tbuckley/cabot-search huggingface dataset:
Primary mediastinal B-cell lymphoma treated with intensive chemotherapy and rituximab compared to CHOP—15 year experience from a single institution
Authors: A. P. Dąbrowska-Iwanicka, J. Romejko-Jarosiśska, B. Ostrowska, K. Domaśska-Czyż, A. Borawska, N. Goekbuget, D. Hoelzer, J. A. Walewski
Journal: Journal of Clinical Oncology (2008)

19506 Background: Optimal therapy of primary mediastinal B-cell lymphoma (PMBCL), a subtype of diffuse large B-cell lymphoma, is a matter of debate. Methods: This is a retrospective analysis involving all PMBCL patients (n=68) treated at the Institute in Warsaw between 1992 and 2006. Initially, 42 pts (62%) were treated with CHOP, 2 pts with MACOP-B, 4 pts with CODOX-M/IVAC regimen (GM Mead et al. Ann Oncol 2002; 13: 1264) - all without rituximab. Starting 2004, all pts (n=20, 29%) were entered into the German Multicenter Study Group for ALL (GMALL) protocol (D Hoelzer et al. Blood 2007; 110: 159a, Abstr. 518) including methotrexate 1.5 g/m2, cytarabine 2 g/m2, and rituximab 375 mg/m2 before each chemotherapy cycle. Of 26 pts treated with intensive (non- CHOP) regimens, 20 (77%) received rituximab. Radiotherapy was given to all responders (87%) at the end of treatment. Results: Median age (range): 28(16–49), female/male: 1.8, LDH>N: 78%, IPI 0–2: 74%. Median (range) follow-up: 48 (8–150) months. 5-year OS and PFS (95% C.I.) of all pts was 61% (49%, 74%) and 52% (40%, 64%), respectively. Type of chemotherapy was significant prognostic factor for survival. For intensive (mostly GMALL) protocols vs. CHOP, OS was 91% vs 50% (p=0.0055) and PFS - 83% vs 33% (p=0.0001), respectively or probability of survival was 85% higher (Cox proportional hazards regression). Other significant factors were performance status and LDH. Relapse/progression occured within 18 months from the start of treatment in 17% and 67% of pts on intensified regimens and CHOP, respectively. There was no treatment related mortality. Conclusion: Intensive chemotherapy including high-dose antimetabolites and rituximab compared to CHOP in PMBCL pts results in significant improvement of survival related to reduced risk of disease progression/relapse. The role of rituximab alone may not be implicated from these data, although survival advantage is higher than expected from the randomized study (M Pfreundschuh et al. Lancet Oncology 2006; 7: 379). No significant financial relationships to disclose.
Abstract 867: The Longevity Factor Sirt1 Exacerbates LV Dysfunction and Energy Depletion in Response to Pressure Overload
Authors: Ralph Alcendor, Chull Hong, Peiyong Zhai, Shumin Gao, Junichi Sadoshima
Journal: Circulation (2007)

