tbuckley/cabot-search huggingface dataset:
Prospective trial of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with advanced non-transitional cell (non-TCC) carcinomas of the urothelial tract
Authors: M. D. Galsky, A. Iasonos, S. Mironov, J. Scattergood, S. M. Donat, B. H. Bochner, H. W. Herr, P. Russo, M. G. Boyle, D. F. Bajorin
Journal: Journal of Clinical Oncology (2006)

4542 Background: Non-TCC’s account for 5–10% of urothelial tract tumors and are each characterized by unique demographics, risk factors, and patterns of spread. A unifying feature of these malignancies is their aggressive course and poor outcomes with standard chemotherapeutic regimens. Given the rarity of these tumors, no prospective data are available to guide management. Methods: Patients with unresectable/metastatic adenocarcinoma, squamous cell, small cell, sarcomatoid, and poorly differentiated carcinomas of the urothelial tract were eligible. Treatment consisted of: Paclitaxel 200 mg/m 2 IV on day 1, cisplatin 70 mg/m 2 IV on day 1, ifosfamide 1500 mg/m 2 IV on days 1–3 + mesna. GCSF was administered with each cycle. Treatment was recycled every 3 weeks for a maximum of 6 cycles. The primary endpoint was the response rate. Results: Twenty patients (pts) were enrolled with the following histologic types: adenocarcinoma 11/20, squamous cell carcinoma 8/20, small cell carcinoma 1/20. Pts received a median of 4 cycles (range, 1–6). The grade 3–4 toxicities included neutropenia (6/20), anemia (9/20), thrombocytopenia (4/20), confusion (1/20), seizure (1/20), neuropathy (1/20), renal insufficiency (2/20), fatigue (2/20), and hyponatremia (1/20). Thirteen of the 20 pts have died. The median survival for pts with adenocarcinoma is 24 months (95% CI 9.6–32.4) and with squamous cell carcinoma is 8.4 months (95% CI 5.3-NR). Five pts achieved durable disease-free survival (1+, 2+, 4+, 6+, and 8+ years) after ITP ± surgical consolidation. Conclusions: ITP is an active regimen in pts with advanced non-TCC’s of the urothelial tract. To our knowledge, this is the first prospective study of a chemotherapeutic regimen in this patient population. [Table: see text] [Table: see text]
Dual targeted nanocarrier for brain ischemic stroke treatment
Authors: Yue Zhao, Yan Jiang, Wei Lv, Zhongyuan Wang, Lingyan Lv, Baoyan Wang, Xin Liu, Yang Liu, Quanyin Hu, Wujin Sun, Qunwei Xu, Hongliang Xin, Zhen Gu
Journal: Journal of Controlled Release (2016)
Long-Term Effects of Evidence-Based Supported Employment on Earnings and on SSI and SSDI Participation Among Individuals With Psychiatric Disabilities
Authors: Judith A. Cook, Jane K. Burke-Miller, Emily Roessel
Journal: American Journal of Psychiatry (2016)

Objective: This study examines the long-term effects of evidence-based supported employment services on three vocational outcomes: labor force participation, earnings, and attainment of Social Security Administration (SSA) nonbeneficiary status through suspension or termination of disability cash payments due to work (NSTW). Method: Data from 449 individuals with psychiatric disabilities who participated in a multisite controlled trial of supported employment were matched to SSA data over a 13-year period (2000–2012) following supported employment services. Long-term outcomes were analyzed using random effects regression models comparing participants in the experimental and control conditions on measures of employment, earnings, and attainment of NSTW. The authors adjusted for time, age, race/ethnicity, gender, education, schizophrenia diagnosis, substance abuse history, and geographic region. Results: Overall outcomes were modest across the 13-year follow-up, with 32.9% of participants having any earned income and 13.1% ever attaining NSTW. Supported employment recipients were almost three times as likely as control subjects to be employed over 13 years (odds ratio=2.89). Although earnings were low, supported employment participants had significantly higher earnings per month than control subjects over time (parameter estimate=$23.82) and were more likely than control subjects to attain NSTW (odds ratio=12.99). The supported employment effect diminished and was completely attenuated over time. Conclusions: The study's findings indicate a small but significant vocational advantage accruing to recipients of evidence-based supported employment in the decade following service delivery, adding to the evidence on the durability of supported employment effects. Results can inform policies designed to help workers enhance economic security and reduce dependence on Social Security disability benefits.
Abstract 6171: High-dose Epoprostenol Therapy Reverses Pulmonary Hypertension by Inducing Pulmonary Artery Smooth Muscle Cell Apoptosis in Patients with Idiopathic Pulmonary Arterial Hypertension
Authors: Satoshi Akagi, Kazufumi Nakamura, Hiromi Matsubara, Satoshi Nagase, Hiroshi Morita, Kengo Kusano, Tohru Ohe
Journal: Circulation (2008)

