tbuckley/cabot-search huggingface dataset:
Insulin Resistance Predicts Cognitive Decline: An 11-Year Follow-up of a Nationally Representative Adult Population Sample
Authors: Laura L. Ekblad, Juha O. Rinne, Pauli Puukka, Hanna Laine, Satu Ahtiluoto, Raimo Sulkava, Matti Viitanen, Antti Jula
Journal: Diabetes Care (2017)

The aim of this study was to examine whether insulin resistance, assessed by HOMA of insulin resistance (HOMA-IR), is an independent predictor of cognitive decline.The roles of HOMA-IR, fasting insulin and glucose, HbA1c, and hs-CRP as predictors of cognitive performance and its change were evaluated in the Finnish nationwide, population-based Health 2000 Health Examination Survey and its 11-year follow-up, the Health 2011 study (n = 3,695, mean age at baseline 49.3 years, 55.5% women). Categorical verbal fluency, word-list learning, and word-list delayed recall were used as measures of cognitive function. Multivariate linear regression analysis was performed and adjusted for previously reported risk factors for cognitive decline.Higher baseline HOMA-IR and fasting insulin levels were independent predictors of poorer verbal fluency performance (P = 0.0002 for both) and of a greater decline in verbal fluency during the follow-up time (P = 0.004 for both). Baseline HOMA-IR and insulin did not predict word-list learning or word-list delayed recall scores. There were no interactions between HOMA-IR and apolipoprotein E ε4 (APOEε4) genotype, hs-CRP, or type 2 diabetes on the cognitive tests. Fasting glucose and hs-CRP levels at baseline were not associated with cognitive functioning.Our results show that higher serum fasting insulin and insulin resistance predict poorer verbal fluency and a steeper decline in verbal fluency during 11 years in a representative sample of an adult population. Prevention and treatment of insulin resistance might help reduce cognitive decline later in life.
Intravascular donor monocytes play a central role in lung transplant ischaemia-reperfusion injury
Authors: Kate Colette Tatham, Kieran Patrick O'Dea, Rosalba Romano, Hannah Elizabeth Donaldson, Kenji Wakabayashi, Brijesh Vipin Patel, Louit Thakuria, Andre Rudiger Simon, Padmini Sarathchandra, Nandor Marczin, Masao Takata
Journal: Thorax (2017)

Rationale Primary graft dysfunction in lung transplant recipients derives from the initial, largely leukocyte-dependent, ischaemia-reperfusion injury. Intravascular lung-marginated monocytes have been shown to play key roles in experimental acute lung injury, but their contribution to lung ischaemia-reperfusion injury post transplantation is unknown. Objective To define the role of donor intravascular monocytes in lung transplant-related acute lung injury and primary graft dysfunction. Methods Isolated perfused C57BL/6 murine lungs were subjected to warm ischaemia (2 hours) and reperfusion (2 hours) under normoxic conditions. Monocyte retention, activation phenotype and the effects of their depletion by intravenous clodronate-liposome treatment on lung inflammation and injury were determined. In human donor lung transplant samples, the presence and activation phenotype of monocytic cells (low side scatter, 27E10+, CD14+, HLA-DR+, CCR2+) were evaluated by flow cytometry and compared with post-implantation lung function. Results In mouse lungs following ischaemia-reperfusion, substantial numbers of lung-marginated monocytes remained within the pulmonary microvasculature, with reduced L-selectin and increased CD86 expression indicating their activation. Monocyte depletion resulted in reductions in lung wet:dry ratios, bronchoalveolar lavage fluid protein, and perfusate levels of RAGE, MIP-2 and KC, while monocyte repletion resulted in a partial restoration of the injury. In human lungs, correlations were observed between pre-implantation donor monocyte numbers/their CD86 and TREM-1 expression and post-implantation lung dysfunction at 48 and 72 hours. Conclusions These results indicate that lung-marginated intravascular monocytes are retained as a ‘passenger’ leukocyte population during lung transplantation, and play a key role in the development of transplant-associated ischaemia-reperfusion injury.