Sirt1, a class III histone deacetylase, extends the lifespan of many organisms. Longevity mechanisms usually confer stress resistance to organisms, and accumulation of stress resistance leads to lifespan extension. We have shown previously that Sirt1 is upregulated by stress up to 10 fold in the heart, and heart specific overexpression (up to 7.5 fold) of Sirt1 in mice not only suppresses histological/biochemical markers of aging, but also induces resistance to oxidative stress in the heart. We examined whether Sirt1 is protective against another pathologically relevant stimulus, namely pressure overload. Cardiac specific Sirt1 transgenic mice (Tg-Sirt1) from line #40, the line which has been shown to be protected against aging and oxidative stress, were subjected to transverse aortic constriction (TAC). Unexpectedly, at 10 days, the left ventricular (LV) ejection fraction (EF) in Tg-Sirt1 was significantly reduced (46 vs 71%, p&lt;0.01), the LV end diastolic dimension was significantly increased (4.1 vs 3.4 mm, p&lt;0.05), and the pressure gradient was reduced (92 vs 57 mmHg, p&lt;0.05), possibly due to reduced LV contractility, in Tg-Sirt1 compared with non-transgenic (NTg) controls. At 4 weeks, LV weight/body weight (BW) (6.4 vs 4.7, p&lt;0.05) and lung weight/BW (18.8 vs 7.0, p&lt;0.05) were significantly increased in Tg-Sirt1, LV +dP/dt was significantly reduced (4617 vs 7513, p&lt;0.05), and the LV end diastolic pressure was significantly elevated (13.6 vs 1.4 mmHg, p&lt;0.05) in Tg-Sirt1 compared with NTg. These results suggest that Tg-Sirt1 mice develop more severe LV dysfunction than NTg in response to TAC. Tg-Sirt1 mice exhibited significantly less apoptosis (−50%, p&lt;0.05) than NTg however, despite the development of LV dysfunction, suggesting that the LV dysfunction may be caused by apoptosis-independent mechanisms. The myocardial ATP content in Tg-Sirt1 was significantly less (−41%, p&lt;0.05) than that in NTg after TAC. These results suggest that the cardioprotective effect of Sirt1 depends on the type of stress: although modest expression of Sirt1 confers resistance to aging and oxidative stress, it exacerbates heart failure in response to TAC through apoptosis-independent mechanisms possibly involving energy depletion.
Abstract 12425: Sirt2 Mediated-Deacetylation Regulates Cellular Iron Homeostasis
Authors: Xiaoyan Yang, Athanassios Vassilopoulos, Seong-Hoon Park, David Gius, Hossein Ardehali
Journal: Circulation (2014)

Background: Sirtuins (SIRTs) are NAD+-dependent deacetylases and critical regulators of energy metabolism and response to oxidative stress in the heart. Iron is essential for these processes but is toxic when present in excess. Thus, SIRTs may regulate iron levels to ensure adequate supply of this element for their biological functions. SIRT2 is among the least characterized SIRTs and is mainly present in the cytoplasm. We hypothesized that SIRT2 might be required for cellular iron homeostasis. Methods and Results: Iron content was significantly lower in SIRT2-/- mouse embryonic fibroblasts (MEFs) compared to SIRT2+/+ MEFs (non-heme iron: 0.073 vs. 0.060 nmol/μg protein, p=0.02). Gene expression of ferroportin-1 (FPN1), the major cellular iron exporter, was significantly increased in SIRT2-/- MEFs. Similarly, silencing SIRT2 in HepG2 cells decreased cellular iron levels and increased FPN1 expression, indicating that enhanced FPN1 in SIRT2 knockout or knockdown condition increases iron export and reduces cellular iron. To investigate the underlying mechanism, we focused our studies on nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a known regulator of FPN1. Our results demonstrated that Nrf2 is upregulated and translocates into the nucleus in SIRT2-/- MEFs and knocking down Nrf2 in SIRT2-/- MEFs reverses iron deficiency and FPN1 expression. Furthermore, Nrf2 is acetylated by P300/CBP and can be deacetylated by SIRT2. Finally, to confirm the role of SIRT2 in iron regulation, cellular heme and non-heme iron in the heart (major iron-consuming organ) and liver (major iron-storage organ) were measured in wild type (WT) and SIRT2-/- mice. Heme and non-heme iron content were significantly decreased in SIRT2-/- mouse livers compared to WT livers (heme: 2.25 vs. 1.65 nmol/mg protein, p=0.002; non-heme iron: 0.073 vs. 0.064 nmol/μg protein, p=0.03). Furthermore, heme levels were also significant decreased in the heart, while non-heme iron was not significantly altered. Conclusions: Our results suggest that SIRT2 regulates cellular iron homeostasis by deacetylating NRF2 and altering iron export through FPN1.
A new measurement of residual cancer burden to predict survival after neoadjuvant chemotherapy
Authors: W. Symmans, F. Peintinger, C. Hatzis, H. Kuerer, V. Valero, B. Hennessy, M. Green, E. Singletary, G. Hortobagyi, L. Pusztai
Journal: Journal of Clinical Oncology (2006)