Background: Intravenous epoprostenol has been shown to improve long-term survival in patients with idiopathic pulmonary arterial hypertension (IPAH). Although most experts believe that the appropriate dose range of epoprostenol is between 25 and 40 ng/kg/min, the optimal dose has not been determined. In the present study, we investigated the hemodynamic change induced by high-dose epoprostenol therapy in IPAH patients, and we determined by experiments the reason why high-dose epoprostenol improves hemodynamics. Methods: We evaluated hemodynamics in 16 IPAH patients (11 females and 5 males, mean epoprostenol dosage was 100.7±35.4 ng/kg/min) treated with high-dose epoprostenol. Lung tissues obtained from 2 IPAH patients and one non-PAH patient were assessed by terminal dUTP nick end-labeling (TUNEL) assays. We examined the induction of apoptosis by epoprostenol in cultured PAH-pulmonary artery smooth muscle cells (PASMCs) and non-PAH-PASMCs. To assess the apoptosis in cultured PASMCs, we performed TUNEL assay, caspase-3,-7 assays and transmission electron microscopy. We also examined the expression of survivin by immunocytochemical analysis. Results: Compared with the baseline state, there were significant reductions in mean pulmonary artery pressure (26%) and pulmonary vascular resistance (66%). Hemodynamic improvements in the present study were superior to those in previous studies. Apoptotic cells were detected in lung tissues obtained from IPAH patients treated with high-dose epoprostenol. TUNEL-positive and caspase-3,-7-active cells were observed in cultured PAH-PASMCs treated with epoprostenol at a high concentration. Condensation of chromatin along the nuclear membrane and fragmentation of the nucleus were observed by transmission electron microscopy. Epoprostenol at a high concentration significantly induced apoptosis in cultured PAH-PASMCs compared with that in non-PAH-PASMCs (7.69% versus 1.92%; P&lt;0.01). Immunocytochemical analysis revealed that epoprostenol suppressed expression of survivin in cultured PAH-PASMCs. Conclusions: The results of the present study showed that high-dose epoprostenol therapy reverses pulmonary hypertension by induction of PASMCs apoptosis.
The clinical significance of chromosome 17p deletion in chronic lymphocytic leukemia: A study of 180 consecutive patients
Authors: C. S. Tam, W. Wierda, S. M. O'Brien, S. Lerner, L. V. Abruzzo, A. Ferrajoli, H. M. Kantarjian, M. J. Keating
Journal: Journal of Clinical Oncology (2008)

7035 Background: Preliminary data indicate that the presence of chromosome 17p deletion (17p-) by fluorescent in-situ hybridization (FISH) in chronic lymphocytic leukemia (CLL) may be uniquely associated with resistance to standard therapy and dismal survival. Methods: In order to determine the significance of 17p- in CLL in a large cohort, we analyzed the clinical course and treatment outcome of 180 consecutive 17p- CLL pts managed at our center. Results: *PT CHARACTERISTICS. 56 (31%) pts were untreated (UNT), and 124 (69%) had relapsed / refractory (RR) disease. RR pts were more likely to have impaired performance status (PS) (p=0.01), Rai stage 3/4 disease (p<0.01), and elevated β2m (p=0.07). *PROGRESSION TO FIRST THERAPY. For UNT patients with asymptomatic CLL, the 18 month progression to therapy risk was 46%, with 18 pts remaining treatment-free at 7 - 47 months. The 17p- clone was lost spontaneously in 2 pts on follow-up. *RESPONSE TO INITIAL THERAPY. Six UNT pts received rituximab, with 4 (67%) objective responses (OR) and 2 (33%) complete clinical responses (CCR). Twenty-nine UNT pts received fludarabine & rituximab therapy, with 22 (76%) OR and 14 (48%) CCR. All CCR pts tested by FISH showed elimination of their 17p- clone. *RESPONSE TO SALVAGE THERAPY. Results by treatment categories were: rituximab, OR 27% & CCR 0%; alemtuzumab containing regimens, OR 50% & CCR 19%; fludarabine & rituximab therapy, OR 44% & CCR 0%; intensive chemotherapy, OR 20% & CCR 4%; investigational agents, OR 10% & CCR 0%. SURVIVAL. UNT pts had a favorable survival substantially better than that reported in previous studies (median not reached, 2 yr survival 81%), whereas RR pts had a median survival of only 14 months (p<0.0001). Among RR pts, those with a normal performance status (n=35) had a favorable 2 year survival of 78%, with no deaths between 12 and 46 months. Conclusions: The outcome of 17p- CLL is not necessarily dismal. Half of early stage pts will not require therapy at a follow-up of up to 4 years. The 17p- clone may be lost spontaneously or be eliminated by effective therapy. Rituximab containing regimens are highly effective particularly in the frontline setting. No significant financial relationships to disclose.
Association of asialo-galactosyl beta 1-3N-acetylgalactosamine on the hinge with a conformational instability of Jacalin-reactive immunoglobulin A1 in immunoglobulin A nephropathy.
Authors: Y Hiki, H Iwase, T Kokubo, A Horii, A Tanaka, J Nishikido, K Hotta, Y Kobayashi
Journal: Journal of the American Society of Nephrology (1996)