A Synthetic Analogue of the Indigo Jeans Dye Tryptanthrin, NT1, Induces Apoptosis in Vitro, Ex Vivo and in Vivo in CD95-Dependent Manner in Pediatric Leukemia and Lymphoma Cells Sensitizing Malignant Cells to Cytostatic Drugs Via Downregulation of XIAP
Authors: Patrick Jesse, Herbert Riepl, Thomas Wieder, Guenter Henze, Aram Prokop
Journal: Blood (2008)
Phase II trial evaluating a 12-week regimen of interdigitating FOLFOX chemotherapy plus pelvic chemoradiation for the simultaneous treatment of primary and metastatic rectal cancer.
Authors: Michael Michael, Joseph James McKendrick, Mathias Bressel, Trevor Leong, Prasad Cooray, Alexander Graham Heriot, Malcolme Steel, Sarat Chander, Bev McClure, Sam Ngan
Journal: Journal of Clinical Oncology (2012)

3629 Background: Current chemotherapy regimens used during chemoradiation (CRT) are adequate for radiosensitization but suboptimal for systemic control. The aim of this study was to assess tolerability, and local/systemic benefits of new regimen delivering intensive chemotherapy and radical radiotherapy in an interdigitating manner. Methods: Phase II prospective study for patients (pts) with untreated simultaneous symptomatic primary and metastatic rectal cancer. The treatment regimen: 12 weeks long. FOLFOX chemotherapy (oxaliplatin 100mg/m2, leucovorin 200mg/m2, 5-FU 400mg/m2 bolus, all day 1, and 5FU continuous infusion [CI] 2.4 g/m2/46 hours) was given in weeks 1, 6, and 11. Pelvic CRT: 25.2 Gy in 3 weeks, 1.8 Gy/fr, with concurrent oxaliplatin 85mg/m2 day 1 and 5-FU CI 200mg/m2/day given in weeks 3-5, and 8-10. Pts received, in 12 weeks, 3 courses of FOLFOX and pelvic radiation 50.4 Gy with concurrent oxaliplatin/5-FU. All pt were staged with CT, MRI and FDG-PET before and post-treatment. Results: 26 pts treated. The mean age was 61 years, 69% male. Rectal primary MRI stage was T2 4%, T3 81% and T4 15%. Liver and lung metastases were present in 81%, and 35% of pts, respectively: 38% of patients had more than one site of metastatic disease. 24 pts (92%) completed the 12-week treatment regimen. All pts received the planned radiation dose. 65% of pts received the planned number of oxaliplatin courses with 88% of pts receiving at least 75% of the protocol oxaliplatin dose. In this 12-week period, grade 3 toxicities were neutropenia 23%, diarrhoea 15%, and radiation perineal skin reaction 12%. Only grade 4 toxicity was neutropenia: 15%. PET metabolic response (CR+PR) rate for rectal primary was 96%. Overall PET metabolic response rate for metastatic disease was 60% (CR rate 16%). Conclusions: It is thus feasible to deliver intensive chemotherapy and radical radiotherapy in an interdigitating manner to treat both primary and metastatic rectal cancer simultaneously. High completion and response rates are encouraging. This regimen is the subject of a current phase II neoadjuvant trial for resectable rectal cancer (TROG 09.01).
Clinical predictive models for chemotherapy-induced febrile neutropenia in breast cancer patients: A validation study.