536 Background: The strength of association between tumor response and survival is critical for neoadjuvant chemotherapy trials. Pathologic complete response (pCR) reliably predicts survival benefit, but residual disease contains a range of pathologic responses that likely contain different prognostic groups, including near complete response and resistance. Methods: Pathologic slides and reports were reviewed from 432 patients in two completed neoadjuvant trials: 1) fluorouracil, doxorubicin and cyclophosphamide (FAC) in 189 patients, and 2) paclitaxel followed by FAC (T/FAC) in 243 patients. Paclitaxel was administered as twelve weekly (n=126) or four 3-weekly cycles (n=117). Residual cancer burden (RCB) was calculated as an index that combines pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size). We compared four RCB categories, from RCB-0 (pCR) to RCB-3 (chemoresistant), and post-treatment revised AJCC Stage (0-III) for prediction of distant relapse-free survival (DRFS) in multivariate Cox regression analyses (stratified by ER status). Results: The pCR rate was greater after T/FAC than FAC (24% vs. 16%, LR p&lt;0.05), and after weekly (vs. 3-weekly) paclitaxel in T/FAC (30% vs. 16%, LR p&lt;0.01). In patients with residual disease, RCB measurements were significantly lower after T/FAC than FAC (t-test, p&lt;0.0001), but were not different between paclitaxel schedules in T/FAC. RCB was a continuous predictor of DRFS after T/FAC (HR=1.86, 95%CI 1.51–2.30) or FAC (HR=1.67, CI 1.38–2.01) with median follow-up 5 and 8 years, respectively. The resistant category RCB-3 predicted relapse more strongly than AJCC Stage III and identified a larger group of high-risk patients ( Table ). Conclusions: RCB is a new continuous measure of pathologic response that is defined from routine pathologic materials, represents the distribution of residual disease, is a significant predictor of DRFS, and defines chemotherapy resistance more effectively than revised AJCC Stage. [Table: see text] [Table: see text]
Utility of four tumor markers, alone and in combination, for detection of hepatocellular carcinoma: AFP, AFP-L3, DCP, and Cystatin
Authors: H. Li, A. Sferruzza, K. Z. Qu, N. H. Afdhal, M. Lai, J. S. Radcliff, R. A. Bender
Journal: Journal of Clinical Oncology (2008)

4585 Background: α-Fetoprotein (AFP) is the most widely used biochemical marker for detection of hepatocellular cancer (HCC), but is also often elevated in non-malignant liver disease. Three other HCC markers have been identified: AFP-L3, des-gamma- carboxyprothrombin (DCP), and cystatin C. We explored the utility of using these markers, alone and in combination, for HCC detection. Method: All 4 markers were measured with commercial assays in serum samples from 60 patients with histologically confirmed HCC and 138 healthy adults of various ethnicities. Results: No positive results were obtained from the 138 healthy adults. As a single marker, AFP had the highest sensitivity for detecting HCC, followed by DCP, cystatin, and AFP-L3% (Table). The combination of AFP, DCP and cystatin C identified 70% of HCC cases with tumor size of <3 cm, and identified 92.5% of cases with tumors of >3 cm. When all cases were combined, the 3 marker panel identified 51 (85.0%) cases. Conclusion: These data suggest that the combination of AFP, DCP, and cystatin C yielded greater sensitivity for detecting HCC than 1) each marker alone, and 2) other combinations of these 4 markers. Further studies are underway to evaluate the utility of these combinations in distinguishing HCC from non-malignant hepatic disease. Table. Sensitivity of AFP, AFP-L3%, DCP, and Cystatin C as Markers of HCC in Patients with Histologically Confirmed HCC (N=60) Marker(s) Small tumor size (< 3cm, N=20) Large tumor size (> 3cm, N=40) Undefined tumor size (N=60) HCC Patients Sensitivity, % HCC Patients Sensitivity, % HCC Patients Sensitivity, % AFP+ 5 30.0 29 72.5 34.0 56.7 DCP+ 4 20.0 27 67.5 31.0 51.7 Cystatin C+ 9 45.0 21 55.0 30.0 50.0 AFP-L3+ 0 0.0 22 52.5 22.0 36.7 DCP+/AFP+ 9 45.0 35 87.5 44.0 73.3 DCP+/Cystatin C+ 10 50.0 34 85.0 44.0 58.3 AFP+/Cystatin C+ 13 65.0 35 87.5 48.0 80.0 DCP+/AFP+/ Cystatin C+ 14 70.0 37 92.5 51.0 85.0 DCP+/AFP+/AFP-L3+/ Cystatin C+ 14 70.0 37 92.5 51.0 85.0 No significant financial relationships to disclose.
Abstract 12287: Atherosclerotic Plaque Development Differs between Vascular Sites with Unique Phenotypic and Gene Expression Profiles
Authors: Robert S Fenning, Eliot G Peyster, Shreya Kangovi, Damir Hamamdzic, Colin H Macphee, Robert L Wilensky
Journal: Circulation (2012)

