tbuckley/cabot-search huggingface dataset:
A phase II trial of nab-paclitaxel (NP) in patients with advanced pancreatic cancer (PC) who have progressed on gemcitabine (G)-based therapy.
Authors: P. J. Hosein, G. d. Lopes, C. M. Gomez, V. H. Pastorini, J. Macintyre, M. Easey, I. M. Reis, J. R. Merchan, P. Bejarano, C. S. Rocha Lima
Journal: Journal of Clinical Oncology (2010)

4120 Background: G is the standard for patients with unresectable PC. There are no approved second-line options. NP (Abraxane) in combination with gemcitabine has shown interesting activity in a phase I/II trial (Von Hoff, ASCO 2009). This study was designed to determine the effectiveness of NP monotherapy in patients who progress on G-based therapy. Methods: In this phase II trial, patients with advanced PC and ECOG PS 0-2 who progressed on G-based therapy, received NP 100 mg/m2 over 30 minutes on days 1, 8, and 15 of a 28- day cycle. The primary endpoint was 6-month overall survival (OS). Secondary endpoints were response rate (by RECIST criteria), progression-free survival (PFS), safety and toxicity profile. Results: Out of 20 patients accrued, 1 patient never received study therapy and was excluded from analysis. The median age was 61 years, 9 (47%) were male, 18 (95%) had stage IV disease, and 15 (79%) had an ECOG PS of 0-1. The 6-month OS was 58% (95% CI 33%-76%) and the median OS was 7.3 months (95% CI 2.8-13.3). The median PFS was 1.6 months (95% CI 1.5- 3.4). One patient had a confirmed partial response (PR) and 6 (32%) had stable disease (SD) as their best response. The remaining 12 patients (63%) had progressive disease (PD) on or before the first response assessment. Five patients are alive with a median follow-up of 12.7 months (range 9.6-16.3), including one with SD on cycle 15 of therapy. After 2 cycles, the median CA 19-9 level decreased by 52% in patients who had SD or PR, versus an 18% drop in the patients with PD. Correlative studies with SPARC expression are ongoing. Nonhematological toxicities were generally mild with grade 1 or 2 nausea, anorexia, hypocalcemia and vomiting occurring in 63%, 47%, 37% and 26% of patients respectively. Grade 3 or 4 neutropenia, neutropenic fever and anemia occurred in 32%, 11% and 11% of patients respectively. There were no cases of grade 3 or 4 neuropathy. Conclusions: NP was well tolerated and provided clinical benefit in 37% of patients who had previously progressed on G-based therapy. Analysis of samples from this study, as well as other ongoing studies, are needed to determine the predictive value of SPARC expression in patients with PC treated with NP. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abraxis BioScience
Abstract 2707: Downregulation of cyclin D1 sensitizes cancer cells to MDM2 antagonist Nutlin-3
Authors: Wenbin Ou, Weicai Chen, Jiaqing Zhu, Grant Eilers, Xuhui Li, Peipei Yang, Hailong Li, Fanguo Meng, Jonathan Fletcher
Journal: Cancer Research (2015)

Abstract The MDM2-p53 pathway plays a prominent role in various cancer pathogenesis. Nutlin-3, a small-molecule antagonist of MDM2, inhibits proliferation in cancer cells with wild-type p53 by blocking the interaction of MDM2 and p53. However, different cancer cells differ greatly sensitivity of Nutlin-3 because of MDM2 amplification and/or p53 mutation status. Herein, we evaluate the sensitivity of Nutlin-3 in different cancer cell lines including four mesothelioma cell lines, one breast cancer line, and one leiomyosarcoma cell line with nonmutant p53 expression, two liposarcoma cell lines harboring MDM2 amplification and wild-type p53, and one control mesothelioma cell line JMN1B harboring p53 point mutation. Unexpectedly, Nutlin-3 treatment induced cyclin D1 expression accompanied with inhibition of MDM2-p53 interaction in nonmutant cancer cell lines. Additive effects were obtained through a coordinated attack on MDM2-p53 interaction and cyclin D1, as demonstrated by immunoblots, cell viability and cell cycle analyses, showing that lentiviral mediated cyclin D1 knockdown or drug inhibition, and block of MDM2-p53 interaction, in cancer cell lines containing wild-type p53, induced greater anti-proliferative effects, compared to either intervention alone. Further results demonstrated that upregulation of cyclin D1 after Nutlin-3 treatment to some extent was dependent on expression and ubiquitin E3-ligase activity of MDM2. These compelling anti-proliferative responses indicate that combination inhibition of cyclin D1 and MDM2-p53 interaction warrants clinical evaluation as a novel therapeutic strategy in cancer cells harboring wild-type p53. Citation Format: Wenbin Ou, Weicai Chen, Jiaqing Zhu, Grant Eilers, Xuhui Li, Peipei Yang, Hailong Li, Fanguo Meng, Jonathan Fletcher. Downregulation of cyclin D1 sensitizes cancer cells to MDM2 antagonist Nutlin-3. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2707. doi:10.1158/1538-7445.AM2015-2707
Abstract 68: Compression Depth Was Correlated with SNR in VF but Not in Nonshockable Rhythms During CPR
Authors: Yongqin Li, Yushun Gong, Bihua Chen, Mi He
Journal: Circulation (2014)