Authors: Kai Chen, Xiaolan Zhang, Liling Zhu, Fengxi Su
Journal: Journal of Clinical Oncology (2014)

1055 Background: This study aims to validate a predictive model (Jenkin’s model) for febrile neutropenia (FN) during chemotherapy in early-stage breast cancer patients. Methods: A total of 428 breast cancer patients who received neoadjuvant/adjuvant chemotherapy (Anthracycline and/or taxane based) without any prophylactic use of colony-stimulating factor were included. Pretreatment absolute neutrophil counts (ANC) and absolute lymphocyte counts (ALC) were used by the Jenkin’s model to assess the risk of FN. In addition, we modified the threshold of Jenkin’s model and generated Model-A and B. We also developed Model-C by incorporating the absolute monocyte count (AMC) as a predictor into Model-A. The rates of FN in the 1st chemotherapy cycle were calculated. A valid model should be able to identify high-risk subgroup of patients with FN rate >20%. Results: Jenkin’s model (Predicted as high-risk when ANC≦3.1*10^9/L;ALC≦1.5*10^9/L) did not identify any patient with a significantly high risk (>20%) of FN in our population, even if we used different thresholds in Model-A(ANC≦4.4*10^9/L;ALC≦2.1*10^9/L) or B(ANC≦3.8*10^9/L;ALC≦1.8*10^9/L) . However, with AMC added as an additional predictor, Model-C(ANC≦4.4*10^9/L;ALC≦2.1*10^9/L; AMC≦0.28*10^9/L) identified a subgroup of patients with a significantly high risk of FN (23.1%). Conclusions: In our population, the threshold of Jenkin's model should be changed and the AMC should be incorporated as a predictor, to have improved predictive ability. Model Group ANC (×10^9/L) ALC (×10^9/L) AMC (×10^9/L) Total N FN rate N(%) P Jenkin's I ≦5.2 ≦2.4 n/a 155 15(9.7) NS II ≦5.2 ≦2.4 n/a 93 9(9.7) III ≦4.4 ≦2.1 n/a 72 14(19.4) IV ≦3.8 ≦1.8 n/a 69 13(18.8) V (high-risk) ≦3.1 ≦1.5 n/a 39 4(10.3) Model-A Low-risk (group I and II) ≦4.1 ≦2.1 n/a 248 24(9.7) <0.05 High-risk (group III, IV, and V) ≦4.4 ≦2.1 n/a 180 31(17.2) Model-B Low-risk (group I, II, and III) ≦3.8 ≦1.8 n/a 320 38(11.9) NS High-risk (group IV and V) ≦3.8 ≦1.8 n/a 108 17(15.7) Model-C Low-risk Not fulfil the criteria of high-risk group 337 34(10.1) <0.01 High-risk ≦4.4 ≦2.1 ≦0.28 91 21(23.1)
Phase II trial of irofulven (IROF) and CPT-11 in metastatic colorectal cancer (MCRC) patients (pts) failing oxaliplatin (OXA)/5FU based chemotherapy
Authors: C. Vallejos, M. Varela, E. Roca, J. Martinez, E. Van Cutsem, J. L. Misset, C. Louvet, E. Cvitkovic, J. MacDonald, E. Wasserman
Journal: Journal of Clinical Oncology (2004)

3713 Background: Topoisomerase I inhibitors (SN38) and IROF (MGI 114), a new illudin derivative, exhibit synergistic activity in preclinical studies. A phase I trial explored IROF followed by CPT-11 on the same day every 2 weeks (Debono, AACR-NCI-EORTC, 2001), with limiting toxicities of neutropenia (N) and thrombocytopenia (T). Preliminary evidence of tolerability and activity prompted us to explore IROF/CPT-11 in pretreated MCRC pts, while inverting the sequence of administration (CPT-11 then IROF). We report the cohort of pts failing OXA/5FU therapy. Methods: This phase II multicenter study was designed to evaluate the activity (RECIST) of CPT-11 125 mg/m2 followed by IROF 0.40 mg/kg (30 min infusion), day 1 and 15 every 28 days (cohort 1). The incidence of severe myelosuppression, primarily grade 3 or 4 N, including febrile neutropenia (FN), led to a reduction in IROF to 0.30 mg/kg in subsequent pts (cohort 2), leading to an improvement in treatment safety. Steroids and 5-HT3 antagonists were given as prophylactic therapy for emesis. 500 ml fluid hydration was recommended before and/or after each IROF infusion. Results: Between Jul 2002 and Dec 2003, 26 pts (cohort 1: 4 pts, cohort 2: 22 pts; 7 centers) received 62 cycles (cy) with 10 pts ongoing. Median age 64 years (41–74), male/female: 11/15, PS 0/1: 19/7, colon/rectum: 20/6, median number metastatic sites: 2 (1–3), second/third line 54%/46%, all pts OXA/5FU resistant, 50% refractory (PD as best response to prior OXA/5FU). Efficacy: 18 pts evaluable (8 too early): 3 PR (1 unconfirmed), 5 SD (3 with sustained >50% marker decrease); 44% tumor control rate (PR+SD) with a median duration of 5.3 months (range 3.3–9.9). Safety: 15 pts and 38 cy evaluable from cohort 2. The main NCI-CTC grade 3–4 toxicities were (% pts / % cy): N: 67/55, FN: 13/5, T: 20/11, diarrhea: 20/8. Conclusion: IROF 0.30 mg/kg and CPT-11 125 mg/m2 every 2 weeks is feasible with preliminary evidence of activity in CRC pts who progressed during or after OXA/5FU. A cohort of CPT-11/ 5FU pretreated pts is also accruing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CAC, Kremlin-Bicetre, France; MGI Pharma Inc, Bloomington, MN MGI Pharma, Inc. MGI Pharma, Inc.
