tbuckley/cabot-search huggingface dataset:
Premedication and Chemotherapy Agents do not Impair Imgatuzumab (GA201)-Mediated Antibody-Dependent Cellular Cytotoxicity and Combination Therapies Enhance Efficacy
Authors: Valeria Gonzalez-Nicolini, Sylvia Herter, Sabine Lang, Inja Waldhauer, Marina Bacac, Michaela Roemmele, Esther Bommer, Olivier Freytag, Erwin van Puijenbroek, Pablo Umaña, Christian A. Gerdes
Journal: Clinical Cancer Research (2015)

Imgatuzumab (GA201) is a novel anti-EGFR mAb that is glycoengineered for enhanced antibody-dependent cellular cytotoxicity (ADCC). Future treatment schedules for imgatuzumab will likely involve the use of potentially immunosuppressive drugs, such as premedication therapies, to mitigate infusion reactions characteristic of mAb therapy and chemotherapy combination partners. Because of the strong immunologic component of mode of action of imgatuzumab, it is important to understand whether these drugs influence imgatuzumab-mediated ADCC and impact efficacy.We performed a series of ADCC assays using human peripheral blood mononuclear cells that were first preincubated in physiologically relevant concentrations of commonly used premedication drugs and cancer chemotherapies. The ability of common chemotherapy agents to enhance the efficacy of imgatuzumab in vivo was then examined using orthotopic xenograft models of human cancer.A majority of premedication and chemotherapy drugs investigated had no significant effect on the ADCC activity of imgatuzumab in vitro Furthermore, enhanced in vivo efficacy was seen with imgatuzumab combination regimens compared with single-agent imgatuzumab, single-agent chemotherapy, or cetuximab combinations.These data indicate that medications currently coadministered with anti-EGFR therapies are unlikely to diminish the ADCC capabilities of imgatuzumab. Further studies using syngeneic models with functional adaptive T-cell responses are now required to fully understand how chemotherapy agents will influence a long-term response to imgatuzumab therapy. Thus, this study and future ones can provide a framework for designing imgatuzumab combination regimens with enhanced efficacy for investigation in phase II trials. Clin Cancer Res; 22(10); 2453-61. ©2015 AACR.
INPP4B Is a Tumor Suppressor in the Context of PTEN Deficiency
Authors: Thanh-Trang T. Vo, David A. Fruman
Journal: Cancer Discovery (2015)

Abstract Summary: Enzymes (PI3K and PTEN) controlling cellular levels of 3-phosphorylated phosphoinositides are known as important drivers or suppressors of tumorigenesis in various cancers. In this issue of Cancer Discovery, Kofuji and colleagues and Chew and colleagues identify the lipid phosphatase INPP4B as a context-specific tumor suppressor that controls phosphoinositide levels and AKT2 activation in PTEN-deficient cells. Cancer Discov; 5(7); 697–700. ©2015 AACR. See related article by Kofuji et al., p. 730. See related article by Chew et al., p. 740.
Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
Authors: Yusuke Shono, Andrea Z. Tuckett, Hsiou-Chi Liou, Ekaterina Doubrovina, Enrico Derenzini, Samedy Ouk, Jennifer J. Tsai, Odette M. Smith, Emily R. Levy, Fabiana M. Kreines, Carly G.K. Ziegler, Mary I. Scallion, Mikhail Doubrovin, Glenn Heller, Anas Younes, Richard J. O'Reilly, Marcel R.M. van den Brink, Johannes L. Zakrzewski
Journal: Cancer Research (2016)

