017)

558 Background: The presence of a systemic inflammatory response (SIR) in patients with advanced cancer is an increasingly recognised prognostic domain and is commonly assessed by the Glasgow Prognostic Score (GPS) and the Neutrophil Lymphocyte Ratio (NLR). However, little work has been carried out to evaluate their role in the field of palliative RT. The aim of the present study was to compare the prognostic value of the GPS and NLR in patients with advanced colorectal cancer receiving palliative pelvic RT. Methods: From a database of all patients undergoing RT in the West of Scotland (2010-2015) patients receiving palliative pelvic RT for colorectal cancer were examined (n = 175). Patients were excluded if they died within 30 days of treatment (n = 15). Demographic data, time from treatment to death/last clinic visit, medical comorbidities, tumour and RT location/dose, CRP, albumin, and differential blood counts were all recorded. GPS, mGPS and NLR were calculated and Cox regression analysis conducted in SPSS. Results: Of the remaining 160 analysed 85 (53%) were male and the median age was 77 (Range: 34-98). The most common clinical indications for palliative radiotherapy were pain (n = 78), bleeding (n = 71) and obstruction/tenesmus (n = 29). Medical comorbidities varied with the most common being hypertension (n- = 75), IHD (n = 36) and diabetes (n = 19). At the time of analysis 130 (81%) of the patients were dead with median survival of 9 months (Range: 1-62 months). On univariate survival analysis Male sex (p = 0.021), GPS (p = 0.015), mGPS (p = 0.028) and NLR ≥ 5 (p = 0.045) but not age &gt; 75 (p = 0.059), Tumour Site (p = 0.637), Performance Status (p = 0.747), ASA (p = 0.525), Delivered Fractions of Radiotherapy (p = 0.062), Dose of RT (p = 0.486) and low Haemoglobin (p = 0.383) were significantly associated with poor survival. On multivariate analysis of the significant variable only male sex (HR: 1.59, 95%CI 1.07-2.36, p = 0.021) and the GPS (HR: 1.47, 95%CI 1.09-1.98, p = 0.011) remained independently associated with survival. Conclusions: In the palliative RT setting systemic inflammation based scores (GPS, mGPS and NLR) had prognostic value and the GPS had independent prognostic value.
Abstract 8274: Resveratrol Brings About Reverse Remodeling In The Heart With A Large Old Myocardial Infarction Through Autophagy Activating amp Kinase Pathway
Authors: Hiromitsu Kanamori, Genzou Takemura, Kazuko Goto, Rumi Maruyama, Akiko Tsujimoto, Atsushi Ogino, Toshiaki Takeyama, Tomonori Kawaguchi, Takatomo Watanabe, Kentaro Morishita, Takako Fujiwara, Hisayoshi Fujiwara, Mitsuru Seishima, Shinya Minatoguchi
Journal: Circulation (2011)

We previously reported that autophagy is activated during postmyocardial infarction and compensates for the lack of energy in cardiomyocytes by digesting and recycling own constituents. Resveratrol is a popular natural polyphenolic compound, abundantly contained in the skin of grapes and red wine, and is recently reported to have not only an anti-oxidant property but also autophagy-accelerating action. We here investigated the effect of resveratrol on established heart failure due to a large old myocardial infarction. Myocardial infarction was induced in mice by the left coronary artery ligation. Four weeks post-infarction, the surviving mice were assigned to four groups: control (saline, n=15); resveratrol (50 mg/kg/day, n=15); chroloquine (an autophagy inhibitor, 10 mg/kg/day, n=15); and combination (resveratrol, 50 mg/kg/day plus chroloquine, 10 mg/kg/day, n=15). The agents were administered for 2 weeks using osmotic mini pump. Resveratrol significantly attenuated and partially reversed left ventricular dilatation (reverse remodeling) and improved function: left ventricular end-diastolic diameter, 4.1±0.2 mm vs. 4.9±0.3 mm in controls; and ejection fraction, 46.9±3.3 % vs. 35.8±3.3 % in controls (p&lt;0.05), accompanying reduction of ventricular expression of atrial natriuretic peptide. In those hearts, autophagic findings were augmented as shown by upregulation of microtubule-associated protein-1 light chain 3-II (LC3-II) and by electron microscopic findings of autophagic vacuoles. The activation of AMP-activated protein kinase was enhanced in the hearts treated with resveratrol while the activation of mammalian target of rapamycin complex 1 (mTORC1) and p70S6 kinase (a direct down-stream target of mTORC1) was suppressed compared to vehicle. Chroloquine brought about an opposite result, including aggravation of cardiac dysfunction and remodeling progression, where autophagic activity was diminished. A combined treatment with resveratrol and chroloquine offset each effect on the postinfarction heart. Any treatment did not affect apoptosis in the infarcted heart. The present findings suggest that resveratrol is new pharmacological strategy -i.e., manipulation of autophagy, against postinfarction cardiac remodeling.
Molecular correlates of clinical benefit from antiangiogenic therapy for patients with lung adenocarcinoma: A hypothesis.
Authors: Frank Hilberg, Christian Haslinger, Pilar Garin Chesa, Guenther R. Adolf
Journal: Journal of Clinical Oncology (2014)

