tbuckley/cabot-search huggingface dataset:
Phase angle for prognostication of survival in patients with advanced cancer.
Authors: David Hui, Swati Bansal, Margarita Morgado, Rony Dev, Gary B. Chisholm, Eduardo Bruera
Journal: Journal of Clinical Oncology (2014)

9555 Background: Accurate survival prediction is essential for decision making in cancer therapies and care planning. Objective physiologic measures may improve the accuracy of prognostication. In this prospective study, we determined the association of phase angle, hand grip strength, and maximal inspiratory pressure with overall survival in patients with advanced cancer. Methods: We enrolled hospitalized patients with advanced cancer who were seen by palliative care for consultation. We assessed the phase angle, hand grip strength, maximal inspiratory pressure and known prognostic factors including Palliative Prognostic Score (PaP), Palliative Prognostic Index (PPI), serum albumin and body composition. We conducted univariate and multivariate survival analysis, and examined the correlation between phase angle and other prognostic variables. Results: 222 patients were enrolled: average age 55 (range 22-79), female 59%, gastrointestinal cancers 33%, mean Karnofsky performance status (KPS) 55%, and median overall survival 106 days (95% confidence interval [CI] 71-128 days). The median survival for patients with phase angle 2-2.9°, 3-3.9°, 4-4.9°, 5-5.9° and ≥6° was 35, 54, 112, 134 and 220 days, respectively (P=0.001). We found that PaP (P<0.001), PPI (P=0.003), KPS (P<0.001), fat free mass (P=0.02) and hypoalbuminemia (P<0.001) were significantly associated with survival, but not cancer diagnosis (P=0.10), hand grip strength (P=0.08) and maximal inspiratory pressure (P=0.08). In multivariate Cox regression analysis, phase angle, PaP, albumin, and fat free mass were independently significant (Table). Phase angle was only weakly (γ<0.4) associated with other prognostic variables. Conclusions: Phase angle was a novel predictor of poor survival, independent of established prognostic factors in the advanced cancer setting. This objective and noninvasive tool may be useful for bedside prognostication. Multivariate survival analysis. Variables Hazard ratio (95% CI) P value Phase angle (per degree increase) 0.86 (0.74-0.99) 0.04 Palliative Prognostic Score (per point increase) 1.07 (1.02-1.13) 0.008 Albumin (per g/dL increase) 0.67 (0.50-0.91) 0.009 Fat free mass (per kg increase) 0.98 (0.96-0.99) 0.02
Induced Apoptosis Investigation in Wild-type and FLT3-ITD Acute Myeloid Leukemia Cells by Nanochannel Electroporation and Single-cell qRT-PCR
Authors: Keliang Gao, Xiaomeng Huang, Chi-Ling Chiang, Xinmei Wang, Lingqian Chang, Pouyan Boukany, Guido Marcucci, Robert Lee, Ly James Lee
Journal: Molecular Therapy (2016)

Nanochannel electroporation (NEP) was applied to deliver precise dosages of myeloid cell leukemia-1 (Mcl-1)-specific siRNA and molecular beacons to two types of acute myeloid leukemia (AML) cells, FMS-like tyrosine kinase-3 wild-type (WT) and internal tandem duplications (ITD) type at the single-cell level. NEP, together with single-cell quantitative reverse transcription PCR, led to an observation showing nearly 20-folds more Mcl-1 siRNA than MCL1 mRNA were required to induce cell death for both cell lines and patient blasts, i.e., ~8,800 siRNAs for ~500 ± 50 mRNAs in ITD cells and ~6,000 siRNAs for ~300 ± 50 mRNAs in WT cells. A time-lapse study revealed that >75% MCL1 mRNA was downregulated within 1 hour after delivery of a small amount of siRNA. However, additional siRNA was required to inhibit the newly transcribed mRNA for >12 hours until the cell lost its ability of self-protection recovery. A multidelivery strategy of low doses and short delivery interval, which require 77% less siRNA and has the potential of lower side effects and clinical cost, was as effective as a single high-dose siRNA delivery. Our method provides a viable analytical tool to investigate gene silencing at the single-cell level for oligonucleotide-based therapy.
Abstract 17297: Heart Rate-Guided Titration of Beta Blockers Stabilizes Ventricular Repolarization in Patients With Chronic Heart Failure
Authors: Misa Fister, Ursa Mikuz, Vito Starc, Francois Haddad, Bojan Vrtovec
Journal: Circulation (2013)