Introduction: Artifacts produced by chest compression (CC) during cardiopulmonary resuscitation (CPR) preclude reliable automated ECG rhythm analysis. Several filtering techniques have been proposed to remove the artifact with the use of compression related signals as reference. In order to test the performance of the filters, CPR-corrupted signals were usually generated at different signal-to-noise ratio (SNR) levels and the improvements in SNR were evaluated. However, SNR in real cardiac arrest data and the relationship between compression depth (CD) and SNR are still unknown. Method: ECG, together with CD signals were recorded through defibrillators in 146 patients who experienced cardiac arrest and CPR. A total of 306 segments (6 seconds length, sample rate 250Hz), including 152 ventricular fibrillation (VF), 91 pulseless electrical activity (PEA) and 63 asystole were analyzed. Each segment consisted of 3 seconds corrupted and adjacent 3 seconds artifact-free signal. The power of signal was calculated from the artifact-free signal and the power of artifact was obtained through subtracting the power of corrupted ECG by the power of artifact-free signal. The relationship between CD and SNR was tested with Pearson correlation coefficients. Results: The average CD was 4.76±1.24cm. SNR of asystole was significantly lower compared to that of VF and PEA (-21.93±7.37 dB vs. -5.04±8.53 dB and -3.70±7.16 dB, p&lt;0.01). As shown in the Figure, the correlation coefficient was -0.16 (p&lt;0.01) between CD and SNR. When each of the rhythms was investigated individually, negative correlation between CD and SNR was only observed in VF (r =–0.21, p &lt; 0.01). Conclusion: In this patient population, SNR of corrupted ECG was not correlated with CD when the underlying rhythms were non-shockable. This may, at least in part, accounted for the reported high sensitivity but low specificity when adaptive filters were used to remove artifact using CD related signals as reference.
Abstract 19908: 5-oxoprolinase: a Novel Cardiac Mediator of the Oxidative Stress Response in the Failing Heart
Authors: Atze van der Pol, Jasper Tromp, Martijn F Hoes, Ibrahim J Domian, Wiek H van Gilst, Herman Silljé, Rudolf A de Boer, Peter V van der Meer
Journal: Circulation (2014)

Introduction: A hallmark of Heart Failure (HF) is the re-emergence of the fetal gene program. The aim of this study was to identify novel genes associated with the fetal gene program in HF, by utilizing a mouse embryonic stem (mES) cell based micro-array. Methods/Results: The micro-array analysis was performed on mES cells, early and late mES-derived cardiac progenitors, and mouse neonatal right ventricular tissue. As expected, our screen effectively identified established fetal genes, including alpha smooth muscle actin. We further uncovered several novel genes behaving like fetal genes. The top 5 hits were validated in an in vivo pressure overload HF model. 5-oxoprolinase (OPLAH) was found to be the most significantly differentially expressed gene in the HF model. In a human organ panel, OPLAH gene expression was highest in cardiac tissue, and found to be expressed mainly in the cytosol of cardiomyocytes. Additionally OPLAH protein levels were reduced by 50-70% in both pressure overload and ischemia induced HF (p=0.001 and p=0.009, respectively). OPLAH is an ATP-hydrolyzing enzyme involved in the γ-Glutamyl cycle, responsible for the conversion of the metabolite 5-oxoproline into glutamate. To study OPLAH function we used siRNA and/or over-expression by means of viral transfection of neonatal rat ventricular myocytes. In vitro silencing of OPLAH resulted in an increased susceptibility towards oxidative stress induced apoptosis (40% increase in cleaved caspase-3 positive cells, p=0.02). Furthermore, exogenous administration of 5-oxoproline increased apoptosis in cardiomyocytes (40% increase in cleaved caspase-3 positive cells, p=0.04). Conclusions: We identified OPLAH as a novel enzyme associated with HF, behaving like fetal genes, which is involved in the innate protection against oxidative stress, by scavenging excess 5-oxoproline.
Abstract 16506: Increased Function of the CD28hi Phenotype Underlies the Reduction of Intimal Thickening by CD8+ T cells
Authors: Paul C Dimayuga, Kuang-Yuh Chyu, Xiaoning Zhao, Juliana Yano, Wai Man Lio, Jianchang Zhou, Tomoyuki Honjo, Portia Trinidad, Prediman K Shah, Bojan Cercek
Journal: Circulation (2012)

