tbuckley/cabot-search huggingface dataset:
Clinical relevance of germ cell cancer cells detected by real time PCR in apheresis products of poor risk patients undergoing high dose chemotherapy.
Authors: A. Burchert, L. Sytik, A. Lorch, J. T. Hartmann, C. Bokemeyer, O. Rick, J. Beyer, T. D. Kim, A. Neubauer
Journal: Journal of Clinical Oncology (2010)

4579 Background: The clinical relevance of germ cell tumor (GCT)-specific mRNA in peripheral blood stem cell (PBSC) harvests of germ-cell cancer patients undergoing high dose chemotherapy (HDCT) is controversial, possibly caused by inappropriate PCR conditions with inadequate sensitivity and specificity and small numbers of patients analyzed. We re-evaluated this issue in a large number of PBSC-products using a novel, GCT-specific quantitative PCR assay. Methods: PBSC-harvests of 140 patients treated with HDCT for relapsed or platinum-refractory GCT were tested for the presence contaminating tumor cells using a highly tumor cell-specific PCR protocol, which amplified the un-conserved 5’-untranslated region (5’UTR) of the germ cell tumor-specific alkaline phosphatase (gcap) gene, but not alkaline phosphatase mRNA, the latter being also present in the peripheral blood of healthy donors. In order to further avoid false positive results by amplification of pseudogenes, all mRNA's were subjected to repeated DNAse digestion before entering cDNA synthesis. Results: The novel 5’UTR gcap specific PCR enabled the quantitative detection of gcap mRNA with an unprecedented specificity and good sensitivity of 10^-5. A total of 140 PBSC apheresis products were screened, with sufficient mRNA and clinical data available from 113 patients. The median time to progression (TTP) was significantly shorter in patients with gcap-positive (n=66) as compared to gcap-negative PBSC products (n=44) (7.0 months versus not reached, p=0.01). With a median follow up of 8 years, the median overall survival was shorter in patients with gcap-positive as compared to gcap-negative PBSC products (20 month vs. not reached). This difference did not reach statistical significance (p=0.08). Conventional qualitative gcap-PCR failed to separate cohorts with different prognosis, underscoring the importance of a validated quantitative PCR assay to address the clinical impact of PBSC tumor cell contamination in GCT. Conclusions: A quantitative and gcap-specific 5’UTR PCR assay detecting gcap-mRNA in PBSC-harvests is a strong adverse prognostic factor in GCT patients undergoing HDCT. No significant financial relationships to disclose.
Tumor SPARC microenvironment signature (SMS) and plasma levels in a phase II trial of unresectable stage IV melanoma treated with <i>nab</i>-paclitaxel and carboplatin: A translational study of NCCTG trial N057E.
Authors: S. Markovic, V. Suman, V. N. Trieu, X. Liu, W. Yeh, L. Hwang, T. Treece, K. Motamed, P. Pramanik, N. Desai
Journal: Journal of Clinical Oncology (2010)

8578 Background: Tumor overexpression of the albumin-binding protein SPARC (secreted protein acidic and rich in cysteine) is associated with poor prognosis in multiple cancers. SPARC in the tumor microenvironment may be associated with tumor cells and stromal components. While previous studies examined SPARC only in tumor cells and/or fibroblasts, it remains unclear which tumor SPARC components may be associated with poor prognosis in different tumors. Recently we have found that plasma SPARC may contribute to poor outcomes in tumor models. Herein, we examined all tumor microenvironment components as well as plasma SPARC levels to develop a SPARC signature that may be correlated to outcomes. Methods: 76 chemo naïve and pretreated patients (pts) with unresectable stage IV melanoma were treated with nab-paclitaxel (nab-P, 100 mg/m2) and carboplatin (C, AUC 2) on d 1, 8, and 15 of a 28 day cycle until disease progression. SPARC in tumor biopsies was measured using a validated SPARC IHC. IHC data were analyzed using array analysis programs. SPARC plasma level in pts (baseline and posttreatment [Tx]) and normal controls were quantitated using a validated SPARC ELISA (blinded to patient outcome). Results: Tumor SPARC IHC data was available for 40 pts. A unique SPARC signature was developed for melanoma pts to distinguish early progressers (LR, n = 9) from later progressers (HR, n = 31). Median PFS increased from 3.8 to 6.7 months (logrank, p = 0.02) and median OS increased from 9.6 to 18.0 months (p = 0.07) for the HR vs. LR groups, respectively. Plasma SPARC levels were higher in melanoma pts than normal controls (median 259 ng/ml [95% CI = 273-327], n = 321 from 76 pts; vs. median 153 ng/mL [95% CI = 99-207], n = 50 from 50 pts; t-test, p < 0.0001). Conclusions: The SPARC microenvironment signatures (SMS) was designed to discriminate between low-risk and high-risk groups with respect to PFS/OS. These data suggest that SPARC in the tumor microenvironment may play an important role in the outcome of melanoma pts. Plasma SPARC levels in melanoma pts were higher than normal controls. Correlation of plasma SPARC with outcomes will be presented at ASCO. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abraxis BioScience Abraxis BioScience Abraxis BioScience Abraxis BioScience
IL-4 impairs wound healing potential in the skin by repressing fibronectin expression
Authors: Ana P.M. Serezani, Gunseli Bozdogan, Sarita Sehra, Daniel Walsh, Purna Krishnamurthy, Elizabeth A. Sierra Potchanant, Grzegorz Nalepa, Shreevrat Goenka, Matthew J. Turner, Dan F. Spandau, Mark H. Kaplan
Journal: Journal of Allergy and Clinical Immunology (2016)
A meta-analysis of weekly cisplatin versus three weekly cisplatin chemotherapy plus current radiotherapy for advanced head and neck cancer.