NF-κB plays a variety of roles in oncogenesis and immunity that may be beneficial for therapeutic targeting, but strategies to selectively inhibit NF-κB to exert antitumor activity have been elusive. Here, we describe IT-901, a bioactive naphthalenethiobarbiturate derivative that potently inhibits the NF-κB subunit c-Rel. IT-901 suppressed graft-versus-host disease while preserving graft-versus-lymphoma activity during allogeneic transplantation. Further preclinical assessment of IT-901 for the treatment of human B-cell lymphoma revealed antitumor properties in vitro and in vivo without restriction to NF-κB-dependent lymphoma. This nondiscriminatory, antilymphoma effect was attributed to modulation of the redox homeostasis in lymphoma cells resulting in oxidative stress. Moreover, NF-κB inhibition by IT-901 resulted in reduced stimulation of the oxidative stress response gene heme oxygenase-1, and we demonstrated that NF-κB inhibition exacerbated oxidative stress induction to inhibit growth of lymphoma cells. Notably, IT-901 did not elicit increased levels of reactive oxygen species in normal leukocytes, illustrating its cancer selective properties. Taken together, our results provide mechanistic insight and preclinical proof of concept for IT-901 as a novel therapeutic agent to treat human lymphoid tumors and ameliorate graft-versus-host disease.
Impact of a new inhaler management policy on the hospitalised patient
Authors: Deirdre Long, Ann Marie Lyons, Tara Byrne, Richard Coatello
Journal: European Respiratory Journal (2014)

An audit using an adherence monitor device (adherence = time and technique) of hospitalised patients identified that 16% of patients overused on their inhalers, 21% of doses were not administered and 40% of doses were taken incorrectly.  Hence a need to change practice to improve patient safety as well as patient and staff awareness regarding inhaler administration and technique was identified. A practice change with the introduction of a new Inhaler Management Policy was developed. This included inhaler education for all staff involved in inhaler administration, supervision of inhaler technique and administration for all patients, a change in the storage of inhalers and updated nursing documentation.  A prospective, observational study was performed following the implementation of this policy. Four key components of the policy were monitored; inhaler storage, patient knowledge, nursing knowledge, and nursing documentation. An audit tool based on the NHS Metrics Assurance framework was devised to monitor the impact of the new policy.  Seventeen wards were included in the study. Monthly audits were performed and results relayed back to the wards with appropriate action plans. Six months after implementation there was a 90-100% improvement in inhaler storage on 15 wards as well as a 90-100% improvement in patients and nurses knowledge regarding inhaler technique on all 17 wards and 7 wards demonstrated a 90-100% improvement in nursing documentation.  In conclusion, a change in practice regarding inhaler management with the introduction of a new inhaler management policy for patients whilst in hospital has improved the safety of inhaler administration and knowledge of inhaler technique for both patients and staff.
A 15-Year-Old Boy With Trisomy 21 and Postoperative Weakness
Authors: Anisha Chandra Schwarz, Catherine Amlie-Lefond
Journal: JAMA Pediatrics (2016)

Four days following resection of a scrotal lipoma, a 15-year-old boy with trisomy 21 presented to the emergency department with somnolence, pain, and paucity of speech with right hand and face weakness. What is your diagnosis?
DNA-RNA measurements in patients with acute leukemia undergoing remission induction therapy.
Authors: A M Maddox, D A Johnston, B Barlogie, E Youness, M Keating, E J Freireich
Journal: Journal of Clinical Oncology (1985)