Background: We recently reported that CD8+ T cells reduced intimal thickening after arterial injury with increased CD28 expression. Under basal conditions, CD28 is expressed by mouse CD8+ T cells (...
Long-Term Propagation of a Murine Erythroblastosis Virus &lt;italic&gt;In Vitro&lt;/italic&gt;&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Somers, K. D., Kirsten, W. H.
Journal: JNCI Journal of the National Cancer Institute (1968)

Journal Article Long-Term Propagation of a Murine Erythroblastosis Virus In Vitro Get access K. D. Somers, K. D. Somers Departments of Pathology, Pediatrics, and Microbiology, Division of Biological Sciences, University of Chicago, Chicago, Illinois 60637 Search for other works by this author on: Oxford Academic PubMed Google Scholar W. H. Kirsten W. H. Kirsten Departments of Pathology, Pediatrics, and Microbiology, Division of Biological Sciences, University of Chicago, Chicago, Illinois 60637 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 40, Issue 5, May 1968, Pages 1053–1065, https://doi.org/10.1093/jnci/40.5.1053 Published: 01 May 1968 Article history Received: 20 November 1967 Accepted: 24 January 1968 Published: 01 May 1968
Genetic and clinical variables identify predictors for chronic kidney disease in type 2 diabetes
Authors: Guozhi Jiang, Cheng Hu, Claudia H.T. Tam, Eric S.H. Lau, Ying Wang, Andrea O.Y. Luk, Xilin Yang, Alice P.S. Kong, Janice S.K. Ho, Vincent K.L. Lam, Heung Man Lee, Jie Wang, Rong Zhang, Stephen K.W. Tsui, Maggie C.Y. Ng, Cheuk-Chun Szeto, Weiping Jia, Xiaodan Fan, Wing Yee So, Juliana C.N. Chan, Ronald C.W. Ma
Journal: Kidney International (2016)
Delinquency, psychomotor epileptic symptoms and paranoid ideation: a triad
Authors: D O Lewis
Journal: American Journal of Psychiatry (1976)

In a retrospective chart-review study, the author found psychomotor epileptic symptoms in 6% (N=18) of children referred to a juvenile court over a 2-year period. Abnormalities appeared in 11 of the 14 available EEGs, but temporal lobe foci were noted in only 3 cases. Of these 18 children, 16 experienced paranoid symptoms that led to aggressive behavior. The incidence of offenses against persons was 50% in this sample, compared to 2--3% in the population of children referred to the juvenile court. The author suggests that psychomotor epilepsy may be far more common among delinquent children than has been reported previously and should therefore be included in the differential diagnosis of court-referred children.
NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models
Authors: Deborah H. Charych, Ute Hoch, John L. Langowski, Steve R. Lee, Murali K. Addepalli, Peter B. Kirk, Dawei Sheng, Xiaofeng Liu, Paul W. Sims, Laurie A. VanderVeen, Cherie F. Ali, Thomas K. Chang, Marina Konakova, Rhoneil L. Pena, Rupesh S. Kanhere, Yolanda M. Kirksey, Chunmei Ji, Yujun Wang, Jicai Huang, Theresa D. Sweeney, Seema S. Kantak, Stephen K. Doberstein
Journal: Clinical Cancer Research (2016)

Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates.We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti-CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates.In a murine melanoma tumor model, the ratio of tumor-killing CD8(+) T cells to Foxp3(+) regulatory T cells was greater than 400 for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single agent and provided durable immunity that was resistant to tumor rechallenge in combination with anti-CTLA-4 antibody. NKTR-214 was well tolerated in non-human primates.These data support further evaluation of NKTR-214 in humans for a variety of tumor types, adding to the repertoire of potent and potentially curative cancer immunotherapies.
Early determination of metastatic potential in breast cancer: The 70-gene signature in small tumors
Authors: M. Knauer, S. Mook, V. Retèl, M. Kok, J. Wesseling, A. M. Glas, E. J. Rutgers, L. J. van 't Veer, S. C. Linn
Journal: Journal of Clinical Oncology (2009)