Continuous quality management for complex blood cancers in Sarah Cannon Blood Cancer Network.
Authors: Suman Kambhampati, Therese Dodd, Cheryl Sheridan, Charles F. LeMaistre
Journal: Journal of Clinical Oncology (2017)

59 Background: Sarah Cannon Blood Cancer Network (SCBCN) is a network of seven markets dedicated to provide high quality and safe care to patients with complex blood cancers. Continuous quality management (QM) and improving patient safety are critical components to the mission of SCBCN. Methods: Four SCBCN disease-specific working groups have developed evidence-based pathways for complex blood cancers. However, there are currently no SCBCN clinical quality of care metrics to monitor value-based care. To address this unmet need, the SCBCN leadership endorsed a team-based approach to measure QM for complex blood cancers, using basic clinical performance metrics proposed by the American Society of Hematology, the American Medical Association-convened Physician Consortium for Performance Improvement, the U.S. Department of Health and Human Services Agency for Healthcare Research and Quality National Quality Measures Clearinghouse, and Centers for Medicare &amp; Medicaid Services. Results: Between 2012 and September 2015, 1221 new adult cases of Acute Myeloid Leukemia (AML) and 253 new adult cases of Myelodysplastic Syndrome (MDS), respectively, were reported within the SCBCN. Based on the volume of cases and to measure QM in AML and MDS, quality indicators were selected based on meaningfulness to program goals and feasibility of data capture, leading to development of quality metrics dashboard for AML and MDS in SCBCN. Also, keeping in mind the changing paradigm of personalized care using new and emerging therapies in AML and MDS, exploratory quality metrics are also proposed to evaluate access to new trials as QM of AML and MDS in SCBCN. Conclusions: SCBCN is a wide network of community hospitals with expertise in managing complex blood cancers. As proof of concept study, the AML and MDS dashboard was developed and chosen as a model for continuous QM for complex blood cancers. This dashboard will initially be tested to evaluate QM at two SCBCN sites to facilitate the overarching programmatic goal of continuous QM for all AML/MDS and other blood cancers presenting within the SCBCN.
Abstract P062: Loss of Plasma Membrane Integrity Occurs in 2 Stages During Early Myocardial Ischemia/Reperfusion Injury
Authors: Ming Zhang, Pradeepkumar Charlagorla, Junying Liu, Javi Balroop, Eun Hee Ko, Danielle Green, Oghomwen Shaka-Idusuyi, Monaliben Patel, Arlan Richardson, Julie Rushbrook
Journal: Circulation Research (2011)

Myocardial ischemia is an acute health emergency. Reperfusion, critical for salvaging ischemic tissues, contributes to the acute tissue damage known as ischemia-reperfusion (I/R) injury. While therapeutic approaches aimed at reducing I/R injury have been promising in preclinical studies, clinical studies have been inconclusive, suggesting an inadequate knowledge of the mechanisms underlying I/R injury and their time-frame. In the current work, myocardial necrosis was evaluated in a murine I/R model using a propidium iodide-based fluorescent method that evaluated loss of plasma membrane integrity (LPMI) during the first 24 hours of reperfusion and permitted histological analysis of other pathological events on adjacent sections. LPMI was found to develop in two stages in WT animals: a significant increase occurred between 0 and 1 hour of reperfusion and was maintained through 6 hours; an additional increase was apparent at 24 hours. Complement C3 deposition lagged LPMI by 2 hours and C3 −/− mice were protected from second-stage LPMI but not first-stage. Transgenic mice overexpressing the anti-oxidant enzymes superoxide dismutase or catalase were protected from first stage LPMI but not second stage. The results provide support for the development of therapeutic approaches that are directed at the early stages of reperfusion and take into account the two phases of ischemia-related myocardial damage, designing strategies targeting the reactive oxygen species of first stage and the complement-mediated events of second stage.