Background: We sought to evaluate the effects of heart-rate guided titration of beta-blockers on ventricular repolarization in patients with chronic heart failure (CHF). Methods: In a prospective s...
IMAB362 plus zoledronic acid (ZA) and interleukin-2 (IL-2) in patients (pts) with advanced gastroesophageal cancer (GEC): Clinical activity and safety data from the PILOT phase I trial.
Authors: Ugur Sahin, Salah-Eddin Al-Batran, Wael Hozaeel, Zanete Zvirbule, Jens Freiberg-Richter, Florian Lordick, Marianne Just, Michael Bitzer, Peter C. Thuss-Patience, Anna Krilova, Volker Brass, Christian Mueller, Elmar Daalman, Oezlem Tureci
Journal: Journal of Clinical Oncology (2015)

e15079 Background: IMAB362 is the first-in-class monoclonal antibody against the tight junction molecule claudin 18.2 (CLDN18.2) executing its antitumor activity via 4 highly potent modes of action (antibody-dependent cellular cytotoxicity [ADCC], complement-dependent cytotoxicity, proliferation inhibition, apoptosis). Previous in vitro and in vivo data showed that ZA and IL-2 augmented IMAB362’s antitumor activity by affecting immune-related mechanisms. This exploratory Phase I trial aimed to evaluate IMAB362 plus ZA/IL-2 in pts with CLDN18.2+GEC. Methods: Pts with CLDN18.2+ chemo-refractory GEC received IMAB362 (800 in cycle [cy] 1, followed by 600 mg/m2 in subsequent cy, IV q3w) plus ZA (4 mg, IV, day 1 of cy 1 & 3) in arm 1; IMAB362, ZA plus low IL-2 (1×106 IU, s.c., days 1–3 of cy 1 & 3) in arm 2; IMAB362, ZA plus intermediate IL-2 (3×106 IU s.c., days 1–3 of cy 1 & 3) in arm 3; and IMAB362 alone in arm 4. Primary endpoints are biomarkers to assess immunomodulatory effects of treatments (modulation of immune cell populations, ADCC; data not available at time of this analysis). Here we report data on safety (NCI-CTCAE v4.0, primary endpoint) and antitumor activity (DCR, PFS, OS, secondary endpoint). Results: 28 pts (median age 56 years), most of which had progressed on ≥ 1 chemotherapy, received a median of 2.5 (1–14) IMAB362 cycles. Treatment was well tolerated and safe. 26 pts had ≥ 1 AE, 13 pts had ≥ 1 SAEs. Two SAEs were related to IMAB362 (grade [gr] 3 vomiting, gr 4 hiatus hernia). All but 1 IMAB362-related AEs were gr 1–3; most commonly nausea and vomiting in 16 (2 pts gr 3) and 15 (2 pts gr 3) pts, respectively. Of 20 evaluable pts 11 had disease control (1 pt, unconfirmed partial response; 10 pts, stable disease). Median PFS was 12.7 and median OS was 40 weeks. The safety and activity profiles did not differ between arms. Conclusions: IMAB362 (q3w) can safely be combined with ZA/IL-2. IMAB362’s safety profile is unaltered by ZA/IL-2. Signs of activity were observed with IMAB362 as single agent and in combination with ZA/IL2. Emerging primary endpoint data will show whether adding ZA/IL2 achieves the desired augmentation of IMAB362-mediated immune effects. Clinical trial information: NCT01671774.
Aromatase Inhibitors: Treatment of Advanced Breast Cancer
Authors: Lawrence C. Panasci, Henning Mouridsen, Hilary A. Chaudri-Ross
Journal: Journal of Clinical Oncology (2001)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.19.3999 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11579125 Aromatase Inhibitors: Treatment of Advanced Breast Cancer Lawrence C. PanascixLawrence C. PanasciSearch for articles by this author Henning MouridsenxHenning MouridsenSearch for articles by this author , Hilary A. Chaudri-RossxHilary A. Chaudri-RossSearch for articles by this author Show More Jewish General Hospital, Montreal, Quebec, CanadaRigshospitalet, Copenhagen, DenmarkNovartis Pharma AG, Basel, Switzerland https://doi.org/10.1200/JCO.2001.19.19.3999 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01102001In Reply:Osteoporosis is not a rare phenomenon in elderly women and may even be more frequent in patients with metastatic breast cancer because of decreased mobility. Although there are concerns as to the potential association between prolonged estrogenic suppression and bone morbidity in terms of osteoporosis/fractures, it should be noted that in postmenopausal women, the magnitude of suppression of estrogens effected by aromatase inhibitors is far smaller than the suppression that occurs when premenopausal women turn postmenopausal. This latter suppression often leads to bone loss and accelerated osteoporosis and possibly fractures.The current study was not designed specifically to address these concerns. However, osteoporosis was reported as an adverse event in one patient who was treated with tamoxifen. This 64-year-old patient entered the study with three assessable bone lesions and no other disease sites. At 6 months, she complained of lumbar and thoracic bone pain, and osteoporosis was also reported. Treatment with tamoxifen was continued until progression of disease 15 months later. At that time, her treatment was switched to letrozole, with which she is currently being treated.Another patient, 56 years old when she entered the study, had three soft tissue lesions at baseline and no other site of disease. After 3 years of tamoxifen, symptoms of osteoporosis were reported. Tamoxifen was continued for a further 3 months, at which time progression of disease in soft tissue was diagnosed.At study entry, 12 patients in the letrozole arm and 18 in the tamoxifen arm had osteoporosis. There was no suggestion that there was a deterioration in the osteoporosis. Our article referred to a median follow-up of approximately 18 months. Further data for approximately another 18 months will be available later this year.The important question about the impact of prolonged estrogen suppression is being addressed in ongoing adjuvant studies, but so far no valid conclusions can be drawn.
Abstract 1891: Mortality After CRT: a Synergetic Effect Between Ventricular Remodeling and Reduced Frequency of Ventricular Arrhythmias. The InSync ICD Italian Registry
Authors: Luigi Di Biase, Maurizio Gasparini, Maurizio Lunati, Massimo Santini, S. Filippo Neri, Maurizio Landolina, S. Matteo, Giuseppe Boriani, S. Orsola, Antonio Curnis, Spedali Civili, Mario Bocchiardo, Antonio Vincenti, S. Gerardo dei Tintori, Alessandra Denaro, Sergio Valsecchi, Medtronic Italia, Andrea Natale, Luigi Padeletti
Journal: Circulation (2007)