Prior to therapy, 111 newly diagnosed adult patients with acute leukemia had DNA content measured (cell-cycle distributions) and 91 had RNA content measured using flow cytometry of acridine orange-stained bone marrow biopsies. The RNA index (RI) (ratio of mean RNA in G0/G1 of the sample to the median RNA in G0/G1 of normal lymphocytes) distinguished acute myelogenous leukemia (AML) from acute lymphocytic leukemia (ALL). The mean RI in AML was 2.2 and in ALL 1.5. RI did not predict for achievement of complete remission (CR). In AML the mean S-phase percent was 11.2 in patients who achieved CR and 13.1 in those who failed to respond to therapy, whereas in ALL it was 14.5 in those responding and 8.0 in those not responding (P = .02). In the 77 patients with either AML or ALL who achieved CR, a low pretreatment S-phase percent and a high RI correlated with a long duration of CR. S-phase percent and RI were also measured during remission induction and during maintenance therapy. Between days 8 and 18, the RI of responders decreased. In both AML and ALL an increase in S-phase percent between days 18 and 22, prior to morphological CR, was observed in responders but not in nonresponders. The mean S-phase percent at the time of morphological remission was 17.3. A high S-phase percent at this time correlated with a longer duration of CR. Although neither pretreatment S-phase percent nor RI was found to predict for achievement of CR in AML, both predicted for length of CR. Increases in S-phase percent during therapy indicated recovery of normal hematopoiesis.
TCT-774 Coronary Microembolization during Transfemoral Transcatheter Aortic Valve Implantation: An Intracoronary Doppler Study
Authors: Fadi Al-Rashid, Heike Hildebrandt, Theodor Baars, Till Neumann, Felix Nensa, Kai nassenstein, Daniel Wendt, Matthias Thielmann, Heinz Jakob, Eva Kottenberg, Jürgen Peters, Raimund Erbel, Gerd Heusch, Philipp Kahlert
Journal: Journal of the American College of Cardiology (2014)
Potent ex vivo expanded, human CD34+ cord blood-derived natural killer cells for cancer immunotherapy
Authors: Xiaokui Zhang, Lin Kang, Ivana Djuretic, Eric Law, Vanessa Voskinarian-Berse, Jeffrey Harris, Uri Herzberg, Wolfgang Hofgartner, Robert Hariri
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Clinical studies suggest that adoptive transfer of allogeneic natural killer (NK) cells represent a promising treatment for patients with hematological malignancies and solid tumors. Celgene Cellular Therapeutics has established a cultivation process to generate human NK cells
Acyclic retinoid inhibits colon carcinogenesis
Authors: Masumi Suzui, Kuniko Naoi, Masanari Hashita, Hideko Nagasawa, Nao Sunagawa, Naoki Yoshimi
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3056 

Background and objective: Acyclic retinoid (ACR) has recently been demonstrated by us to inhibit the in vitro growth of human carcinoma cells by modulating the expression levels of the cell cycle-related molecules. We then investigated cancer preventive effect of ACR in the colon carcinogenesis animal models. Materials and methods: Exp. 1: Eight-week-old male and female Min mice in groups 2 and 3 were fed a diet containing 50 and 150 ppm ACR, respectively, for 13 weeks. Mice in group 1 were given the control diet alone. Exp. 2: Five-week-old male F344 rats were randomly assigned to the experimental groups. Rats in groups 1-3 received subcutaneous injections of 1,2-dimethylhydrazine (DMH) once a week for 2 weeks to induce aberrant crypt foci (ACF). One week before the first injection of DMH, rats in groups 2 and 3 were fed a diet containing 50 and 150 ppm ACR, respectively, for 5 weeks. Rats in group 4 were fed a diet containing 150 ppm ACR. Rats in group 5 were given the control diet alone and served as untreated controls. The rats were sacrificed at 5 weeks after the start of the experiment. Exp. 3: Five-week-old male F344 rats in groups 1-3 were given subcutaneous injections of DMH once a week for 2 weeks. Starting 1 week after the last injection, the rats received 1% dextran sodium sulfate (DSS) in drinking water for 1 week. One week after the DSS treatment, rats in groups 2 and 3 were fed a diet containing 50 and 150 ppm ACR, respectively, for 16 weeks. Rats in group 4 were fed a diet containing 150 ppm ACR. Rats in group 5 were given the control diet alone and served as untreated controls. The rats were sacrificed at 16 weeks after the start of the experiment. Results: (Exp. 1) ACR caused a significant decrease in tumor multiplicity and size compared to the control group ( P <0.05). (Exp. 2) Oral administration at both dose levels of ACR significantly decreased the number of ACF compared to the control group. ACR also inhibited proliferating nuclear cell antigen (PCNA) positive index and the levels of expression of the cyclin D1 protein and increased apoptotic index in the colonic epithelial cells treated with DMH. (Exp. 3) Continuous oral administration at both dose levels of ACR caused a significant decrease in tumor multiplicity ( P <0.005) and volume ( P <0.05) compared to the control group. ACR also decreased the PCNA positive index and induced apoptosis in the colon tumor. Treatment of the animals with ACR did not cause any toxic side effects in any of the organ examined. In parallel studies, we also found that the combination of ACR and TX-402, an antiangiogenic hypotoxic cytotoxin, exerted synergistic inhibition of the growth of HT29 human colon carcinoma cells. Conclusions: These results suggest that ACR suppresses colon carcinogenesis by inhibiting cell proliferation and by inducing apoptosis. Therefore, ACR may be a valuable compound in the chemoprevention and therapy of human colon cancer.
RELMb is a hypoxic induced mitogenic factor in human adenocarcinoma A549 celline
Authors: F. Rose, A. Renigunta, F. Grimminger, W. Seeger, J. Hänze
Journal: Journal of Clinical Oncology (2006)

