tbuckley/cabot-search huggingface dataset:
Results of a phase I trial of the proteasome inhibitor carfilzomib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL).
Authors: Jennifer Ann Woyach, Joseph M. Flynn, Jeffrey Alan Jones, Leslie A. Andritsos, Margaret Lucas, Weihong Chase, Ying Yang, David M Lucas, Ellen Sass, Sharon Waymer, Yonghua Ling, Yao Jiang, Mitch A. Phelps, John C. Byrd
Journal: Journal of Clinical Oncology (2013)

7077 Background: CLL is an incurable malignancy, and survival for patients (pts) with relapsed disease is limited. Carfilzomib (CFZ) has shown efficacy in multiple myeloma, and our group has shown significant in vitro activity in primary CLL cells. Therefore, we have undertaken a phase I trial of this agent in CLL. Methods: This is a single institution phase I trial of CFZ in pts with relapsed or refractory CLL. Primary endpoints were to determine maximal tolerated dose (MTD) and describe toxicity. Pts with CLL relapsed after at least one therapy were enrolled using a 3x3 design. CFZ was administered on the standard myeloma schedule. The first two doses were administered at 20 mg/m 2 with remainder given at doses starting at 27 mg/m 2 for dose level 1 with escalation to 56 mg/m 2 . Results: 17 pts received at least 1 dose of CFZ. 12 pts completed at least 1 cycle of therapy, with the remaining 5 experiencing PD during cycle 1. The MTD was not reached, with 3 pts accrued to each dose level to the maximal dose tested without dose limiting toxicity. Most adverse events (AE) were grade (G) 1 or 2. G3/4 AE were quickly reversible and included G3 neutropenia (4 pts), G4 neutropenia (2), G3 febrile neutropenia (1), and G3 thrombocytopenia (3). G1/2 toxicities observed in ≥ 20% of pts included anemia (10), thrombocytopenia (7), and hypocalcemia (8). Median number of cycles was 3, with 9 pts achieving stable disease after 2 cycles. Of 3 pts enrolled at maximal dose level, 2 remain on therapy after 5 and 7 months, with 1 achieving a clinical partial response. Of 5 evaluable pts, at least 50% proteasome inhibition was seen in all at 1 hour, with minimal recovery at 24 hours. PK was best characterized by a two-compartment model. Maximum plasma concentrations across all dose levels ranged from 0.81 to 8.1 uM. Across the evaluated dose range, area under the curve increased in an apparent dose-proportional manner. Conclusions: Despite relatively limited efficacy in this study, CFZ has acceptable toxicity in CLL, with no MTD identified up to 56 mg/m 2 . This suggests that CFZ may be better studied in CLL using a different schedule or in combination with other active agents. Clinical trial information: NCT01212380.
<i>TP53</i> mutation and BUBR1 overexpression characterize the DNA aneuploidy of gastric cancer.
Authors: Eiji Oki, Koji Ando, Satoshi Ida, Yasue Kimura, Hiroshi Saeki, Masaru Morita, Tetsuya Kusumoto, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2013)

e15039 Background: Gastric cancers show a high frequency of DNA aneuploidy, which is a phenotype of chromosomal instability. Gastric carcinomas with aneuploidy have been shown to have higher proliferative activity and metastatic or invasive potential than diploid tumors, which leads to a poor prognosis. It has been suggested that an abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. In this study, we focused on the TP53 gene and BUBR1 protein in gastric cancer to elucidate their relation with the features of DNA aneuploidy. Methods: The study included 178 unselected Japanese patients with primary gastric cancer who underwent gastrectomy between 1994 and 2006 at Kyushu University Hospital, Fukuoka. DNA ploidy status, TP53 gene status, and BUBR1 expression were analyzed. Nuclear DNA content was measured using laser scanning cytometry. The TP53 gene was amplified from exon 5 to exon 9, including exon-intron junctions, by PCR using p53 primers (Nippon Gene, Tokyo, Japan) and Ex Taq DNA polymerase (TaKaRa Bio Inc., Tokyo, Japan). Results: DNA aneuploidy was identified in 108 cases, and TP53 gene mutation was seen in 28 of 143 cases. Both DNA aneuploidy and TP53-mutated tumors correlated with high age and differentiated type tumors. BUBR1 aberrant expression, investigated using immunohistochemistry, was seen in 89 cases, and it correlated with malignant features such as deep invasion, and lymph node and liver metastases. DNA aneuploidy was significantly related to high BUBR1 expression (P = 0.0055), and a more significant relation was found between DNA aneuploidy and TP53mutation (P = 0.0032). Tumors with high BUBR1 expression showed poor prognosis. Conclusions: DNA aneuploidy is associated with the carcinogenesis and prognosis of gastric cancer. Therefore, there has been considerable interest in targeting cell cycle checkpoints, particularly in emerging and alternative anticancer strategies. The development of selection markers to aid in the selection of appropriate therapies for patients will be the primary focus of future research. TP53 mutation and BUBR1 expression may provide clinically useful diagnostic, therapeutic, and prognostic information.
Prognostic value of HER2 on breast cancer survival.
Authors: Nora Katzorke, Brigitte Kathrin Rack, Lothar Haeberle, Julia Katharina Neugebauer, Carola Anna Melcher, Carsten Hagenbeck, Helmut Forstbauer, Hans Ulrich Ulmer, Ulrike Soeling, Rolf Kreienberg, Tanja N. Fehm, Andreas Schneeweiss, Matthias W. Beckmann, Peter A. Fasching, Wolfgang Janni
Journal: Journal of Clinical Oncology (2013)

