tbuckley/cabot-search huggingface dataset:
Clinical activity and correlative DCE-MRI imaging of G-202, a thapsigargin-based prostate-specific membrane antigen-activated prodrug, in progressive hepatocellular cancer.
Authors: Devalingam Mahalingam, Benjamin Tubb, John J. Nemunaitis, Putao Cen, Julie Haewon Rowe, John Sarantopoulos, Michael R. Kurman, Victoria Allgood, Luis T. Campos
Journal: Journal of Clinical Oncology (2015)

301 Background: G-202 is a thapsigargin-based prodrug whose cytotoxic activity is blocked by a masking peptide that is cleaved by prostate-specific membrane antigen (PSMA), a membrane-bound protease expressed in prostate cancer and the endothelium of tumor vasculature but not in most other tissues or normal tissue vasculature. In a Phase I study of G-202, prolonged disease stabilization was observed in the subset of patients with hepatocellular carcinoma (HCC) and prompted development of a Phase II study to further evaluate activity of G-202 in patients with HCC who have progressed on sorafenib. Methods: G-202 is administered by iv infusion on Days 1, 2 and 3 of a 28-day cycle; prophylactic hydration is administered with infusion to ameliorate incidence of creatinine elevations. HCC is typically highly-vascularized, and DCE-MRI is performed in consenting patients at baseline and after treatment on approximately Day 6 of Cycle 2 to evaluate possible effects of G-202 on blood flow metrics in hepatic lesions. DCE-MRI is a non-invasive method of investigating vascular structure and function and is sensitive to alterations in vascular permeability and blood flow. DCE-MRI measurements were made on 1.5 Tesla MRI and the volume transfer coefficients, K trans , of HCC tumor lesions were calculated using arterial input function derived from signal in abdominal aorta. Results: Among the 22 patients treated to date, G-202 related SAEs in this patient population have been creatinine increase/acute renal failure/acute kidney injury (3 pts) and congestive heart failure (1 pt). While objective responses (CR, PR) have not been observed in these patients with advanced disease, the rate of disease stabilization has been remarkable, with &gt;70% of patients exhibiting SD. In patients undergoing DCE-MRI, an average 56% decrease in K trans has been observed after administration of G-202. Conclusions: G-202 is generally well-tolerated and promotes disease stabilization in patients with advanced HCC who have progressed on sorafenib. DCE-MRI findings of decreased tumor K trans values suggests that G-202 reduces early arterial blood flow in hepatic lesions. Clinical trial information: NCT01777594.
Aggressive combined treatment of synovial sarcoma patients (pts) without distant metastases - single-center experience
Authors: W. Ruka, P. Rutkowski, S. Falkowski, T. Morysinski, Z. I. Nowecki
Journal: Journal of Clinical Oncology (2004)

9018 Background: Synovial sarcoma (SS) is a common type of high-grade soft tissue sarcoma (STS) with significant sensitivity to chemotherapy and poor prognosis (ASCO 1994, abst. 1645). The aim of this single-center study was to analyze the results of intensive chemo- and radiotherapy treatment in pts with nonmetastastic (M0) SS. Methods: One hundred consecutive M0 SS pts (median age 32 years, range: 15–70; 23 pts had primary tumors and 77 pts - recurrences or scars after non-radical excision, 40% of tumors >5 cm) treated between 1995 and 2003 received chemotherapy (2 cycles of high-dose ifosfamide at dose of 11.9g/m2/7 days) and radiotherapy (20Gy over 5 days - 4Gy/fractions; fields contained the tumor - primary, recurrent or scar with drain sites and margins ≥ 5 cm) before surgical resection, followed by 4 cycles of postoperative multiagent chemotherapy (2 of ifosfamide - 11.9g/m2/7days and 2 of doxorubicin - 60mg/m2 and cisplatin - 120mg/m2). Median follow-up time was 21 months. Results: 92 pts received complete treatment, grade 3 and 4 toxicity (CTC 2.0) was observed in 27% of pts. There were no toxic deaths. All pts underwent surgery (conservative - 89 pts, amputations - 11pts); resections were microscopically assessed as R0 in 83 pts and R1 in 15 pts. Wound complications were observed in 38% of pts. There were 15 deaths due to disease progression and 31 recurrences of the disease (primary: mostly - lung metastases in 18 pts and local recurrences in 7 pts). Estimated 5-year overall survival (OS) rate was 76% and 5-year disease free survival (DFS) rate was 50%. Conclusions: The encouraging results of intensive combined treatment of pts with localized SS indicate the 5-year survival rate of about 80% in this highly malignant type of STS. No significant financial relationships to disclose.
Induction of Epstein-Barr Virus-Specific Cytotoxic T-Lymphocyte Responses Using Dendritic Cells Pulsed With EBNA-3A Peptides or UV-Inactivated, Recombinant EBNA-3A Vaccinia Virus
Authors: Marion Subklewe, Ann Chahroudi, Alan Schmaljohn, Michael G. Kurilla, Nina Bhardwaj, Ralph M. Steinman
Journal: Blood (1999)
Sub-Saharan African migrants living with HIV acquired after migration, France, ANRS PARCOURS study, 2012 to 2013
Authors: Annabel Desgrées-du-Loû, Julie Pannetier, Andrainolo Ravalihasy, Anne Gosselin, Virginie Supervie, Henri Panjo, Nathalie Bajos, France Lert, Nathalie Lydié, Rosemary Dray-Spira
Journal: Eurosurveillance (2015)