518 Background: Small breast cancers are often considered as low risk tumors in clinico-pathologic risk assessment and treatment guidelines. However, since the ability to metastasize is an early and inherent genetic property of breast cancer and consequently even small tumors can metastasize, identification of prognostic subgroups for patients with small tumors would help to optimize treatment strategies. In the present study the 70-gene prognosis signature (MammaPrint), validated as independent prognostic indicator for node-negative and positive patients, was used to assess prognosis for pT1 breast cancer. Methods: 965 tumor samples of women with pT1 breast cancer from 7 previously reported studies were analyzed and classified by MammaPrint as good or poor prognosis. 10-year distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS) was analyzed according to the 70-gene prognosis signature separately for pT1a/b (1–10mm) and pT1c (11–20mm) tumors. Results: Median follow-up was 7.1 years (range 0.2–25.2). 526 of 965 patients (55%) were classified as good prognosis and 439 (45%) as poor prognosis by the 70-gene signature. 562 patients (59%) received no adjuvant treatment, 19% received hormonal treatment only, 10% chemotherapy only and 12% both respectively. The 70-gene signature accurately predicted differences in 10-year DDFS (HR 2.7 [1.9–3.9], p&lt;0.01) and BCSS (HR 4.0 [2.6–6.3], p&lt;0.01) for all T1 tumors. Similar results were obtained by multivariate analysis for all patients, adjusted for known prognostic factors and adjuvant therapy, as well as for adjuvant untreated patients. At 10 years, for small pT1a/b tumors (n=140), DDFS was 93% vs. 78% for the good and poor prognosis groups (HR 3.9 [1.0–15.2], p=0.048), while in the T1c group (n=825) DDFS was 86% vs. 72% (HR 2.6 [1.8–4.0], p&lt;0.01). BCSS was 87% vs. 73% for the good and poor prognosis groups in the T1a/b group (HR 2.4 [0.8–7.7], p=0.128) and 92% vs. 72% (HR 4.4 [2.7–7.1], p&lt;0.01) in T1c tumors, respectively. Conclusions: The 70-gene signature is a strong and independent prognostic indicator also in small breast tumors. Patients with T1a/b or T1c tumors and a genomic high risk gene signature for developing distant metastases may be selected for additional adjuvant hormonal and chemotherapy. [Table: see text]
MIME chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide) as treatment for recurrent Hodgkin's disease.
Authors: F B Hagemeister, N Tannir, P McLaughlin, P Salvador, S Riggs, W S Velasquez, F Cabanillas
Journal: Journal of Clinical Oncology (1987)

Forty-seven patients with Hodgkin's disease in relapse were treated with MIME combination chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide). All patients had previously received nitrogen mustard, vincristine, prednisone, procarbazine (MOPP) or similar regimens and doxorubicin-containing combinations, and many had received extensive irradiation. Complete remission (CR) occurred in 23%, and was influenced by presence of extranodal disease, hemoglobin, lactic dehydrogenase (LDH), and number of prior relapses. Median survival for all patients was 50 weeks, and was affected adversely by the presence of extranodal disease and the number of prior relapses. Toxicity was significant, including infections (23%), neutropenic fever (34%), and hemorrhagic cystitis (23%), but was related in part to the extent of prior therapy. These results with this novel chemotherapy program in heavily pretreated patients suggest that MIME should be studied in less extensively treated patients and considered as a part of treatment programs for patients with Hodgkin's disease in first relapse.
Preliminary efficacy and safety results of glufosfamide (GLU) in relapsed soft tissue sarcoma: Results of a phase II trial
Authors: G. Z. D’Amato, C. F. Verschraegen, L. D. Cranmer, K. N. Ganjoo, G. Rosen, D. R. Adkins, D. S. Mendelson, V. K. Langmuir, S. Kroll
Journal: Journal of Clinical Oncology (2008)