Authors: Yue Zhang, Jian Guan, Qinyang Li, Nanjie Xiao, Lu Li, Min Chen, Mi Yang, Yongmei Dai, Chi Zhang, Longhua Chen
Journal: Journal of Clinical Oncology (2015)

6035 Background: Cisplatin based chemoradiotherapy (CRT) is the standard treatment for advanced head and neck cancer (HNC), currently the recommended doses are 30-40 mg/m2 every week or 80-100mg/m2 every three weeks. However, there has no meta-analysis to evaluate the adverse effects and survival events of the two schedules for HNC patients Methods: We conducted a systematic review and meta-analysis by searching PubMed, MEDLINE, ScineceDirect, Cochrane Library and China National Knowledge Infrastructure (CNKI) databases (1982-2015). Study endpoints included overall survival (OS), locoregional recurrence-free survival (LRFS), and grade ≥ 3 adverse events. Hazard ratios with 95% confidence intervals (95%CIs) were calculated for OS and LRFS, and risk ratios were for adverse events. Kaplan-Meier curves were read by Engauge-Digitizer, and RevMan 5.2 software was used to perform this meta-analysis. Results: 779 patients of 10 studies were eligible. There was no significant difference on OS (2-year: HR 1.05, 95%CI 0.61-1.81; 3-year: HR 1.12, 95%CI 0.68-1.85; 5-year: HR 1.79, 95%C 0.97-3.31) and LRFS (1-year: HR 1.26, 95%CI 0.46-3.46; 2-year: HR 1.14, 95%CI 0.51-2.56) between the patients treated with weekly and three weekly cisplatin CRT. Risk ratios of neutropenia, dermatitis and anemia were similar in the two groups. There was a trend that patients treated with weekly cisplatin had less gastrointestinal reactions than those of three weekly (RR = 0.59, p = 0.06). In subgroup analysis, patients in weekly group had more grade ≥ 3 mucositis when the primary disease located in oral cavity, oropharynx, hypopharynx or larynx (RR = 1.72, p = 0.01). In addition, the occurrence of therapy related delay or interrupt was obviously higher in weekly cisplatin compared to three weekly (RR = 2.37, P = 0.01). Conclusions: Three weekly cisplatin CRT didn’t differ with weekly in OS and LRFS. Weekly cisplatin had higher risk in dermatitis, therapy delay and interrupt, but lower in gastrointestinal reactions. In subgroup analysis, threeweekly cisplatin had less grade ≥ 3 mucositis in non-nasopharynx of HNC patients, it might be more easily accepted by patients in terms of comfort or financial burden.