We estimated the proportion of migrants from sub-Saharan Africa who acquired human immunodeficiency virus (HIV) while living in France. Life-event and clinical information was collected in 2012 and 2013 from a random sample of HIV-infected outpatients born in sub-Saharan Africa and living in the Paris region. We assumed HIV infection in France if at least one of the following was fulfilled: (i) HIV diagnosis at least 11 years after arrival in France, (ii) at least one negative HIV test in France, (iii) sexual debut after arrival in France. Otherwise, time of HIV infection was based on statistical modelling of first CD4 + T-cell count; infection in France was assumed if more than 50% (median scenario) or more than 95% (conservative scenario) of modelled infection times occurred after migration. We estimated that 49% of 898 HIV-infected adults born in sub-Saharan Africa (95% confidence interval (CI): 45–53) in the median and 35% (95% CI: 31–39) in the conservative scenario acquired HIV while living in France. This proportion was higher in men than women (44% (95% CI: 37–51) vs 30% (95% CI: 25–35); conservative scenario) and increased with length of stay in France. These high proportions highlight the need for improved HIV policies targeting migrants.
Response to Letters Regarding Article “Segmental Aortic Stiffness in Children and Young Adults With Connective Tissue Disorders: Relationships With Age, Aortic Size, Rate of Dilation, and Surgical Root Replacement”
Authors: Ashwin Prakash, Himanshu Adlakha, Nicole Rabideau, Cara J. Hass, Shaine A. Morris, Tal Geva, Kimberlee Gauvreau, Michael N. Singh, Ronald V. Lacro
Journal: Circulation (2016)

We thank Murakami et al for their interest in our article. 1They propose that the aortic dilatation observed in patients with connective tissue disorders is a compensatory response to increased aortic stiffness to preserve coronary blood flow.Although our study was not designed to test this interesting hypothesis, we agree that future investigations designed specifically to address this theory are warranted.Weismann et al question the use of aortic strain in our study and suggest that its relationship with adverse aortic outcomes may be driven by aortic size alone.However, their comments fail to take into account that, in addition to aortic size, several other factors affect aortic strain, including the viscoelastic properties of the aortic wall.The relationships between aortic size, distensibility, and area change have previously been derived as follows 2-4 :
Control of Foxp3 stability through modulation of TET activity
Authors: Xiaojing Yue, Sara Trifari, Tarmo Äijö, Ageliki Tsagaratou, William A. Pastor, Jorge A. Zepeda-Martínez, Chan-Wang J. Lio, Xiang Li, Yun Huang, Pandurangan Vijayanand, Harri Lähdesmäki, Anjana Rao
Journal: The Journal of Experimental Medicine (2016)

Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and other oxidized methylcytosines, intermediates in DNA demethylation. In this study, we examine the role of TET proteins in regulating Foxp3, a transcription factor essential for the development and function of regulatory T cells (T reg cells), a distinct lineage of CD4+ T cells that prevent autoimmunity and maintain immune homeostasis. We show that during T reg cell development in the thymus, TET proteins mediate the loss of 5mC in T reg cell–specific hypomethylated regions, including CNS1 and CNS2, intronic cis-regulatory elements in the Foxp3 locus. Similar to CNS2-deficient T reg cells, the stability of Foxp3 expression is markedly compromised in T reg cells from Tet2/Tet3 double-deficient mice. Vitamin C potentiates TET activity and acts through Tet2/Tet3 to increase the stability of Foxp3 expression in TGF-β–induced T reg cells. Our data suggest that targeting TET enzymes with small molecule activators such as vitamin C might increase induced T reg cell efficacy.
Colony-Stimulating Factor Produced by Murine Adrenocortical Tumor Cells
Authors: A Pessina, M G Neri, A Muschiato, P Brambilla, A Marocchi, P Mocarelli
Journal: JNCI Journal of the National Cancer Institute (1986)