It is unclear whether the same inflammatory pathways play a role in coronary and peripheral atherosclerosis. Using a diabetic (DM), hypercholesterolemic (HC) porcine model, we hypothesized that cor...
Retrospective analysis of 105 cases of uterine sarcoma
Authors: A. Yoney, S. Eskici, B. Eren, A. Salman, M. Unsal
Journal: Journal of Clinical Oncology (2007)

16079 Background: Currently there is no randomized study based or widely accepted therapeutic modality in uterine sarcomas which are rare tumors forming a heterogeneous group in respect to their pathologic classification. Methods: In our trial, 105 pts. with uterine sarcoma who were referred to our clinic between years 1995–2003 have been retrospectively researched to evaluate the results in this tumor group. 43.8% had Leiomyosarcoma (LMS), 28.6% had Endometrial Stromal Sarcoma (ESS) and 27.6% had a Malign Mullarian Mixed Tumor (MMMT) while the distribution according to the histological subgroups were found to be 58.8% and 41.2% in low + middle grade tumors combined and in high grade tumors respectively. 76.2% had a Total Abdominal Hysterectomy + Bilateral Salphingooverectomy (TAH+BSO), 18.1% had a Total Abdominal Hysterectomy + Bilateral Salphingooverectomy + Lymphadenectomy (TAH+BSO+LND) and 5.7% had a suboptimal surgery as a surgical procedure. 38.1% of the pts. had Radiotherapy (RT), 18.1% had Chemotherapy (CT) and 12.4% had Chemo-radiotherapy (CT+RT) in addition to surgery. Results: The median age of the whole group is 51 (24–87). 55% of our pts. are under 50 years old and 68.5% had an “organ limited disease” ( stages I-II combined). The distant metastases rate is 30% and the local recurrence is 16.2%. All the local recurrences and 90% of the distant metastases have occurred within the first two years. The disease free survival rates at 3 and 5 years are 54.46% and 49.88% ; while the overall survival rates at 3 and 5 years are 54.63% and 51.09% all respectively. The stage is the most important factor effecting on the O.S and 5- year O.S rate is 68.43% in Stage I disease. Conclusions: The aggressive tumor progression pattern and the poor prognosis of uterine sarcomas require adjuvant therapies. The merit of current therapeutic options are still on debate since none of them has proved any specific effects. Planning further multi-center retrospective studies with high number of pts., a more clear description of the prognostic factors and thus the determination of the most appropriate therapeutic option is definitely needed. No significant financial relationships to disclose.
Abstract 13324: Sex Differences in Presentation, Management, and Outcomes of Acute Coronary Syndrome in India: Results from the Detection and Management of Coronary Heart Disease (DEMAT) Registry
Authors: Mark Huffman
Journal: Circulation (2010)