10591 Background: Glufosfamide is glucose linked to isophosphoramide mustard, the active metabolite of ifosfamide. Ifosfamide is known to have activity in soft tissue sarcoma. The objectives of this study are to evaluate the safety and efficacy of GLU in patients (pts) with soft tissue sarcoma. Methods: This 1-stage phase 2 study planned to enroll 22 pts with metastatic and/or advanced unresectable soft tissue sarcoma previously treated with 1–2 prior systemic therapies. Prior ifosfamide was allowed unless most recent relapse occurred within 4 weeks of completion of ifosfamide. Pts received GLU 5000 mg/m2 IV over 1 hour every 21 days for up to 6 cycles. Primary endpoint was confirmed response rate. FDG PET scans were collected prior to Cycle 3 if PET positive at baseline. Results: 11 male/11 female pts enrolled; 2 did not meet all eligibility criteria. Median age 52 y (range: 19–77); ECOG 0/1 (16) and 2 (6). Histology: leiomyosarcoma (8), synovial (5), angiosarcoma (3), other (6). Four pts completed 6 cycles; including 2 pts receiving additional cycles. Pts discontinued for progressive disease (PD; 9), adverse event (AE; 5), subject/MD decision (4). One pt (4.5%; 95% CI: 0.1–22.8%) with synovial sarcoma had a partial response (duration >4 months). Seven pts (32%) had stable disease (SD) lasting 37+ to 155+ days. Four pts (18%) were not evaluable. PET data are being analyzed. Five subjects died, 4 from PD and 1 from renal failure. The most common severe AE was renal failure (5 pts; 2 each grade 3 and 4, 1 grade 5). Possible risk factors for renal failure were low CrCL at baseline (3), ECOG 2 (4), dosing errors (2) and aggressive use of diuretics (2). Grade 3/4 neutropenia occurred in 2 pts and grade 3 thrombocytopenia in 1 pt. Common grade 1/2 Aes were nausea (13), vomiting (10) and fatigue (7). Conclusions: GLU resulted in a 36% SD or better response rate in pts with relapsed sarcoma. Because renal toxicity was higher than in other GLU studies, different dosing regimens are being considered to improve the therapeutic ratio. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Threshold Aptium Oncology, Pfizer Oncology, Threshold Threshold Amgen, Schering-Plough Threshold Pharmaceuticals
Histological evaluation of tumor response in metastatic lymph node after preoperative chemotherapy for gastric cancer.
Authors: Shinsaku Honda, Yuichiro Miki, Yutaka Tanizawa, Wataru Takagi, Fumiko Hirata, Hayato Omori, Taichi Tatsubayashi, Rie Makuuchi, Masanori Tokunaga, Etsuro Bando, Taiichi Kawamura, Takashi Nakajima, Masanori Terashima
Journal: Journal of Clinical Oncology (2015)

51 Background: Preoperative chemotherapy is thought to be an option for treatment of advanced gastric cancer. However, optimal predictive marker for survival of preoperative chemotherapy had not yet been established. Histological response is thought to be a good candidate of predictive marker, however, it had been determined only in primary tumor, not in the metastatic lymph node. The aim of this study is to evaluate the role of histological response in metastatic lymph node on the survival in patients received preoperative chemotherapy for advanced gastric cancer. Methods: A total of 38 patients who underwent curative resection after preoperative chemotherapy from were included. For histological evaluation in lymph node, we determined it as positive if remaining viable tumor cells are less than 30% of the tumor area at one or more of the resected metastatic lymph nodes. We also evaluated histological response in primary tumor according to the Japanese Gastric Cancer Classification. Results: 21 patients received preoperative chemotherapy as planned neo-adjuvant chemotherapy and remaining 17 received chemotherapy as palliative intent and then converted to surgery. Pathological TNM stage was 0 in 2, I in 5, II in 13, III in 11, and IV in 7, respectively. In lymph node, histological response was able to evaluate in 31 of 38 patients. Among them, positive response was observed in 15 patients. Histological tumor response in primary tumor was grade 0 in 2, grade 1a in 10, grade 1b in 7, grade 2 in 10, and grade 3 in 2. The 3-year relapse-free survival (RFS) rate was significantly better in patients with positive histological response in lymph node (71 %) than in those without response (21 %) (p = 0.003). Similarly, 3-year RFS rate was significantly better in patients with histological response in primary tumor (grade 2, 3) (73 %) than in those without response (grade 0, 1a, 1b) (30 %) (p=0.007). Three-year RFS in patients who demonstrate histological response both in primary tumor and lymph node was as high as 89 %. Conclusions: Histological responses in lymph nodes, as well as primary tumor, appear to be a useful predictive marker for survival in patients underwent curative resection after preoperative chemotherapy.