Endoscopic Duodenal Mucosal Resurfacing for the Treatment of Type 2 Diabetes: 6-Month Interim Analysis From the First-in-Human Proof-of-Concept Study
Authors: Harith Rajagopalan, Alan D. Cherrington, Christopher C. Thompson, Lee M. Kaplan, Francesco Rubino, Geltrude Mingrone, Pablo Becerra, Patricia Rodriguez, Paulina Vignolo, Jay Caplan, Leonardo Rodriguez, Manoel P. Galvao Neto
Journal: Diabetes Care (2016)

OBJECTIVE To assess procedural safety and glycemic indices at 6 months in a first-in-human study of duodenal mucosal resurfacing (DMR), a novel, minimally invasive, upper endoscopic procedure involving hydrothermal ablation of the duodenal mucosa, in patients with type 2 diabetes and HbA1c ≥7.5% (58 mmol/mol) on one or more oral antidiabetic agents. RESEARCH DESIGN AND METHODS Using novel balloon catheters, DMR was conducted on varying lengths of duodenum in anesthetized patients at a single medical center. RESULTS A total of 39 patients with type 2 diabetes (screening HbA1c 9.5% [80 mmol/mol]; BMI 31 kg/m2) were treated and included in the interim efficacy analysis: 28 had a long duodenal segment ablated (LS; ∼9.3 cm treated) and 11 had a short segment ablated (SS; ∼3.4 cm treated). Overall, DMR was well tolerated with minimal gastrointestinal symptoms postprocedure. Three patients experienced duodenal stenosis treated successfully by balloon dilation. HbA1c was reduced by 1.2% at 6 months in the full cohort (P &amp;lt; 0.001). More potent glycemic effects were observed among the LS cohort, who experienced a 2.5% reduction in mean HbA1c at 3 months postprocedure vs. 1.2% in the SS group (P &amp;lt; 0.05) and a 1.4% reduction at 6 months vs. 0.7% in the SS group (P = 0.3). This occurred despite net medication reductions in the LS cohort between 0 and 6 months. Among LS patients with a screening HbA1c of 7.5–10% (58–86 mmol/mol) and on stable antidiabetic medications postprocedure, HbA1c was reduced by 1.8% at 6 months (P &amp;lt; 0.01). CONCLUSIONS Single-procedure DMR elicits a clinically significant improvement in hyperglycemia in patients with type 2 diabetes in the short-term, with acceptable safety and tolerability. Long-term safety, efficacy, and durability and possible mechanisms of action require further investigation.
OP09 The development and testing of the University College London liver support device (UCL-ARSeNEL): improvement of survival in paracetamol-induced acute liver failure pigs
Authors: K Thiel, A Proven, N Davies, P Leckie, R Frieg, M Storr, A Koenigsrainer, M Schenk
Journal: Gut (2010)

Introduction  An effective liver support device to remove metabolic toxins is an unmet clinical need. We have demonstrated that in liver failure, albumin function is irreversibly damaged, preventing detoxification processes, and that bacterial endotoxins induce neutrophil dysfunction causing indiscriminate damage and immune failure. Previous generations of artificial devices were designed to remove toxins from patients’ plasma, but did not address albumin damage and/or inflammation. An albumin replacement system with a novel endotoxin ligation (ARSeNEL) component was developed to selectively filter plasma to adsorb endotoxin and replace damaged albumin.  Method  The device consists of three components; plasmapheresis, endotoxin and high cut-off (100 kDa) cartridges; with fresh frozen plasma replacing ultrafiltered plasma. We tested the device in a model of acetominophen-induced acute liver failure (ALF). Sixteen female landrace pigs (3 sham, 8 ALF, 5 ALF+UCL-ARSeNEL) were studied. ALF was induced via intra-gastric acetaminophen administration, confirmed by deranged clotting function (ca. 20hrs to ALF). Animals were treated with UCL-ARSeNEL or haemofiltration control within 2 h of ALF confirmation. Endpoints were: survival; ICP; standard biochemistry; cytokines; albumin damage; and plasma endotoxin levels.  Results  Survival post ALF was significantly increased using UCL-ARSeNEL (ALF 15.8±2.4 h vs UCL-ARSeNEL 23.8±1.9 h; p=0.02). No haematological or biocompatibility issues were observed. Endotoxin reduced by a quarter (1.99±0.18 Eu/ml vs 1.42±0.21 Eu/ml) in the device group at 16hrs. The changes in ICP index (1.7±0.07 vs 1.4±1.58), INR (16.6±6.6 vs 6.8±0.5), ischaemia-modified albumin ratio (0.45±0.166 vs 0.35±0.108), ammonia (177±131 vs 153±84 μM) and mean arterial pressure (71±7.6 vs 87±6.0 mm Hg) showed marked improvement in the UCL-ARSeNEL group.  Conclusion  The results of the study confirm that UCL-ARSeNEL is safe and effectively improves survival in ALF pigs by addressing the key pathophysiological derangements such as albumin dysfunction and endotoxinaemia; which impact upon end-organ function. The results justify a clinical trial, which is being planned.
Neoadjuvant anti-PD1, nivolumab, in early stage resectable non-small-cell lung cancer.