Conditioned medium obtained from the adrenocortical LAF1 mouse tumor (Y-1) cell cultures was able to stimulate the proliferation and the differentiation of granulocyte-macrophage precursors in the normal murine bone marrow. Colony-stimulating factor (CSF) was spontaneously produced by Y-1 cells also in serum-free cultures. By two cycles of gel chromatography on Sephadex G-150 of concentrated conditioned medium two peaks of colony-stimulating activity were isolated that corresponded to apparent molecular radii of 100,000 and 29,000, respectively. At this step of purification, the two factors gave a similar dose-response curve, showed a remarkable resistance to the heat treatment and pH changes, and were not extracted by ether. Because Y-1 cells resulted in infection by retrovirus, they provide a useful model to investigate the relations between viral coded information and CSF production.
Treatment of unresectable or metastatic gallbladder cancer with single-agent gemcitabine or in combination with cisplatin
Authors: J. Gallardo, B. Rubio, O. Barajas, L. Villanueva, M. Fodor
Journal: Journal of Clinical Oncology (2005)

4211 Background: Gallbladder carcinomas (GC) are often diagnosed at an advanced/metastatic stage amenable only to palliative surgery. Published data on palliative CT for GC are quite scarce and frequently, erroneously mixed with others biliary tract cancers, their median survival is only around 8 to 12 weeks. Results of chemotherapy for advanced GC are extremely poor with traditional treatment based on 5-FU. Methods: Since 1997 we have been studying the effect of gemcitabine. We retrospectively reviewed data of two different protocol treatments, we made possible. In both trials pts had similar characteristics, they all pts had measurable locally or metastatic GC with histological or cytological proof, no prior chemotherapy or radiotherapy. The main endpoint was RR and secondary endpoints were treatment toxicity and overall survival. We reviewed pts data and outcomes. In first trial 26 pts with advanced GC were treated with GEM 1000 mg/m2 i.v. for 30 minutes weekly for 3 weeks out of every 4 until disease progression and/or toxicity. In second cohort, 44 pts received Gem 1200 mg/m2 and Cis 35 mg/m2 on d1and 8, every 21d for a total of 6 courses. RR was evaluated by abdominal CT scan. Pts were treated on an outpatient basis. Results: Twenty-five pts and 42 pts were, evaluated for response. There were 0/4 CRs and 9/16 PRs for gem vs gem + cispl. All pts were evaluated for toxicity. Four and 1 died due to disease progression, one pt. died due to renal toxicity in the arm gem +cispl. In one pt occurred hepatotoxicity grade 4 in arm gem alone. The main grade 3 hematology toxicities included thrombocytopenia (0% vs 2%), neutropenia (3.8% vs 23%) and anemia (3.8% vs 14%) in the group gem vs gem + cispl. Median survival time was 8.7 mos. vs 7 mos. for the entire population, 14.1 mos. vs 9 mos. for responders, and 6.1 mos. vs. 5 mos. for non-responders. Conclusions: GEM is active against advanced, unresectable recurrent and/or metastatic GC with a good tolerability. The low toxicity profile of GEM should be considered when a treatment choice is to be made for a patient with advanced GC. GEM combined cisplatin, resulting in an increased frequency and severity of side effects and not improved rates responses in comparison with gem alone No significant financial relationships to disclose.
Low frequency of RAS and absence of FLT3-ITD gene mutations in patients with Myelodysplastic Syndromes in India: AIIMS experience
Authors: R. Chaubey, S. Sazawal, M. Mahapatra, R. Saxena
Journal: Journal of Clinical Oncology (2009)

e22231 Background: Chromosomal abnormalities and molecular detection has potential importance for diagnosis and prognosis of MDS, although the mechanisms underlying the development of MDS and their progressive evolution to AML are still largely unknown. Since, no studies have been reported from India on the prevalence of N-RAS, K- RAS point mutation in codon 12 and FLT3-ITD mutations in patients with MDS, we undertook this study. Methods: DNA and RNA were extracted from bone marrow /peripheral blood. Using RT-PCR the patients were screened for length mutations in FLT3 gene. PCR-RFLP and nested PCR-RFLP were used for the detection of point mutation in codon 12 of N-RAS and K-RAS. Results: A total of 53 patients (median age 39 yrs, range 9–78yrs; M: F 2:1; median TLC-3.9×10 9 /l, range 0.8–116 ×10 9 /l Median platelet count- 87 ×10 9 /l, range 1–349 ×10 9 /l, Median hemoglobin -6.8 g/dl, range 2.7- 16.1 g/dl, were studied. One out of 53 patients (2%) was found positive for N-RAS and four patients were positive for K-RAS (8%) mutation. FLT3-ITD mutation was studied in 47 patients; all the patients were found negative. The mean observation of all the patients was 30 months and the median overall survival was 28 months. Nine patients died during follow up. The presence of N-RAS codon 12 mutation was associated with the poor survival. FLT3-ITD mutation was not observed in any of our cases, which is in contrast to 3% reported from the West. Conclusions: Thus, it appears that the RAS and FLT3 mutations are uncommon in MDS patients in India. No significant financial relationships to disclose.
A pharmacokinetic model for predicting ANC nadir following amonafide treatment
Authors: C. K. Grieshaber, R. Dubon, J. Paterson, M. Drouin, A. Ajami
Journal: Journal of Clinical Oncology (2005)