640 Background: HER2 overexpression and overamplification have originally been described as a prognostic factor indicating a poor prognosis. However the highly effective anti-HER2 treatment was approved in 2006 after several large randomized trials showing that the prognosis in HER2 positive women could be improved. Few data has been generated comparing HER2 positive patients treated with trastuzumab with comparable HER2 negative patients. Aim of this analysis was to investigate the prognostic relevance of HER2 status in a post trastuzumab approval study. Methods: The SUCCESS trial is an open-label, multicenter, randomized controlled, phase III study comparing FEC-docetaxel (Doc) vs. FEC-Doc-gemcitabine (Doc-G) regime and 2 vs. 5 year treatment with zoledronat in 3754 patients with primary breast cancer (N+ or high risk). All patients were treated per protocol with trastuzumab, if HER2 status was shown to be positive by local pathology. Furthermore HER2 status was a stratification factor. The prognostic value of HER2 status with respect to overall survival (OS) and progression-free survival (PFS), disregarding the above stated treatment arms, was studied with Cox proportional hazards regression models in univariate as well as multivariate analyses adjusted for age, BMI, tumor size, nodal status, grading, estrogen receptor status and progesterone receptor status. Results: 2628 patients were included into this analysis. Median Follow up time was 4.8 years, 221 deaths and 412 recurrences were recorded until data base closure. HER2 was not a prognostic factor in the univariate analysis (OS: HR= 0.86, 95% CI: 0.63 to 1.19; PFS: HR = 0.95, 95% CI: 0.76 to 1.19). In the multivariate analysis all of the above stated prognostic factors were of prognostic relevance. HER2 was of prognostic relevance with a HR of 0.67 (OS, 95% CI: 0.48 to 0.92) and 0.79 (PFS, 95% CI: 0.62 to 0.99) indicating that patients with a positive HER2 status had a better prognosis. Conclusions: Patients treated with trastuzumab showed a more favourable prognosis compared to HER2 negative patients in this prospectively randomized trial, possibly due to the therapeutic effect of HER2-targeted treatment.
Minute Myocardial Injury as Measured by High-Sensitive Troponin T Serum Levels Predicts the Response to Intracoronary Infusion of Bone Marrow-Derived Mononuclear Cells in Patients With Stable Chronic Post-Infarction Heart Failure
Authors: Brigitte Luu, David M. Leistner, Eva Herrmann, Florian H. Seeger, Joerg Honold, Stephan Fichtlscherer, Andreas M. Zeiher, Birgit Assmus
Journal: Circulation Research (2017)