Final report of phase I/II study of PR104, a hypoxia-activated pro-drug, in relapsed/refractory acute leukemia.
Authors: Cecilia Ysabel Arana Yi, Gautam Borthakur, Peter F. Thall, Andrew L. Coveler, Farhad Ravandi, Elias Jabbour, Stefan Faderl, Deborah A. Thomas, Jorge E. Cortes, Tapan M. Kadia, Steven Mitchell Kornblau, Naval Guastad Daver, Naveen Pemmaraju, Hoang Q. Nguyen, William R. Wilson, Teresa J. Melink, John Gutheil, Hagop M. Kantarjian, Elihu Estey, Marina Konopleva
Journal: Journal of Clinical Oncology (2013)

7074 Background: Hypoxia is prevalent in leukemia bone marrow (BM) microenvironment, suggesting its role as a therapeutic target. PR104 is a pro-drug activated by hypoxia-dependent reductases and by hypoxia-independent aldo-ketoreductase 1C3 (AKR1C3). Methods: Patients (pts) with relapsed/refractory AML (n=40) after 1 or 2 prior treatments; or ALL (n=10) after any number of prior treatments received PR104 as a 1-hr i.v. infusion q 2 weeks. Biomarkers for hypoxia and AKR1C3 were assessed. Results: Pts received PR104 at doses of 1.1 (n=6), 1.6 (n=1), 2.2 (n=1), 3 (n=20) and 4 gm/m2 (n=22) for a median of 1 cycle (range, 1 – 3 cycles). 17 pts had PR104 doses assigned using an adaptive method using toxicity-response trade-offs, patient age, and prior remission duration, and 33 pts were assigned doses by investigators for cohort expansion at 3 and 4gm/m 2 . Most common treatment-related grade 3/4 adverse events included myelosupression (anemia 44%, neutropenia 56%, thrombocytopenia 52%), febrile neutropenia (22%), infection (22%) and enterocolitis (14%). 3 (14%) PR104-related deaths occurred at the 4 gm/m 2 dose level: hepatic failure (n=1), enterocolitis (n=1) and pneumonia (n=1). 49 of 50 pts were evaluable for response. No CRs were seen at doses &lt; 3 gm/m 2 . 10 of 31 AML pts (32%, (0.19, 0.5)% CI) and 2 of 10 ALL pts (20%, (0.06,0.51)% CI) at 3 or 4 gm/m 2 had responses (CR, n=1; CRp, n=5; morphologic leukemia-free state (MLFS), n=6). In AML pts with 1 prior treatment, responses were seen in 7 of 21 pts (CR, n=1; CRp, n=3; MLFS, n=3). Median overall survival of all pts treated at 3 and 4 gm/m 2 was 72 days, and of pts who achieved CR/CRp/MLFS 143 days. 3 pts with AML (MLFS, n=2; CRp, n=1) and 1 with B-ALL (CRp, n=1) underwent allogeneic stem cell transplantation. Biomarker studies showed hypoxia in the BM; and levels of AKR1C3 in leukemic blasts did not correlate with responses (Benito et al., ASH 2012). Conclusions: PR104 administered at doses 3 to 4x the solid tumor MTD had moderate toxicity (most commonly myelosuppression and enterocolitis) in pts with relapsed/refractory AML and ALL. Evidence of activity supports continued evaluation of hypoxia-activated cytotoxins in acute leukemias. Clinical trial information: NCT01037556.