Introduction: Prior research in high-income countries suggests that women with acute coronary syndromes (ACS) are managed less aggressively than men, even after adjustment for age and co-morbiditie...
Treatment of a cancer patient by an adoptive cell therapy protocol combining DC vaccination with cbl-b ex vivo silencing
Authors: Monika Sachet, Guenther Lametschwandtner, Hubert Hayden, Michaela Hassler, Hans Loibner, Pierre Triozzi, Josef Friedl
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts The E3 ubiquitin ligase cbl-b has been identified as a key intracellular checkpoint limiting T and NK cell activation. Concordantly, blockade of cbl-b function by genetic deletion strongly enhances anti-tumor immune responses, thereby validating cbl-b as target for immunotherapy.
Superantigen-based immunotherapy: a phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer.
Authors: B J Giantonio, R K Alpaugh, J Schultz, C McAleer, D W Newton, B Shannon, Y Guedez, M Kotb, L Vitek, R Persson, P O Gunnarsson, T Kalland, M Dohlsten, B Persson, L M Weiner
Journal: Journal of Clinical Oncology (1997)

To establish the maximum-tolerated dose (MTD) and define the toxicities of a single-dose infusion of PNU-214565, a recombinant Escherichia coli-derived fusion protein of Staphylococcal enterotoxin A (SEA) and the Fab-fragment of the C242 monoclonal antibody in patients with advanced colorectal and pancreatic carcinomas. To investigate the capability of PNU-214565 to induce a superantigen (SAg) response resulting in cytokine production and tumor regression.Twenty-one patients (age range, 39 to 76 years; median, 64; 12 men, nine women; 18 colorectal, three pancreatic cancers) were treated with a single 3-hour infusion of PNU-214565, with doses ranging from 0.01 to 1.5 ng/kg. All patients had prior chemotherapy and a good performance status Eastern Cooperative Oncology Group [ECOG] performance status [PS] = 0 [n = 10]; PS = 1 [n = 11]), 10 had prior radiation, and 18 had prior surgery.Fever and hypotension were the most common toxicities. Fever of any grade occurred in 16 of 21 patients (76%): four of 21 (19%) with grade 2 and two of 21 (9.5%) with grade 3. Hypotension of any grade occurred in 13 of 21 (62%): four of 21 with grade 2 and one of 21 (5%) with grade 3. Interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF alpha) induction correlated with toxicity. In the two patients with grade 3 fever, peak IL-2 and TNF alpha levels were 2.9 IU/mL and 165 pg/mL, and 8.3 IU/mL and 245 pg/mL, respectively. Transient, > or = 50% decreases in circulating monocytes were observed in 17 of 21 patients as early as 0.5 hours (median time, 2 hours) from the start of infusion. Decreases (mean 33%) in circulating lymphocytes were observed in seven of 21 patients. All three patients with grade 3 toxicity were treated at the 0.5-ng/kg dose. The significance of baseline anti-SEA, human antimouse antibody (HAMA), CA242-soluble antigen levels, and T-cell receptor variable beta region (TCR V beta) subsets and histocompatibility leukocyte antigen-DR (HLA-DR) genotypes was assessed as possible predictors of toxicity. All toxicities were transient and easily managed. No grade 3 toxicity occurred at the higher dose levels.PNU-214565, a SAg-based tumor targeted therapy, is safe when given as a single 3-hour infusion at doses up to 1.5 ng/kg. The MTD for a single dose was not determined. The safety of a repeated dose schedule is currently under investigation, beginning with doses determined to be safe in this trial.
Abstract 242: The Association Between Global Hemodynamics, Cerebral Oxygenation and Survival in Post--Cardiac Arrest Patients
Authors: Koen Ameloot, Cathy De Deyne, Ingrid Meex, Cornelia Genbrugge, Wilfried Mullens, Frank Jans, Mathias Dupont, Jo Dens
Journal: Circulation (2014)