Cell-based therapies are a promising option in patients with chronic postinfarction heart failure (ischemic cardiomyopathy [ICM]). However, the responses after intracoronary infusion of autologous bone marrow-derived mononuclear cells (BMCs) are heterogeneous, which may be related to impaired cell retention in patients with ICM. Ischemic injury is associated with upregulation of prototypical chemoattractant cytokines mediating retention and homing of circulating cells. The development of ultrasensitive tests to measure high-sensitive troponin T (hs-TnT) serum levels revealed the presence of ongoing minute myocardial injury even in patients with stable ICM.To test the hypothesis that serum levels of hs-TnT correlate with cell retention and determine the response to intracoronary BMC application in patients with ICM.About 157 patients with stable ICM and no substantial impairment of kidney function received intracoronary BMC administration. Immediately prior to cell application, hs-TnT levels to measure myocardial injury and NT-proBNP levels as marker of left ventricular wall stress were determined. Patients with elevated hs-TnT were older and had more severe heart failure. Importantly, only patients with elevated baseline hs-TnT≥15.19 pg/mL (upper tertile) demonstrated a significant (P=0.04) reduction in NT-proBNP serum levels (-250 [-1465; 33] pg/mL; relative reduction -24%) 4 months after BMC administration, whereas NT-proBNP levels remained unchanged in patients in the 2 lower hs-TnT tertiles. The absolute decrease in NT-proBNP at 4 months was inversely correlated with baseline hs-TnT (r=-0.27, P=0.001). Finally, retention of intracoronarily infused, 111Indium-labeled cells within the heart was closely associated with hs-TnT levels in patients with chronic ischemic heart failure (P=0.0008, n=10, triple measurements).The extent of ongoing myocardial injury as measured by serum levels of hs-TnT predicts the reduction of NT-proBNP serum levels at 4 months after intracoronary BMC administration in patients with ICM, suggesting that the beneficial effects of BMC application on LV remodeling and wall stress are confined to patients with ongoing minute myocardial injury.URL: www.clinicaltrials.gov. Unique identifier: NCT00962364.
Effect of a mixed type Lauren's classification on agressiveness and lymph node metastasis in early gastric cancer.
Authors: Jeunghui Pyo, Hyuk Lee, In Seub Shin, Tae Jun Kim, Yang Won Min, Jun Haeng Lee, Jae J. Kim, Byung-Hoon Min
Journal: Journal of Clinical Oncology (2017)

28 Background: The clinicopathological features of mixed type (MT) early gastric cancer (EGC) according to Lauren’s classification remain uninvestigated. This study aimed to clarify the clinicopathological features of MT EGC, particularly in relation to lymph node metastasis (LNM) and long-term survival. Methods: This study included 5,309 patients who underwent gastrectomy for EGC. The clinicopathological features, LNM, and long-term outcomes of patients with MT carcinomas were compared to those with intestinal type (IT) and diffuse type (DT) cancers. Furthermore, we evaluated the predictors of LNM in each Lauren classification subgroup. Results: Patients with MT carcinomas were more likely to have larger tumors, submucosal invasion, lymphovascular invasion (LVI), and LNM compared to those with IT or DT carcinomas. Multivariate logistic regression analysis revealed that Lauren’s classification was a significant predictor of LNM ( P &lt; 0.001). The significant predictors of LNM in MT carcinomas were female sex, greater tumor size, presence of submucosal invasion, and LVI. However, the overall survival of patients with MT carcinoma was not significantly different from that of patients with IT or DT carcinomas ( P= 0.104). Conclusions: The presence of MT EGC carries a higher risk of LNM compared to IT or DT carcinomas. Therefore, MT carcinomas should be managed with gastrectomy that includes lymph node dissection instead of endoscopic resection.
A proposed definition of microbiota transplantation for regulatory purposes
Authors: Diane E. Hoffmann, Francis B. Palumbo, Jacques Ravel, Virginia Rowthorn, Erik von Rosenvinge
Journal: Gut Microbes (2017)

The advent of fecal microbiota transplantation (FMT) and the prospect of other types of microbiota transplants (MT), e.g. vaginal, skin, oral and nasal, are challenging regulatory agencies. Although FDA is regulating FMT (as a biologic), there is currently no widely accepted or agreed upon scientific or legal definition of FMT or MT. The authors report on discussions regarding a definition of MT that took place among a working group of stakeholders convened under a National Institutes for Allergies and Infectious Diseases grant to address the regulation of MT. In arriving at a definition, the group considered the 1) nature of the material being transplanted; 2) degree of manipulation of the transferred materials prior to implantation; 3) ability to characterize the transplanted product using external techniques; and 4) origin of the stool product (single vs multiple donors).
Cervix cancer regression measured using weekly MR imaging during fractionated radiotherapy: Radiobiologic modeling and correlation with tumor hypoxia
Authors: K. S. Lim, P. Chan, R. Dinniwell, A. Fyles, M. Haider, Y. Cho, D. Jaffray, L. Manchul, W. Levin, R. P. Hill, M. Milosevic
Journal: Journal of Clinical Oncology (2007)