20072 Background: RELMb (resistin-like molecule) represents the closest related human homologue of mouse RELMa, also known as hypoxic-induced-mitogenic-factor (HIMF). However, no orthologous gene of mouse HIMF exists in human. Results and Methods: In this study, we cloned human RELMb cDNA from lung and performed regulatory and functional expression studies in adenocarcinoma A549 cell line. RELMb mRNA was found to be strongly upregulated in hypoxia in these cells. Upon transfection of a RELMb encoding expression plasmid, we observed significant induction of proliferation in A549 cells, which could be blocked by phosphatidyl-inositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin. Conclusions: The results suggest that human RELMb may contribute to hypoxic-induced proliferative responses in adenocarcinoma cells via PI3K dependent signal transduction. No significant financial relationships to disclose.
Paclitaxel, carboplatin plus gemcitabine (PCG) as first-line treatment for advanced epithelial ovarian cancer (EOC): Pathologic complete response (pCR) and impact on cognitive functioning
Authors: M. L. Hensley, D. Correa, H. Thaler, A. Wilton, E. Venkatraman, P. Sabbatini, D. Chi, D. Spriggs, C. Aghajanian
Journal: Journal of Clinical Oncology (2005)

5016 Objective: to determine the pCR rate achieved with PCG for treatment of stage III or IV EOC, and to determine the impact of chemotherapy on cognitive functioning and quality of life (QOL) during and after completion of first-line treatment. Methods: Patients received P 80 mg/m2 days 1 and 8, C AUC 5 day 1, G 800 mg/m2 days 1 and 8 every 21 days for 6 cycles followed by second look laparoscopy to determine pCR. Patients completed a neurocognitive tests of attention and executive functions (Trails A, B, Digit span) and reported self-perception of their concentration/memory, prior to chemotherapy, after cycles 3 and 6, and after 6 months of follow-up, and QOL (FACT-O) assessment. Results: 27 patients (20 optimal stage III, 7 suboptimal stage III/stage IV) were treated and evaluable. 52% (95% confidence interval 30.6–73.2%) achieved pCR. The main toxicity was myelosuppression (platelets grade 3: 63%, grade 4: 4%; hemoglobin grade 3: 11%, grade 4: 7%; neutrophils grade 3: 22%, grade 4: 11%). There were no neutropenic fevers or deaths. Cognitive functioning did not decline significantly during or after chemotherapy (see table). The subgroup of patients with >14 years education reported significantly decreased self-perception of a decline in cognitive function, but this improved to baseline levels at 6 months’ follow-up. QOL was maintained throughout treatment. Conclusion: PCG achieves high pCR rates in stage III (optimal or suboptimal) and IV EOC which compares favorably to that achieved with PC (53% pCR in GOG 158, which enrolled only optimal stage III patients). Attention and executive function were not impaired in the short-term by objective measures, though highly educated women reported subjective transient impairment in cognitive functioning. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly
Role of Peri-infarct Zone Detected With Two-Dimensional Speckle Tracking Echocardiography on Ventricular Arrhythmia Inducibility in Patients With Chronic Ischemic Cardiomyopathy
Authors: Matteo Bertini, Arnold C. Ng, C. Jan Willem Borleffs, Gaetano Nucifora, Victoria Delgado, Giuseppe Boriani, Dominic Y. Leung, Martin J. Schalij, Jeroen J. Bax
Journal: Circulation (2009)
Toxic Mail
Authors: F. J. Ingelfinger
Journal: New England Journal of Medicine (1974)