Purpose: the relationship between global hemodynamics, cerebral saturation and patient survival has been poorly investigated in post-cardiac arrest patients. In analogy with sepsis, current guidelines recommend to target mean arterial pressure (MAP) above 65mmHg and SVO2 above 70%. This is unsupported by mortality or cerebral perfusion data. Therefore the aims of the present study were to explore the relationships between MAP, SVO2, cerebral oxygenation and patient survival in post-cardiac arrest patients. Methods: Prospective observational study in 82 post-cardiac arrest patients Results: During the first 24 hours after ICU admission, the mean SVO2 was 67±9% and the mean MAP 76±8mmHg. Thirty-nine patients died and 43 survived (43/82 patients, 52%) until ICU discharge. The mean SVO2 range during the first 24 hours after admission associated with maximal survival was 67-72% (OR 8.23, 95% CI [2.07; 32.68], p=0.001). The mean MAP range associated with maximal survival was 76-86 mmHg (OR 2.63, 95% CI [1.01; 6.88], p=0.04). Achievement of the currently recommended MAP above 65mmHg or SVO2 above 70% was not associated with increased survival. Multivariate regression revealed early bystander CPR and a mean SVO2 in the optimal range (OR 6.30, 95% CI [1.12; 35.5], p=0.04) as independent factors associated with increased survival. Based on more than 1625000 data points, we found a strong linear relation between SVO2 (range 40-90%) and average cerebral saturation (R2 0.86) and between MAP and average cerebral saturation for MAP’s between 40-87 mmHg (R2 0.70). The predicted optimal SVO2 (72%) and MAP (87mmHg) based on this hemodynamic model matched with the optimal SVO2 (67-72%) and MAP (76-86mmHg) associated with maximal survival. Conclusion: We found an SVO2 between 67-72 % and a MAP between 76-86 mmHg during the first 24 hours after cardiac arrest to result in optimal cerebral oxygenation while being associated with maximal survival. Prospective intervention studies to reach or maintain these targets are needed to confirm these findings.
Meta-analysis of insulin glargine and cancer risk.
Authors: P. Boyle, A. Koechlin, P. Boffetta, M. Boniol, G. Bolli, J. Rosenstock
Journal: Journal of Clinical Oncology (2011)

1584 Background: Considerable confusion entered the minds of physicians and patients when a database study reported an increased risk of cancer (of all forms) in diabetics using insulin glargine. Subsequent studies have been interpreted variously to support or contradict this hypothesis. Methods: There have been five observational studies of routinely collected national databases which have reported risk of cancer among users of insulin glargine. In addition, a meta-analysis of randomized trials of glargine, a randomized controlled trial of glargine primarily assessing retinopathy progression and a small Italian case-control study have also examined cancer risk and glargine. A meta-analysis of all these studies was undertaken using a random effects model with tests for statistical significance, publication bias and heterogeneity. Results: For the 5 database studies (Germany, Sweden, Scotland, England and Taiwan), the combined Odds Ratio (OR) for cancer among glargine users was 0.92 (95% Confidence Interval [C.I.] 0.79, 1.06). When these studies were combined with the 2 randomized trials, the odds ratio was 0.93 (95% C.I. 0.83, 1.03). When the case-control study was added to these seven studies, the odds ratio marginally changed (OR ==0.95 [95% C.I. 0.84, 1.07]). When the highest OR from the original German study was introduced, produced by erroneous dose adjustment, the worst case scenario OR was 1.04 (95% CI 0.81. 1.33). The inclusion of a phantom study with a OR of 10 and CI as in the meta-analysis estimate did not result in a positive association between glargine and cancer risk. Conclusions: Potential limitations to this meta-analysis include that the comparison group was not the same in all studies. The randomized trials had several insulin comparators and the retinopathy study had NPH as the comparator. This is not likely to invalidate the findings of this analysis nor would the fact that different adjustments were made in the individual studies. The current evidence gives no support to the hypothesis that insulin glargine is associated with an increased risk of cancer as compared to other insulin therapies even when the worst-case is considered and a further study with a OR as large as 10 would not result in a statistically significant association.