5547 Background: To utilize cervix cancer volumetry, as measured with MR imaging during definitive chemoirradiation (RT-CT), to derive radiobiological parameters using a mathematical model of tumor regression, and compare them to pre-treatment measurements of tumor hypoxia. Methods: Twenty-eight patients receiving RT-CT for cervix cancer underwent weekly magnetic resonance imaging (MRI) scans. Tumor volume was assessed on each of these scans and the rate of regression plotted. A mathematical model of tumor regression was formulated to simulate the relationship between three independent radiobiological parameters, 1) surviving fraction of cells after 2 Gy, SF 2 , 2) the cell clearance constant T c , and 3) the cellular proliferation constant T p . Non-linear regression analysis was applied to fit the MR-derived tumor volumes to the mathematical model and to derive SF 2 and T c values for each patient. These were compared to pre-treatment hypoxia measurements. Results: Initial tumor volume ranged between 8 and 209 cm 3 . Relative reduction in volume during treatment was 0.02 to 0.79. Simulations using representative values of the independent biologic variables derived from the literature showed SF 2 and T c to strongly influence the shape of the volume response curves. Non-linear regression analysis yielded a median SF 2 of 0.71 and median T c of 10 days. Radioresistant tumors (SF 2 &gt;0.71) were significantly more hypoxic at diagnosis (p=0.02). Conclusion: Based on serial MR imaging during treatment, a marked variation in cervix tumor regression is seen from patient to patient. Through our radiobiological model, tumors can be classified as radioresistant or radiosensitive, which correlates with hypoxia [Table: see text] No significant financial relationships to disclose.
Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study
Authors: Claudia K. Suemoto, Renata E. L. Ferretti-Rebustini, Roberta D. Rodriguez, Renata E. P. Leite, Luciana Soterio, Sonia M. D. Brucki, Raphael R. Spera, Tarcila M. Cippiciani, Jose M. Farfel, Alexandre Chiavegatto Filho, Michel Satya Naslavsky, Mayana Zatz, Carlos A. Pasqualucci, Wilson Jacob-Filho, Ricardo Nitrini, Lea T. Grinberg
Journal: PLoS Medicine (2017)

Background Clinicopathological studies are important in determining the brain lesions underlying dementia. Although almost 60% of individuals with dementia live in developing countries, few clinicopathological studies focus on these individuals. We investigated the frequency of neurodegenerative and vascular-related neuropathological lesions in 1,092 Brazilian admixed older adults, their correlation with cognitive and neuropsychiatric symptoms, and the accuracy of dementia subtype diagnosis. Methods and findings In this cross-sectional study, we describe clinical and neuropathological variables related to cognitive impairment in 1,092 participants (mean age = 74 y, 49% male, 69% white, and mean education = 4 y). Cognitive function was investigated using the Clinical Dementia Rating (CDR) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE); neuropsychiatric symptoms were evaluated using the Neuropsychiatric Inventory (NPI). Associations between neuropathological lesions and cognitive impairment were investigated using ordinal logistic regression. We developed a neuropathological comorbidity (NPC) score and compared it to CDR, IQCODE, and NPI scores. We also described and compared the frequency of neuropathological diagnosis to clinical diagnosis of dementia subtype. Forty-four percent of the sample met criteria for neuropathological diagnosis. Among these participants, 50% had neuropathological diagnoses of Alzheimer disease (AD), and 35% of vascular dementia (VaD). Neurofibrillary tangles (NFTs), hippocampal sclerosis, lacunar infarcts, hyaline atherosclerosis, siderocalcinosis, and Lewy body disease were independently associated with cognitive impairment. Higher NPC scores were associated with worse scores in the CDR sum of boxes (β = 1.33, 95% CI 1.20–1.46), IQCODE (β = 0.14, 95% CI 0.13–0.16), and NPI (β = 1.74, 95% CI = 1.33–2.16). Compared to neuropathological diagnoses, clinical diagnosis had high sensitivity to AD and high specificity to dementia with Lewy body/Parkinson dementia. The major limitation of our study is the lack of clinical follow-up of participants during life. Conclusions NFT deposition, vascular lesions, and high NPC scorewere associated with cognitive impairment in a unique Brazilian sample with low education. Our results confirm the high prevalence of neuropathological diagnosis in older adults and the mismatch between clinical and neuropathological diagnoses.
γδ T Cells Mediate Angiotensin II-Induced Hypertension and Vascular Injury
Authors: Antoine Caillon, Muhammad Oneeb Rehman Mian, Julio C. Fraulob-Aquino, Ku-Geng Huo, Tlili Barhoumi, Sofiane Ouerd, Peter R. Sinnaeve, Pierre Paradis, Ernesto L. Schiffrin
Journal: Circulation (2017)