Once in a while, in spite of regulations and social sanctions, noxious or offensive material reaches an unsuspecting victim through the mails. There is, moreover, little that can be done to control the hate letter that plagues the prominent, the politician, and even the editor. Granted that such purposeful acts of aggression via the mails are difficult to contain, why should not regulations at least be such as to protect the addressee from harm that may be accidental rather than intentional, but that may be nonetheless lethal?Recently, the mailman left at the private residence of two hospital-based physicians a . . .
Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy
Authors: Ryan M. Naylor, Karthik B. Jeganathan, Xiuqi Cao, Jan M. van Deursen
Journal: Journal of Clinical Investigation (2016)

The nuclear pore complex protein NUP88 is frequently elevated in aggressive human cancers and correlates with reduced patient survival; however, it is unclear whether and how NUP88 overexpression drives tumorigenesis. Here, we show that mice overexpressing NUP88 are cancer prone and form intestinal tumors. To determine whether overexpression of NUP88 drives tumorigenesis, we engineered transgenic mice with doxycycline-inducible expression of Nup88. Surprisingly, NUP88 overexpression did not alter global nuclear transport, but was a potent inducer of aneuploidy and chromosomal instability. We determined that NUP88 and the nuclear transport factors NUP98 and RAE1 comprise a regulatory network that inhibits premitotic activity of the anaphase-promoting complex/cyclosome (APC/C). When overexpressed, NUP88 sequesters NUP98-RAE1 away from APC/CCDH1, triggering proteolysis of polo-like kinase 1 (PLK1), a tumor suppressor and multitasking mitotic kinase. Premitotic destruction of PLK1 disrupts centrosome separation, causing mitotic spindle asymmetry, merotelic microtubule-kinetochore attachments, lagging chromosomes, and aneuploidy. These effects were replicated by PLK1 insufficiency, indicating that PLK1 is responsible for the mitotic defects associated with NUP88 overexpression. These findings demonstrate that the NUP88-NUP98-RAE1-APC/CCDH1 axis contributes to aneuploidy and suggest that it may be deregulated in the initiating stages of a broad spectrum of human cancers.
Abstract 14851: Early Detection of Cardiac Sarcoidosis: A Multimodality Imaging Approach
Authors: Constantina Aggeli, Ioannis Felekos, Elias Gialafos, Emmanouil Poulidakis, Elissabet Sfendouraki, Iosif Koutagiar, Erifilli Venieri, Aggeliki Rapti, Christodoulos Stefanadis
Journal: Circulation (2012)

Background: Speckle tracking and late gadolinium enhancement cardiac MRI (LGE-CMR) have revolutionised the understanding of myocardial function . The aim of this study was to evaluate left ventricu...
C-reactive protein on postoperative day 3 as a predictor of infectious complications following gastric cancer resection.
Authors: Kazumasa Fujitani, Yuji Shishido, Kazuyoshi Yamamoto, Motohiro Hirao, Toshimasa Tsujinaka, Mitsugu Sekimoto
Journal: Journal of Clinical Oncology (2015)