Authors: Patrick M. Forde, Kellie Smith, Jamie E. Chaft, Matthew David Hellmann, Taha Merghoub, Jedd D. Wolchok, Stephen C. Yang, Richard J. Battafarano, Edward Gabrielson, Christos Georgiades, France Verde, Gary L. Rosner, Valsamo Anagnostou, Victor E. Velculescu, Suzanne Louise Topalian, Drew M. Pardoll, Julie R. Brahmer
Journal: Journal of Clinical Oncology (2016)

e20005 Background: Nivolumab is an anti-PD1 immune checkpoint blocker which has demonstrated durable responses and improved survival vs. second-line chemotherapy in metastatic non-small-cell lung cancer (NSCLC). This is the first report of anti-PD1/PD-L1 administration in early stage I-IIIA NSCLC as neoadjuvant therapy prior to surgical resection. Methods: Patients (pts) with resectable stage I-IIIA NSCLC underwent pretreatment tumor biopsy and then received 2 doses of nivolumab administered at 4 and 2 weeks prior to surgical resection. Postoperatively, standard adjuvant therapy was administered. The primary endpoint is safety and feasibility of anti-PD1 administration prior to surgery; exploratory endpoints include pathologic response and evaluation of changes in tumor and blood immune markers assessed by flow cytometry, immunohistochemistry and sequencing of tumor and T cell receptors in blood, tumor and draining lymph nodes. 16 pts in total will be enrolled. Results: Six pts have been enrolled to date. Results from the first three pts undergoing surgical resection after neoadjuvant nivolumab demonstrate no treatment-related toxicities or delays to surgery. Two of three patients had major radiologic and pathologic responses at the time of surgery including one pathologic complete response in an 8 cm squamous tumor. Resection specimens were characterized by brisk T cell infiltration, greater than seen in pre-treatment biopsies. Expansion of specific T cell clones was observed in both tumor and peripheral blood after nivolumab. Detailed genomic, immunologic and immunohistochemical analyses of pre- and post-treatment tissues are ongoing. Conclusions: Two of three pts with NSCLC receiving neoadjuvant nivolumab have had a major pathologic response to treatment at time of surgery. To date, preoperative nivolumab has been feasible with no toxicity-related delays to surgery or postoperative recovery. Intensive correlative analyses of pre- and post-treatment tissues are ongoing and will be reported. Clinical trial information: NCT02259621.
Systemic inflammation in decompensated cirrhosis: Characterization and role in acute‐on‐chronic liver failure
Authors: Joan Clària, Rudolf E. Stauber, Minneke J. Coenraad, Richard Moreau, Rajiv Jalan, Marco Pavesi, Àlex Amorós, Esther Titos, José Alcaraz‐Quiles, Karl Oettl, Manuel Morales‐Ruiz, Paolo Angeli, Marco Domenicali, Carlo Alessandria, Alexander Gerbes, Julia Wendon, Frederik Nevens, Jonel Trebicka, Wim Laleman, Faouzi Saliba, Tania M. Welzel, Agustin Albillos, Thierry Gustot, Daniel Benten, François Durand, Pere Ginès, Mauro Bernardi, Vicente Arroyo
Journal: Hepatology (2016)

Acute-on-chronic liver failure (ACLF) in cirrhosis is characterized by acute decompensation (AD), organ failure(s), and high short-term mortality. Recently, we have proposed (systemic inflammation [SI] hypothesis) that ACLF is the expression of an acute exacerbation of the SI already present in decompensated cirrhosis. This study was aimed at testing this hypothesis and included 522 patients with decompensated cirrhosis (237 with ACLF) and 40 healthy subjects. SI was assessed by measuring 29 cytokines and the redox state of circulating albumin (HNA2), a marker of systemic oxidative stress. Systemic circulatory dysfunction (SCD) was estimated by plasma renin (PRC) and copeptin (PCC) concentrations. Measurements were performed at enrollment (baseline) in all patients and sequentially during hospitalization in 255. The main findings of this study were: (1) Patients with AD without ACLF showed very high baseline levels of inflammatory cytokines, HNA2, PRC, and PCC. Patients with ACLF showed significantly higher levels of these markers than those without ACLF; (2) different cytokine profiles were identified according to the type of ACLF precipitating event (active alcoholism/acute alcoholic hepatitis, bacterial infection, and others); (3) severity of SI and frequency and severity of ACLF at enrollment were strongly associated. The course of SI and the course of ACLF (improvement, no change, or worsening) during hospitalization and short-term mortality were also strongly associated; and (4) the strength of association of ACLF with SI was higher than with SCD.These data support SI as the primary driver of ACLF in cirrhosis. (Hepatology 2016;64:1249-1264).