Innate antigen-presenting cells and adaptive immune T cells have been implicated in the development of hypertension. However, the T-lymphocyte subsets involved in the pathophysiology of hypertension remain unclear. A small subset of innate-like T cells expressing the γδ T cell receptor (TCR) rather than the αβ TCR could play a role in the initiation of the immune response in hypertension. We aimed to determine whether angiotensin (Ang) II caused kinetic changes in γδ T cells; deficiency in γδ T cells blunted Ang II-induced hypertension, vascular injury, and T-cell activation; and γδ T cells are associated with human hypertension.Male C57BL/6 wild-type and Tcrδ-/- mice, which are devoid of γδ T cells, or wild-type mice injected IP with control isotype IgG or γδ T cell-depleting antibodies, were infused or not with Ang II for 3, 7, or 14 days. T-cell profiling was determined by flow cytometry, systolic blood pressure (SBP) by telemetry, and mesentery artery endothelial function by pressurized myography. TCR γ constant region gene expression levels and clinical data of a whole blood gene expression microarray study, including normotensive and hypertensive subjects, were used to demonstrate an association between γδ T cells and SBP.Seven- and 14-day Ang II infusion increased γδ T-cell numbers and activation in the spleen of wild-type mice (P<0.05). Fourteen days of Ang II infusion increased SBP (P<0.01) and decreased mesenteric artery endothelial function (P<0.01) in wild-type mice, both of which were abrogated in Tcrδ-/- mice (P<0.01). Anti-TCRγδ antibody-induced γδ T-cell depletion blunted Ang II-induced SBP rise and endothelial dysfunction (P<0.05), compared with isotype antibody-treated Ang II-infused mice. Ang II-induced T-cell activation in the spleen and perivascular adipose tissue was blunted in Tcrδ-/- mice (P<0.01). In humans, the association between SBP and γδ T cells was demonstrated by a multiple linear regression model integrating whole blood TCR γ constant region gene expression levels and age and sex (R2=0.12, P<1×10-6).γδ T cells mediate Ang II-induced SBP elevation, vascular injury, and T-cell activation in mice. γδ T cells might contribute to the development of hypertension in humans.
Racial differences in the impact of financial hardship on the intensity of end-of-life cancer care.
Authors: Reginald D Tucker-Seeley, Gregory Alan Abel, Holly Gwen Prigerson
Journal: Journal of Clinical Oncology (2012)

6012 Background: Research suggests that Black cancer patients have higher end-of-life (EOL) medical costs than White patients; and that Black, compared with White, families are more likely to use all or most of their savings to pay for EOL care. Although Black cancer patients receive more intense EOL care than Whites, research has yet to determine the effect of financial hardship on receipt of intensive EOL care, and whether the effect varies by the patient’s race. Methods: Coping with Cancer (CwC) is a longitudinal, multi-site cohort study of advanced cancer patients and their informal caregivers recruited from September 2002-February 2008. CwC was designed to investigate Black/White differences in EOL care. The purpose of this analysis was to determine the association between baseline financial hardship and receipt of intensive EOL care in the last week of life (CwC deceased cohort N=342), and to identify racial differences in this association. Financial hardship was defined as whether the household had to use all or most of their savings due to the family member’s illness (response =yes/no). Intensive EOL care was defined as the receipt of ventilation or resuscitation in the last week of life assessed by medical record review and patient’s caregiver. Results: Patients reporting financial hardship had higher odds of receiving intensive EOL care (OR = 2.83, CI: 1.33, 6.05). After adjusting for socio-demographic characteristics the significant association remained (OR = 2.55, CI: 1.13, 5.81). Race-stratified fully adjusted models revealed no statistically significant association between financial hardship and intensive EOL care for Whites; however, for Blacks, those reporting financial hardship had over five times higher odds of receiving intensive EOL care (OR = 5.21, CI: 1.51, 17.99) compared to those not reporting financial hardship. Conclusions: Financial hardship was associated with greater likelihood of receiving intensive EOL care. The intensity of EOL care received by White patients was insensitive to financial hardship; in contrast Black patients reporting depletion of life savings for cancer care were much more likely to die receiving intensive EOL care than their non-financially strained counterparts.