26 Background: Postoperative infectious complications (PICs) after gastric cancer resection remain a clinically relevant problem. Early detection of PICs, before critical illness develops, may be of considerable clinical benefit. The aims of this study were to investigate the predictive factors for PICs and to define the clinical parameters for their early detection in patients with gastric cancer resection. Methods: Clinical data of 417 consecutive patients undergoing elective gastrectomy for primary gastric cancer between 2009 and 2012 were retrospectively analyzed. Diagnostic accuracy was determined by the area under the receiver operating characteristic curve (AUC). Univariate and multivariate logistic regression analyses identified clinical factors predicting PICs of grade III or more according to the Clavien-Dindo classification. Results: Forty-four patients developed PICs of grade ≥ III (10.6%, 95% confidence interval [CI] 7.6–13.5%). As a systemic inflammatory marker, C-reactive protein (CRP) on postoperative day (POD) 3 had superior diagnostic accuracy for PICs (AUC 0.802, 95% CI 0.735–0.870) with a calculated cut-off value of 17.7 mg/dl, yielding a sensitivity of 0.66 (95% CI 0.524–0.774) and a specificity of 0.84 (95% CI 0.821–0.850). Multivariate analysis identified CRP on POD 3 of 17.7 mg/dl or greater (odds ratio [OR] 8.094, 95% CI 3.568–19.342) as well as clinical stage ≥ II (OR 4.445, 95% CI 1.478–15.881) and operation time ≥ 250 min (OR 3.638, 95% CI 1.449–10.137) as significant predictive factors for PICs after gastrectomy. Conclusions: Elevated CRP levels on POD 3 will help physicians predict postoperative course and facilitate decision-making regarding the prompt, comprehensive clinical search and therapeutic approach for PICs.
Resectable pancreatic small cell carcinoma: The experience of two institutions and review of the literature.
Authors: J. M. Winter, A. K. Narang, A. S. Mansfield, J. M. Herman, J. L. Cameron, D. Laheru, F. E. Eckhauser, M. Olson, R. C. Miller, D. K. Andersen
Journal: Journal of Clinical Oncology (2011)

333 Background: Primary pancreatic small cell carcinoma (SCC) is rare, with just over 30 cases reported in the literature. Only 7 of these patients underwent surgical resection with a median survival of 6 months. Prognosis of SCC is therefore considered to be poor, and the role of adjuvant therapy is uncertain. Here we report two institutions' experience with resectable pancreatic SCC. Methods: Six patients with pancreatic SCC at the Johns Hopkins Hospital (4 patients) and the Mayo Clinic (2 patients) were identified from prospectively collected pancreatic cancer databases and re-reviewed by pathology. All six patients underwent a pancreaticoduodenectomy. Clinicopathologic data was analyzed, and the literature on pancreatic SCC was reviewed. Results: Median age at diagnosis was 50 years (range 27-60). Half of the patients were male, and half were known smokers. All six masses were limited to the pancreatic head. Median tumor size was 3 cm, and all cases had positive lymph nodes except for one patient who only had five nodes sampled. There was no perioperative mortality, although three patients had postoperative complications. All six patients received adjuvant chemotherapy therapy, five of whom were given cisplatin and etoposide. Of these five patients, three were known to have received radiation, while the remaining two had a plan for radiation at an outside facility. Median survival was 20 months with a range of 9-173 months. The patient who lived for 9 months received chemotherapy only, while the patient who lived for 173 months was given chemoradiation with cisplatin and etoposide and represents the longest reported survival time from pancreatic SCC to date. Conclusions: Pancreatic SCC is an extremely rare form of cancer with a poor prognosis. Patients in this surgical series showed improved survival rates when compared to prior experiences with both resected and unresectable cases. Cisplatin and etoposide appears to be the preferred chemotherapy regimen, although its efficacy remains uncertain, as does the role of combined modality treatment with radiation. No significant financial relationships to disclose.