Introduction: It is currently debated whether cardiac resynchronization therapy (CRT) has an effect on the burden of ventricular arrhythmias (VA). We investigated whether the reverse remodeling after CRT may reduce the occurrence of VA. Methods : The study included 398 patients enrolled in the InSync ICD Italian Registry, treated with CRT-D and with a follow-up of at least 12 months. Spontaneous VA detected by the device were reviewed and validated. Results: After 6 months of follow-up no VA episodes occurred in 319 patients (group 1), while VA episodes persisted in the remaining 79 (group 2). At baseline, clinical and echocardiographic characteristics of the two groups were comparable: NYHA class (2.9±0.6 vs. 3.0±0.7), QRS width (166±31ms vs. 163±34ms), ejection fraction (26±7% vs. 26±6%), LVEDV (251±98ml vs. 226±45ml), LVESV (182±84ml vs. 158±38ml) (All p=NS). At 6 month visit, ventricular remodeling was apparent only in group 2 pts: LVEDV (200±83ml, p=0.042 vs. Baseline), LVESV (133±65ml, p=0.002 vs. Baseline). No changes were evident in group 2 pts: LVEDV (216±69ml, p=0.769 vs. Baseline), LVESV (160±59ml, p=0.521 vs. Baseline). The long-term survival from all-cause death resulted higher in group 1 pts (Log-rank test: p=0.032). (Figure ) Conclusions: In patients treated with CRT, a reduction of ventricular arrhythmic events occurs during the initial 12 months following implant and is correlated with the degree of ventricular remodeling induced by the therapy. Patients demonstrating the remission of arrhythmic episodes will have better survival and more pronounced long term improvements.
Nicolaus Coppernic (1473–1543)
Authors: Robert W. Buck
Journal: New England Journal of Medicine (1954)