The O-glycans in Jacalin-binding immunoglobulin A1 (IgA1) were released by gas-phase hydrazinolysis and were fractionated by gel filtration and reversed-phase HPLC. Four peaks (P1 to P4) were obtained. There was a significant shift from Peak 2 (monosialylated Gal beta 1-3GalNAc) to Peak 4 (asialo-Gal beta 1-3GalNAc) in the IgA-nephropathy group compared with the negative control group (P < 0.05). One of the functions of the carbohydrate side chains is to stabilize the three-dimensional structure of the glycopeptides. In order to evaluate the stability of the Jacalin-binding IgA1 molecule, the increase in turbidity as a consequence of the increase of the aggregated IgA1 level under the condition of high temperature (63 degrees C) was observed. The increase in the turbidity was significantly higher in the IgA nephropathy group compared with the negative control group (21.7 vs. 5.9% at 150 min, P < 0.02). From a sample of IgA1 solution that had originated from a pooled normal serum, heat-tolerant (nonaggregated) and intolerant (aggregated) IgA1 molecules were separated by gel filtration. The heat-intolerant IgA1 had lower amounts of sialic acid (27.4 micrograms/mg IgA1) than the tolerant IgA1 (37.6 micrograms/mg IgA1). Further, the analysis of the O-glycans released from another IgA1 sample by the hydrazinolysis revealed that the ratio of the asialo-Gal beta 1-3GalNAc/total Gal beta 1-3GalNAc in the heat-in-tolerant IgA1 (27.2%) was increased compared with that in the heat-tolerant IgA1 (18.2%). From these results, it was suggested that unusual glycosylation on the hinge region of Jacalin-binding IgA1 induced an insufficient conformational stiffness to the hinge peptide, resulting in the aggregation of the IgA1 molecule in IgA nephropathy.
Public T cell receptors confer high-avidity CD4 responses to HIV controllers
Authors: Daniela Benati, Moran Galperin, Olivier Lambotte, Stéphanie Gras, Annick Lim, Madhura Mukhopadhyay, Alexandre Nouël, Kristy-Anne Campbell, Brigitte Lemercier, Mathieu Claireaux, Samia Hendou, Pierre Lechat, Pierre de Truchis, Faroudy Boufassa, Jamie Rossjohn, Jean-François Delfraissy, Fernando Arenzana-Seisdedos, Lisa A. Chakrabarti
Journal: Journal of Clinical Investigation (2016)

The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes. The most prevalent public clonotypes generated TCRs with affinities at the higher end of values reported for naturally occurring TCRs. The high-affinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for the expression of these TCRs in HIV controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctionality, thus recapitulating key features of the controller CD4 response. Transfer of a high-affinity Gag293-specific TCR also redirected CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. Together, these findings indicate that TCR clonotypes with superior functions are associated with HIV control. Amplification or transfer of such clonotypes may contribute to immunotherapeutic approaches aiming at a functional HIV cure.
Case 4-1994
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Nesli Basgoz, Anthony R. Mattia
Journal: New England Journal of Medicine (1994)