Incorporating Marrow Plasma Cell Infiltration at Diagnosis and Cytogenetic Features into Prognostic Scoring at Point of Autologous Stem Cell Transplantation for Multiple Myeloma
Authors: Matthias Klammer, Chrissy Giles, Alistair G Reid, Fiona M Ross, Richard M. Szydlo, Jiri Pavlu, Jane F. Apperley, Amin Rahemtulla
Journal: Blood (2008)
Bortezomib (BOR)-Thalidomide-Dexamethasone (VTD) and High-Dose Melphalan (HDM) As First Line Treatment for Multiple Myeloma (MM) Is Associated with a Lower Rate of Second Primary Malignancies (SPMs) Compared to TD Plus HDM
Authors: Annamaria Brioli, Annalisa Pezzi, Daniele Derudas, Maria Concetta Petti, Beatrice Anna Zannetti, Felicetto Ferrara, Serena Rocchi, Francesco Nobile, Anna Baraldi, Pellegrino Musto, Francesco Lanza, Katia Mancuso, Letizia Canepa, Lucio Catalano, Antonio Lazzaro, Graziella Pinotti, Mario Boccadoro, Michele Cavo
Journal: Blood (2014)
Highlights of the Year in JACC 2012
Authors: Anthony N. DeMaria, Jeroen J. Bax, Gregory K. Feld, Barry H. Greenberg, Jennifer L. Hall, Mark A. Hlatky, Wilbur Y.W. Lew, João A.C. Lima, Ehtisham Mahmud, Alan S. Maisel, Sanjiv M. Narayan, Steven E. Nissen, David J. Sahn, Sotirios Tsimikas
Journal: Journal of the American College of Cardiology (2013)
Lesinurad Combined With Allopurinol: A Randomized, Double‐Blind, Placebo‐Controlled Study in Gout Patients With an Inadequate Response to Standard‐of‐Care Allopurinol (a US‐Based Study)
Authors: Kenneth G. Saag, David Fitz‐Patrick, Jeff Kopicko, Maple Fung, Nihar Bhakta, Scott Adler, Chris Storgard, Scott Baumgartner, Michael A. Becker
Journal: Arthritis & Rheumatology (2016)

Objective Lesinurad is a selective uric acid reabsorption inhibitor used for the treatment of gout in combination with a xanthine oxidase inhibitor. The Combining Lesinurad with Allopurinol Standard of Care in Inadequate Responders (CLEAR 1) study, a 12‐month, multicenter, randomized, double‐blind, placebo‐controlled phase III trial, was conducted to investigate daily lesinurad (200 mg or 400 mg orally) added to allopurinol versus placebo plus allopurinol in patients with serum urate (UA) levels above a target of &lt;6.0 mg/dl. Methods Patients receiving ≥300 mg of allopurinol (≥200 mg in those with moderate renal impairment) who had serum UA levels ≥6.5 mg/dl at screening and ≥2 gout flares during the previous year were studied. The primary end point was the proportion of patients achieving a serum UA level of &lt;6.0 mg/dl at month 6. Key secondary end points were the mean gout flare rate requiring treatment (months 7–12) and the proportions of patients with complete resolution of ≥1 target tophus (month 12). Safety assessments included adverse events and laboratory data. Results The study patients (n = 603) were predominantly male and had a mean ± SD age of 51.9 ± 11.3 years, a gout duration of 11.8 ± 9.4 years, a baseline serum UA level of 6.94 ± 1.27 mg/dl, and were receiving an allopurinol dosage of 306.6 ± 59.58 mg/day. Lesinurad at doses of 200 mg or 400 mg added to allopurinol therapy significantly increased the proportions of patients who achieved serum UA target levels by month 6 as compared with those receiving allopurinol alone (54.2%, 59.2%, and 27.9%, respectively, P &lt; 0.0001). Lesinurad was not significantly superior to allopurinol alone in terms of the secondary end points: rates of gout flares and complete resolution of tophi. Lesinurad was generally well‐tolerated; the safety profile of the 200‐mg dose was comparable to that of allopurinol alone, except for higher incidences of predominantly reversible elevations of serum creatinine levels. Conclusion Lesinurad added to allopurinol provided benefit as compared with allopurinol alone in reducing serum UA levels and represents a new treatment option for patients needing additional urate‐lowering therapy.
RBC Alloimmunization Burden Is High in Regularly RBC-Transfused Myelodysplastic Syndrome (MDS) Patients: A Report from South Australian-MDS Registry
Authors: Deepak Singhal, Sophia Hague, David Roxby, L Amilia Wee, Oi-Lin Lee, Romi Sinha, Rakchha Chhetri, James X Gray, Pratyush Giri, Kathryn Robinson, Shriram Nath, Nicholas Wickham, Chi-hung Hui, David T Yeung, David M Ross, Ian D Lewis, Peter G Bardy, L Bik To, Devendra K Hiwase
Journal: Blood (2015)