THE only definitive biography of Copernicus— that by Leopold Prowe1—is not approved by Polish patriots, because it honors him as a great Prussian rather than as a Pole. He was born in Thorn, an East Prussian city founded by the Knights of the Teutonic order, of Silesian parentage, and (fortunately) wrote only in German and Latin, but he certainly acknowledged the sovereignty of a Polish king. Copernicus is celebrated, however, not for being a Silesian, Prussian or Pole, but as the elabora tor (with the probable aid of no instrument other than a home-made wooden triquetrum) of a new . . .
Phase I study of anti-CD3 x anti-EGFR–armed activated T-cells for treatment of advanced colorectal or pancreatic cancer.
Authors: Minsig Choi, Greg Dyson, Archana Thakur, Hemchandra Mahaseth, Philip Agop Philip, Anthony Frank Shields, Abhinav Deol, Lawrence G. Lum
Journal: Journal of Clinical Oncology (2015)

698 Background: Advanced colorectal cancer (CRC) and pancreatic cancer (PC) are common gastrointestinal cancers with poor prognosis. Novel therapy with less toxicity using immune system is an attractive avenue for treatment. Preclinical studies have shown targeted tumor cell killing when anti-CD3 and anti-EGFR were heteroconjugated (EGFRBi) and added to cell cultures of colon cancer, lung cancer and breast cancer including tumor-xenograft models. Methods: Patients who have no standard treatment options with advanced CRC and PC were treated with immunotherapy. Peripheral blood mononuclear cells (PBMC) for the generation of armed activated T cells (ATC) was collected using 1 leukapheresis to obtain 8-20 x 10 9 PBMC for T cell expansion. The PBMC was activated with anti-CD3 monoclonal antibody (anti-CD3) and expanded in IL-2. ATC was harvested, armed with EGFRBi, and cryopreserved in aliquots for 4 infusions. The primary objective of the study was to determine the feasibility and safety of immunotherapy. Secondary endpoints were immune response, tumor response and overall survival. Results: The study accrued 13 patients with 10 patients receiving at least 3 weekly immunotherapy. In two patients (age 73 and 78) no viable cells were grown and one patient developed symptomatic brain metastasis after leukapharesis. Median age was 58 (50-78) and 8 patients had CRC and 5 patients had PC. Total of 34 billion activated T cells ( range 0-50 billions) were infused with no significant toxicity. Infusion related headache, fever, chills and blood pressure changes was most common adverse events and most of the symptoms resolved within 48 hours of infusion. No objective tumor regression was noted but stable disease was noted lasting 2.5 to 7.6 months. Among 10 patients treated with immunotherapy OS was 13.4 months while 3 patients who did not receive therapy was 5.4 months. Overall survival for all patients (n=13) was 11.4 months. Conclusions: Activated T-cells armed with anti-CD3 x anti-EGFR can be produced and infused in patients with advanced CRC and PC with minimal toxicity. Further studies in larger number of patient will test efficacy of this immunotherapy strategy (clinical trial info NCT01420874). Clinical trial information: NCT01420874.
P87 Peripheral markers of immune activation are not associated with depression and cognitive impairment before and during antiviral therapy in chronic hepatitis C infection
Authors: M Gess, D Forton
Journal: Gut (2010)

Introduction  Cognitive impairment (CI) and depression are associated with chronic HCV infection and its treatment with alpha-interferon (IFN). Chronic immune activation may predispose susceptible individuals to IFN-induced CNS effects. Neopterin (Neo) and beta-2-microglobulin (s2m) are both IFN-induced markers of cellular immune activation. Raised serum Neo concentrations have been linked with CI in a number of inflammatory states.  Aim  We hypothesised that peripheral markers of immune activation might identify/predict patients who develop CNS effects on IFN.  Method  42 HCV-infected patients (RNA+ve, HIV−ve) with mild liver disease and no significant comorbidities were compared to 20 matched controls. Subjects completed depression questionnaires (HADS-D) and cognitive testing on a computerised battery (United BioSource, UK) after appropriate training, at baseline, week 4 (W4) and W12. Serum Neo was measured by ELISA, s2m nephelometrically.  Results  At baseline 28% of patients showed significant deficits in tests of attention, 12% had depressive symptoms (HADS-D>8). Neo and s2m levels were significantly greater in HCV patients compared to controls (mean 8.3 SD (2.1) vs 6.6 (2.6) and 2.4 (0.4) vs 1.7 (0.6), p 1SD compared to baseline performance, which were not associated with Δ HADS-D, Δ Neo or Δ s2m. Neither baseline performance nor baseline Neo or s2m were predictive of significant on-treatment CI. There were improvements in “speed of memory” on treatment from 3452 (641) ms at baseline to 3330 (630) ms at W12 (p=0.006) which had no statistical associations.  Conclusion  We confirm the high incidence of IFN- induced depression and CI. The improvements in memory are unexplained but may be due to a learning effect on the battery. The lack of an association with Neo and s2m suggests that CNS effects of IFN are unrelated to peripheral immune activation. Emerging evidence of HCV infection of the brain and microglial activation may represent a central susceptibility to IFN-induced CNS symptoms.
SRRM4 Drives Neuroendocrine Transdifferentiation of Prostate Adenocarcinoma Under Androgen Receptor Pathway Inhibition
Authors: Yinan Li, Nilgun Donmez, Cenk Sahinalp, Ning Xie, Yuwei Wang, Hui Xue, Fan Mo, Himisha Beltran, Martin Gleave, Yuzhuo Wang, Colin Collins, Xuesen Dong
Journal: European Urology (2016)
Prediction of the Risk of Myocardial Infarction from Polymorphisms in Candidate Genes
Authors: Yoshiji Yamada, Hideo Izawa, Sahoko Ichihara, Fumimaro Takatsu, Hitoshi Ishihara, Haruo Hirayama, Takahito Sone, Masashi Tanaka, Mitsuhiro Yokota
Journal: New England Journal of Medicine (2002)