Presentation of CaseA 38-year-old man was admitted to the hospital because of bloody diarrhea, weakness, and dyspnea.There was a history of intravenous drug abuse and bisexual activity. Ten months before admission the patient was first seen at this hospital because of seizures. A computed tomographic (CT) scan of the brain (Figure 1) showed a left parietal ring-enhancing lesion, 1.0 cm, with extensive surrounding edema. Further evaluation revealed evidence of toxoplasmosis. A test for human immunodeficiency virus (HIV) antibodies was positive; the CD4+ cell count was 100 per cubic millimeter, and a tuberculin skin test with controls disclosed anergy. . . .
TCTAP C-171 Successful Decompressive Laparotomy for Abdominal Compartment Syndrome After EVAR Due to Ruptured Abdominal Aortic Aneurysm
Authors: Kiyonori Nanto, Osamu Iida, Shin Okamoto, Takayuki Ishihara, Tatsuya Shiraki, Takuya Tsujimura, Shota Okuno, Koji Yanaka, Masaaki Uematsu
Journal: Journal of the American College of Cardiology (2016)
Evaluation of a new circulating tumor cell (CTC) platform to predict response and survival in metastatic urothelial carcinoma (UC) patients receiving cabozantinib (cabo).
Authors: Andrea Borghese Apolo, Min-Jung Lee, Yusuke Tomita, Sunmin Lee, Piyush K. Agarwal, Gloria Jackson, Deneise C Francis, Elizabeth Lamping, Lauren Buford, Saori Tomita, Katherine Mackall, Howard L. Parnes, William L. Dahut, James L. Gulley, Jane B. Trepel
Journal: Journal of Clinical Oncology (2015)

e15501 Background: CTC evaluation has the potential to guide precision cancer therapy. Ideally, this analysis can be performed on the day blood is drawn, in the same institution, using compact instruments available to most laboratories and be rapidly adapted to new questions of clinical importance. Flow cytometric approaches have been restricted by the rarity of CTCs and limitations on the total number of cells that can be acquired. We report the development of a new flow cytometric CTC method and the successful application of this platform to predict response and survival in metastatic UC patients (pts) receiving cabo monotherapy. Methods: Pre-enrichment of a rare target population dramatically increases flow cytometric sensitivity. Our method integrates magnetic pre-enrichment and flow cytometric analysis in a single automated workflow. Peripheral blood (10 cc) was obtained from 29 pts with metastatic UC on a phase 2 cabo trial. Magnetic enrichment of epithelial cell adhesion molecule (EpCAM)-positive cells was performed. After enumeration of viable nucleated, CD45-negative, EpCAM-positive cells, CTCs were further characterized for expression of a cancer vaccine target (MUC1), the bone marrow homing molecule CXCR4 and the stem cell marker CD133. Results: A baseline CTC level of < 5 cells/10 ml was positively associated with response to cabo (n = 22, p = 0.035); ≥ 5 CTCs at baseline was inversely associated with progression-free (p = 0.032) and overall survival (p = 0.049). Metastases in > 2 versus ≤ 2 metastatic organ sites was associated with a higher CTC number (p = 0.0079). Heterogeneous expression of MUC1, CXCR4 and CD133 expression was detected, consistent with circulating CTC subsets. Conclusions: Using this flow cytometry-based platform, baseline CTC count predicted response and survival in pts with metastatic UC receiving cabo. This new platform places CTC analysis within the clinical investigator’s institution to promote precision medicine in drug development. The CTC assay has been modified to incorporate quantification of PD-L1 expression for an ongoing phase 1 trial of cabo + nivolumab +/- ipilimumab in this population.
TCTAP C-172 Successful Endovascular Treatment for Renal Artery Occlusion of Non-protected Side After EVAR for Juxtarenal Aortic Aneurysm Using Chimney Method
Authors: Kiyonori Nanto, Osamu Iida, Shin Okamoto, Takayuki Ishihara, Tatsuya Shiraki, Takuya Tsujimura, Shota Okuno, Koji Yanaka, Masaaki Uematsu
Journal: Journal of the American College of Cardiology (2016)
PI3K pathway and downstream signaling analysis in malignant pleural mesothelioma (MPM).
Authors: S. Cedres Perez, M. A. Montero, D. Torrejon, P. Martínez, V. Freixinos, N. Mulet-Margalef, G. Argiles, I. Nuñez, E. Lopez, L. Prudkin, M. Salcedo, N. Tallada, S. Ramon y Cajal, E. Felip
Journal: Journal of Clinical Oncology (2011)