2065 Background: Amonafide malate (Xanafide, Xan) is currently under study in AIPC as an individualized therapy based on the rate of Xan conversion to its N-acetyl metabolite by NAT-2. The current analysis was designed to develop a minimal PK model, to define PK guided parameters of drug/metabolite exposure and to test correlation with post-treatment ANC decline from baseline. Methods: Plasma concentrations of Xan and metabolite from a reference cohort of 64 patients (32m, 30f) were fitted to a biexponential model. Analysis was performed with the entire data set and then with reduced sets consisting of 2 or 4 samples. Relative fractional exposure (A rFE & NA rFE) and relative exposure (A rE & NA rE) were also determined for each analyte (rFE = A or NA AUC divided by the sum of both A & NA AUC); rE= rFE x Dose (in mMols)). To test correlations between PK derived parameters and ANC decline, two additional data sets were used; a female cohort (n=23) treated for MBC and a male cohort (N=11) treated for AIPC. The derived AUC, rFE, and rE values were analyzed by multilinear regression with the ANC decline as the response variable. Results: The PK parameters derived from the 2 and 4 point models were significantly correlated to their counterparts in the entire data set model. On AUC determinations, the accuracy was 92% and 98%. In females, the most significant correlated value with ANC nadir was NA rE with R2 = 0.78 (p<0.05). In men, the most significant correlated value with ANC nadir was A rE with R2 = 0.88 (p<0.05). Addition of individual AUCs for both drug species in a trivariate model increased the predictive correlation to an adjusted R2 = 0.97 (p<0.0025) for females and to an adjusted R2 = 0.95 (p<0.0025) for men. Conclusions: Minimal sampling models for Xan are valid alternatives to full sampling. Drug exposure at the start of therapy, as defined by the rE variable introduced here, is predictive of subsequent ANC decline, although the differences between female and male cohorts and the effects of different dosing protocols remains to be elucidated. The 2 point model allows an early prediction of ANC nadir and has the potential to allow in-cycle drug safety management. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Xanthus Life Sciences
Monitoring Early CMV-Specific CD8+ T-Cell Responses After Allogeneic Stem Cell Transplantation By Pentamer and Streptamer Staining
Authors: Lorea Beloki, Miriam Ciaurriz, Natalia Ramirez, Amaya Zabalza, Cristina Mansilla, Eva Bandres, Mercedes Rodriguez Calvillo, Eduardo Olavarría
Journal: Blood (2013)
Phase I study of MORAb-003, a humanized anti-folate receptor-alpha monoclonal antibody, in platinum resistant ovarian cancer
Authors: J. A. Konner, S. Ahmed, S. Gerst, N. Vander Els, S. Pezzuli, P. Sabbatini, M. Hensley, J. Dupont, W. Tew, C. Aghajanian
Journal: Journal of Clinical Oncology (2006)