Although epidemiologic studies have suggested that several genetic variants increase the risk of myocardial infarction, large-scale association studies that examine many polymorphisms simultaneously are required to allow reliable prediction of the genetic risk of myocardial infarction.We used a fluorescence- or colorimetry-based allele-specific DNA-primer-probe assay system to determine the genotypes of 112 polymorphisms of 71 candidate genes in 2819 unrelated Japanese patients with myocardial infarction (2003 men and 816 women) and 2242 unrelated Japanese controls (1306 men and 936 women).In an initial screening of the 112 polymorphisms for an association with myocardial infarction in 909 subjects, 19 polymorphisms were selected in men and 18 in women by means of logistic-regression analysis, after adjustment for age, body-mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia. In a large-scale study involving the selected polymorphisms and the remaining 4152 subjects, similar logistic-regression analysis revealed that the risk of myocardial infarction was significantly associated with the C1019T polymorphism in the connexin 37 gene (P<0.001) in men and the 4G-668/5G polymorphism in the plasminogen-activator inhibitor type 1 gene (P<0.001) and the 5A-1171/6A polymorphism in the stromelysin-1 gene (P<0.001) in women.Determination of the genotypes of the connexin 37, plasminogen-activator inhibitor type 1, and stromelysin-1 genes may prove reliable in predicting the genetic risk of myocardial infarction and might thus contribute to the primary prevention of this condition.
Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD
Authors: Hung M. Bui, David Enis, Marius R. Robciuc, Harri J. Nurmi, Jennifer Cohen, Mei Chen, Yiqing Yang, Veerpal Dhillon, Kathy Johnson, Hong Zhang, Robert Kirkpatrick, Elizabeth Traxler, Andrey Anisimov, Kari Alitalo, Mark L. Kahn
Journal: Journal of Clinical Investigation (2016)

Lymphangiogenesis is supported by 2 homologous VEGFR3 ligands, VEGFC and VEGFD. VEGFC is required for lymphatic development, while VEGFD is not. VEGFC and VEGFD are proteolytically cleaved after cell secretion in vitro, and recent studies have implicated the protease a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3) and the secreted factor collagen and calcium binding EGF domains 1 (CCBE1) in this process. It is not well understood how ligand proteolysis is controlled at the molecular level or how this process regulates lymphangiogenesis, because these complex molecular interactions have been difficult to follow ex vivo and test in vivo. Here, we have developed and used biochemical and cellular tools to demonstrate that an ADAMTS3-CCBE1 complex can form independently of VEGFR3 and is required to convert VEGFC, but not VEGFD, into an active ligand. Consistent with these ex vivo findings, mouse genetic studies revealed that ADAMTS3 is required for lymphatic development in a manner that is identical to the requirement of VEGFC and CCBE1 for lymphatic development. Moreover, CCBE1 was required for in vivo lymphangiogenesis stimulated by VEGFC but not VEGFD. Together, these studies reveal that lymphangiogenesis is regulated by two distinct proteolytic mechanisms of ligand activation: one in which VEGFC activation by ADAMTS3 and CCBE1 spatially and temporally patterns developing lymphatics, and one in which VEGFD activation by a distinct proteolytic mechanism may be stimulated during inflammatory lymphatic growth.