7057 Background: MPM frequently expresses elevated AKT/mTOR activity. This study explored the expression and phosphorylation status of PTEN, PI3K/AKT and downstream signaling in MPM and its relationship with the patient's (pts) prognosis. Methods: Thirty-three consecutive MPM pts were retrospectively collected from our institution between 2002 and 2009. Paraffin-embedded biopsies were used for immunohistochemical profile quantified through the H-score method. Total and phosphorylated (p) proteins analyzed: PTEN, mTOR, MAPK, AKT, 4EBP-1, eiF4E, S6 and FOXO3a. Staining results of each antibody were compared with clinical features and the results were calculated according to the median H-score. Results: Demographics: male/female (25/8); median age 68 (range 52-83); histology epithelial/no-epithelial (22:11); neutrophil/lymphocyte ratio (NLR) >/≤5 (14/18). All patients were treated with chemotherapy. Median OS was 16.4months. Expression of PTEN, pMAPK, mTOR, 4EBP-1, p4EBP-1, eif4E, peif4E, pAKT, p-S6 and FOXO3a in MPM was found in 90%, 100%, 93.3%, 100%, 43.3%, 96.7%, 100%, 80%, 63.3% and 100% of tumors respectively. No correlations were found between proteins and age, performance status, stage and response to chemotherapy. We found a significant correlation between low pS6 protein expression and longer progression free survival (PFS: 7.88 v 5.55 months; p=0.044) and overall survival (OS: 23.36 v 5.59 months; p=0.05). A trend to better results in pts with high levels of FOXO3a (PFS 7.88 v 3.11 months, p=0.062; OS 16.36 v 4.04 months, p= 0.065) and to worse results in cases of overexpression of p4EBP-1 (PFS 7.69, OS 23.36, p>0.05) was found. In multivariate analysis histology and NLR were independent prognostic factors (HR 5.42; 95%CI, 0.44-3.15, p=0.007 and HR 3.43; 95%CI 1.22-10.79, p=0.018 respectively), but pS6 only showed a trend (HR 1.22; 95%CI 0.35-4.07; p=0.7). Conclusions: This study shows PI3K pathway and downstream proteins in MPM are frequently activated. Epithelial histology, NRL ratio and pS6 are prognostic factors. The role of pS6 assessment is worth of prospective validation in future studies on MPM.
Phase II study of lenalidomide in distantly metastatic, rapidly progressive, and radioiodine-unresponsive thyroid carcinomas: preliminary results
Authors: K. B. Ain, C. Lee, K. M. Holbrook, J. M. Dziba, K. D. Williams
Journal: Journal of Clinical Oncology (2008)

6027 Background: Rapidly-progressive, distantly metastatic thyroid cancers, unresponsive to I-131, are lethal and haven't known effective systemic therapies. Disease modifying cytostatic agents may prevent or delay disease progression. Our prior thalidomide trial in this context had 50% response rate (PR + SD), 6 months mean durability and significant toxicity (Thyroid 17:663, 2007). Our preclinical studies of related derivatives in thyroid cancer xenografts showed lenalidomide with significant activity. We are studying efficacy of lenalidomide in such patients, correlating response with angiogenesis markers. Methods: In this open-label phase II trial, 25 adult patients with distantly metastatic, I-131-unresponsive (papillary, follicular, or insular) thyroid cancers with >30% tumor volume progression documented within 12 months of entry, receive 25 mg oral lenalidomide daily. Bimonthly CT scans, thyroglobulin levels, & angiogenic markers (VEGF-A, sVEGFR-1, sVEGFR-2 & TSP-1; plasma banked for later analysis) assess responses. Pre-study rapid progression, makes SD a positive response, with responders as: SD, PR, or CR defined by total tumor volumes measured on CT scans. Attributable grade 3 toxicities evoked dose reductions to minimum of 5 mg daily in 5 mg decrements. Primary endpoint is overall response rate; secondary endpoints: toxicity, progression free survival, overall survival & tumor/angiogenic marker response. Results: From 4/06 - 12/07, 21 subjects (60% male, 30–71 yrs old; 65% papillary, 15% follicular, 20% Hürthle cell; 89% lung metastases) enrolled with 18 evaluable patients (treated >6 months) to date. 67% are responders (44% SD, 22% PR). Of 10 patients enrolled by 1/07, 6 were responders (2 PR, 4 SD) with 3 maintaining response to date (>12 months). Treatment failures were in skull base, pleural, & mediastinal tumor sites. Lenalidomide is well tolerated (grade 3 toxicities are hematological: 44% neutropenia, 22% thrombocytopenia, respond to dose reduction) with mean dosage 20 mg daily. Conclusion: Lenalidomide is a potent, well-tolerated suppressor of rapidly progressive thyroid carcinoma. Full accrual and long-term data analysis will be more informative. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene Celgene