e22080 Background: Nintedanib, an oral triple-angiokinase inhibitor, in combination with docetaxel has demonstrated efficacy as a second-line treatment for NSCLC patients (pts) regardless of histology and significantly improved survival for adenocarcinoma pts. Survival benefit was most pronounced in pts with poor prognosis (PD within 9 m of initiation of first-line therapy; Reck et al. 2014). To develop a mechanistic hypothesis explaining these observations, gene expression and clinical outcome data derived from a large NSCLC database were analysed. Methods: Gene set enrichment analysis (GSEA) based on MSigDB v3.1 was applied to RMA normalised expression data generated by the Director´s Challenge Consortium (Shedden et al. 2008). Gene sets with an FDR q value < 0.05 were considered. Results: GSEA of lung adenocarcinomas from pts who died within 2 y (n = 104) and those who died more than 5 y after diagnosis (n=169) revealed significant differences in the expression of 135 out of 1454 gene sets. Most of the top-ranking sets enriched in tumors of pts with poor outcome consisted of genes relevant for DNA replication and mitosis. In a comparison of tumors of pts who died within 1 y (n = 48) and pts who died later than 5 y after diagnosis (n = 169), the top-ranking sets again consisted of genes relevant for cell proliferation and additionally of genes representing mitochondria. When GSEA was performed for a subset of pts who had received adjuvant chemotherapy, 18 gene sets were significantly enriched in tumors from pts who died within 1 y (n = 8) vs. those who lived more than 5 y (n = 32); most of these consisted of genes related to mitochondria. Conclusions: Expression of genes relevant for cell proliferation is high in lung adenocarcinomas from patients with rapid progression, indicating a large fraction of proliferating cells. High levels of O2 and nutrients are required to sustain proliferation. Consequently, these tumors require high levels of vascularization and contain many immature, growth factor-dependent blood vessels. By destruction of these vessels and inhibition of vascular sprouting, nintedanib combined with docetaxel provides greater benefit to lung adenocarcinoma patients with rapidly progressive disease.
Incidence and survival for young women with operable breast cancer: SEER 1992-2011.
Authors: Mary Chen Schroeder, Susan Slycord, Charles Lynch, Alexandra Thomas
Journal: Journal of Clinical Oncology (2015)

536 Background: Recent work has shown an increasing incidence of Stage IV breast cancer (bc) in young women (wm). We examined the incidence and survival of young wm with operable bc. Methods: Wm ages 20-39 diagnosed with stages 1-3 bc from 1992-2011 were identified from SEER data and categorized by hormone receptor (HR) status and grade (low = well/moderately differentiated, high = poor/undifferentiated). Those with missing information were excluded. Annual percent change (APC) in age-adjusted incidence rates for the SEER 13 registries were calculated. Kaplan Meier survival curves were estimated by HR and grade. Results: We identified 3,566 wm aged 20-29 and 34,508 wm 30-39. For wm 20-29, stages 1, 2, 3 comprised 25.2, 50.5, and 24.3% of the sample versus 30.6, 47.1, and 22.3% for wm 30-39 (all p < 0.001). HR status and grade also differed significantly by age. Wm 20-29 were more likely to have HR- disease (40.4 v 34.2%), less likely to have HR+ low grade disease (25.7 v 35.6%) and more likely to have HR+ high grade disease (33.9 v 30.2%) than wm 30-39 (all p < 0.001). APC in incidence along with 5- and 10-yr survival is reported in the table. In HR+ disease, regardless of grade, survival decreased more rapidly beyond 5 years from diagnosis for 20-29 than 30-39. This was not seen for HR- disease. Conclusions: Wm age 20-39 presented more frequently with Stage II bc. Wm 20-29, unlike wm 30-39, have not seen a decline in Stage III disease. Low and high grade HR+ disease in wm 20-29 also increased with the highest APC in incidence. 10-year survival for 20-39 year old wm with HR+ disease showed continued late deaths. This was most pronounced for wm 20-29. 20-29 yrs 30-39 yrs p APC in incidence Full cohort 0.9* 0.7* < 0.001 Stage 1 .2 -.3 < 0.001 Stage 2 1.5* 1.8* < 0.001 Stage 3 .4 -.1* < 0.001 HR- -.4 .6 < 0.001 HR+ low grade 6.6* 4.1* < 0.001 HR+ high grade 3.4* 2.3* < 0.001 Survival at 5(10) yrs ** Full cohort 0.82 (0.71) 0.86 (0.76) < 0.001 Stage 1 .94 (.87) .96 (.90) 0.020 Stage 2 .87 (.76) .88 (.79) 0.041 Stage 3 .59 (.42) .67 (.50) < 0.001 HR- .78 (.72) .79 (.72) 0.822 HR+ low grade .92 (.76) .94 (.84) < 0.001 HR+ high grade .79 (.62) .86 (.72) < 0.001 * APC significantly different from zero (p < 0.05); ** p-value compares 10-yr survival of the two age groups