5027 Background: Folate receptor alpha (FRA) is over-expressed in the majority of epithelial ovarian cancers (EOC) but largely absent from normal tissue. MORAb-003 (M3) is a humanized monoclonal antibody (MAb) to FRA. Binding of M3 to FRA can prevent phosphorylation of substrates specific for the Lyn kinase; suppress proliferation of cells over-expressing FRA; mediate FRA-positive tumor cell killing via antibody-dependent cellular and complement-dependent mechanisms; and suppress tumor growth in vivo of FRA-expressing tumors in rodent xenograft models. Toxicology studies in non-human primates found no evidence of toxicity with M3 at supra-pharmacological doses. This open-label, multiple-infusion, first-in-human, dose-escalation trial evaluates the safety, pharmacokinetics (PK), and antitumor activity of M3 in patients with platinum-resistant EOC. Methods: Sequential cohorts of patients receive four weekly infusions at escalating dose levels of M3, from 12.5 mg/m 2 to 100 mg/m 2 . Human anti-human antibody (HAHA) and PK analyses are performed. Eligible patients have EOC that relapsed &lt; 6 months after platinum-based therapy, acceptable organ function, Karnofsky Performance Status ≥ 70%, and measurable disease by GOG-RECIST criteria. Patients undergo pulmonary function testing (PFT) at baseline, and at end of study. Results: To date, 7 women have been treated with M3: 3 at the 12.5 mg/m 2 dose, 3 at 25 mg/m 2 , and 1 at 37.5 mg/m 2 . Median age was 60. Neither dose limiting toxicity nor HAHA has been observed. Grade 1 rash occurred in 1 patient. Grade 1/2 fever following drug administration occurred in 2 patients. Grade 2 FEV1 decrease was observed in a patient with likely pulmonary lymphangitic metastasis. One subject at 25 mg/m 2 had radiographically stable disease. At low doses, the PK analysis demonstrated the half-life to be shorter than anticipated based on animal studies, possibly due to tumor binding. Radiolableled imaging studies are underway to determine the distribution of M3. Conclusions: The FRA-specific MAb MORAb-003 appears to be well tolerated in patients with EOC. Enrollment continues and updated results will be presented. No significant financial relationships to disclose.
Sleep disorders in patients on continuous ambulatory peritoneal dialysis.
Authors: E Stepanski, M Faber, F Zorick, R Basner, T Roth
Journal: Journal of the American Society of Nephrology (1995)

Sleep complaints, habits, and medical history were surveyed in 81 patients chronically receiving continuous ambulatory peritoneal dialysis. Seventy-three percent of the sample reported insomnia, and 52% reported unintentional napping during the day. Behavioral factors (such as caffeine or alcohol use) or the severity of concurrent medical disease did not account for the sleep problems. Eighteen of these patients subsequently underwent polysomnography and objective measurement of daytime sleepiness. Clinically significant sleep apnea syndrome was present in 11. The presence of sleep apnea was associated with increased levels of psychological distress and daytime sleepiness. Periodic leg movements during sleep were also frequently observed but had minimal effect on sleep quality. Implications of these findings for clinical practice are discussed.
Clearance of monoclonal antibody (mAb) CP-675,206 by therapeutic plasma exchange (TPE) or plasmapheresis
Authors: A. Sharma, P. Bumerts, J. Gomez-Navarro, D. Pavlov, A. Ribas
Journal: Journal of Clinical Oncology (2007)

13515 Background: CP-675,206 is a fully human, cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blocking mAb with immune stimulating properties under development for the treatment of metastatic melanoma. The pharmacokinetics of CP-675,206 is similar to endogenous IgG, with a long plasma half-life (22 days). We explored the use of TPE in two patients (pts) receiving CP-675,206, postulating that TPE could be used to remove mAb in cases where toxicities are thought to result from persistence of mAb in circulation. Methods: For both pts, five TPEs were performed over 7 days using a Cobe Spectra blood cell separator (TPE daily x 3, 2 days rest, and TPE daily x 2). One plasma volume was processed per TPE and replaced with a 60%/40% albumin/saline solution. Plasma CP-675,206 concentration was measured at baseline and after the 3rd and 5th TPE. Results: Patient 1 was a 62 year-old with metastatic melanoma who received 8 monthly doses of CP-675,206 (10 mg/kg). Six days after the last dose, the pt was found to have elevated ALT and bilirubin and detectable anti- smooth muscle and anti-microsomal antibodies. Based on a suspicion of therapy-related autoimmune hepatitis, the pt underwent TPE. Plasma CP-675,206 concentration declined by 96% following the 5th TPE, and ALT and bilirubin normalized over the 4 weeks following TPE with no other evidence of clinical hepatitis. Patient 2 was a 78 year-old with in-transit melanoma who received 3 monthly doses of CP-675,206 (10 mg/kg) and was responding to therapy. Two weeks after the last dose the pt developed diffuse bilateral arthralgias. The pt was diagnosed with rheumatoid factor-negative rheumatoid arthritis, presumably related to therapy with CP-675,206, and underwent TPE. Pre- and post-TPE plasma CP-675,206 concentrations are pending. The arthralgias persisted, and the pt subsequently received oral methotrexate with slow improvement in symptoms over the next 6 months. Conclusions: TPE is highly effective for reducing the plasma concentration of CP-675,206 and may be useful to avert the progression of drug-related adverse events. Clinical benefit from TPE may vary depending on the interval from dosing and may be limited by slow reversibility of T-cell immunostimulation. [Table: see text]