The Impact of Continuous Glucose Monitoring on Markers of Quality of Life in Adults With Type 1 Diabetes: Further Findings From the DIAMOND Randomized Clinical Trial
Authors: William H. Polonsky, Danielle Hessler, Katrina J. Ruedy, Roy W. Beck
Journal: Diabetes Care (2017)

OBJECTIVE Continuous glucose monitoring (CGM) improves glycemic control, but data are inconclusive about its influence on quality of life (QOL). We investigated the impact of 24 weeks of CGM use on QOL in adults with type 1 diabetes (T1D) who use multiple daily insulin injections. RESEARCH DESIGN AND METHODS DIAMOND (Multiple Daily Injections and Continuous Glucose Monitoring in Diabetes) was a prospective randomized trial that assessed CGM versus self-monitoring of blood glucose (SMBG) only in 158 adults with poorly controlled T1D. At baseline and study end, participants completed QOL measures that assessed overall well-being (WHO-5), health status (EQ-5D-5L), diabetes distress (DDS), hypoglycemic fear (worry subscale of the HFS-II), and hypoglycemic confidence (HCS). At study end, CGM participants completed the CGM Satisfaction Survey. Linear regression analyses compared treatment group changes in QOL outcomes over time. Associations between CGM satisfaction and change in QOL outcomes and in glycemic control indices were assessed. RESULTS The CGM group demonstrated a greater increase in hypoglycemic confidence (P = 0.01) and a greater decrease in diabetes distress (P = 0.01) than the SMBG group. No significant group differences in well-being, health status, or hypoglycemic fear were observed. CGM satisfaction was not significantly associated with glycemic changes but was associated with reductions in diabetes distress (P &amp;lt; 0.001) and hypoglycemic fear (P = 0.02) and increases in hypoglycemic confidence (P &amp;lt; 0.001) and well-being (P = 0.01). CONCLUSIONS CGM contributes to significant improvement in diabetes-specific QOL (i.e., diabetes distress, hypoglycemic confidence) in adults with T1D, but not with QOL measures not specific to diabetes (i.e., well-being, health status). CGM satisfaction was associated with most of the QOL outcomes but not with glycemic outcomes.
Pharmacokinetics (PK) and pharmacodynamics (PD) of epoetin alfa in cancer patients with anemia receiving cyclic chemotherapy
Authors: B. Dannemann, M. Wacholtz, H. Lau, W. Cheung
Journal: Journal of Clinical Oncology (2004)

8203 Background: PK and PD profiles of epoetin alfa for healthy subjects after subcutaneous (SC) administration of epoetin alfa 150 IU/kg 3 times weekly (TIW) or 40,000 IU weekly (QW) have been previously described. This is our first report of PK/PD profiles in anemic cancer patients (pts) receiving chemotherapy (CT). Methods: This was a randomized, open-label, parallel-design, 6-week, multicenter study to determine PK/PD profiles of epoetin alfa 150 IU/kg TIW and 40,000 IU QW in cancer pts. Measurements began when cancer pts received their first dose of epoetin alfa and were scheduled to receive at least 1 cytotoxic CT agent (Day 1). All subjects had a PK profile during Week 1 and an optional profile again at Week 3 (cancer pts not scheduled to receive chemotherapy between Days 15 and 21). Any transfusions were recorded. Results: 29 of 36 cancer pts were evaluable for PK. The 40,000 IU QW regimen had a higher Cmax, higher exposure to epoetin alfa/erythropoietin in serum (in terms of AUC0–7days), and a lower clearance (CL/F) than the 150 IU/kg TIW regimen. Despite differences in concentration–time profiles and overall exposure to epoetin alfa/erythropoietin between the 2 treatment groups, responses as indicated by profiles of changes in PD parameters and their AUC (% reticulocytes, hemoglobin [Hb], and total RBCs) were similar. The AUC of change in Hb in cancer pts over 6 weeks is shown in the table. Conclusions: Epoetin alfa was safe and well tolerated in this study. Despite differences in PK profiles between the 2 regimens, this study indicates that the PD responses to epoetin alfa were similar. Thus, total systemic exposure is not the sole determinant of the PD effects of epoetin alfa. Other factors, such as pattern of exposure or duration of exposure above a critical threshold level, may also contribute to PD effects. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration J & J Pharmaceutical Research & Development, LLC J & J Pharmaceutical Research & Development, LLC; Johnson & Johnson J & J Pharmaceutical Research & Development, LLC; Johnson & Johnson