tbuckley/cabot-search huggingface dataset:
Mechanism of Decline of Natural Killer Cell Activity in &lt;italic&gt;Corynehacterium parvum&lt;/italic&gt;-Treated Mice: Inhibition by Erythroblasts and Thy 1.2&lt;sup&gt;+&lt;/sup&gt; Lymphocytes&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: C A Savary, E Lotzová
Journal: JNCI Journal of the National Cancer Institute (1987)

Injection of (C57BL/6 X DBA/2)F1 mice with Corynebacterium parvum (CP), iv, resulted in a depression of splenic natural killer (NK) cell activity 7-17 days after treatment. This decline in reactivity was accompanied by an increase in splenic tumor-binding cells and a decrease in cytotoxic tumor-binding cells as evaluated in a single-cell assay. Morphologic analysis indicated that the increased tumor-binding cells following CP injection were due to erythroblasts binding to YAC-1 tumor cells. With the use of a double-fluorescent binding technique, nonlytic tumor-binding cells of CP-treated mice inhibited NK cytotoxicity of normal syngeneic mice by competing with effectors for binding to tumor cells. Removal of erythroblasts by hypotonic shock treatment eliminated this competition and significantly improved the lytic capacity of CP-treated mice, thus indicating that erythroblasts contributed to the suppression of NK activity in these mice. The presence of a second inhibitory mechanism in CP-treated mice was found following asialo GM1 treatment or Percoll density gradient separation of erythroblast-depleted CP splenocytes; this inhibitory population was identified as Thy 1.2+ lymphocytes. Further analysis of the mechanism of suppression indicated that it was mediated by a soluble factor. In addition to the presence of suppressor cells, CP-treated mice displayed a decrease in splenic large granular lymphocyte content, which may also contribute to their NK deficiency.
Abstract P031: Multimorbidity in Heart Failure with Preserved and Reduced Ejection Fraction: A Community Study
Authors: Alanna M Chamberlain, Yariv Gerber, Sheila M McNallan, Shannon M Dunlay, Susan A Weston, Veronique L Roger
Journal: Circulation (2014)

Background: Multimorbidity is common in heart failure (HF), yet differences in co-morbid chronic conditions by type of HF (HF with preserved vs. reduced ejection fraction (EF)) are not well documented. Methods: We determined the prevalence and distribution of 25 chronic conditions by preserved vs. reduced EF among patients with incident HF enrolled in a community study from 9/2003-6/2012. HF was validated by the Framingham criteria, and an EF ≥50% defined preserved EF. Chronic conditions were identified within the 5 years prior to HF by codes defined by Centers for Medicare &amp; Medicaid Services. Logistic regression determined associations of each comorbidity with type of HF (preserved vs. reduced EF) after adjusting for age and sex. Results: Among 668 incident HF patients (mean age 74±14, 51% male), the most common co-morbid conditions were hypertension, hyperlipidemia, and ischemic heart disease. Cataracts, rheumatoid arthritis/osteoarthritis, and anemia were also common, occurring in &gt;1/3 of HF patients. On average, patients with preserved EF had 1 extra co-morbid condition compared to those with reduced EF (6 vs. 5, respectively). After adjusting for age and sex, comorbidities associated with HF with preserved EF include hypertension, hyperlipidemia, cataracts, rheumatoid arthritis/osteoarthritis, anemia, chronic kidney disease, chronic obstructive pulmonary disease, and depression, whereas a prior myocardial infarction was associated with presenting with reduced EF (figure). The remaining co-morbid conditions (including some not shown in the figure, such as breast, colorectal, lung, endometrial, and prostate cancer, and benign prostatic hyperplasia) were not associated with type of HF. Conclusions: HF patients presenting with preserved EF have more co-morbid chronic conditions compared to those with reduced EF. This excess comorbidity burden is important to characterize and understand as it may explain differences in outcomes and healthcare utilization between HF patients with preserved and reduced EF.
Long-term outcomes after invasive breast tumor recurrence (IBTR) in women with DCIS in NSABP B-17 and B-24
Authors: I. Wapnir, J. Dignam, T. B. Julian, S. Land, E. P. Mamounas, S. Anderson, V. Fourchotte, J. Costantino, N. Wolmark
Journal: Journal of Clinical Oncology (2007)

520 Background: DCIS patients treated with lumpectomy have a very favorable outcome but are at risk for IBTR. Local control is improved by radiotherapy (RT) and adjuvant tamoxifen (TAM). Local failures, specifically invasive IBTRs (I-IBTR), may impact on long-term outcome. We present long-term outcome results from a cohort of DCIS patients from two NSABP randomized trials. Patients and Methods: A total of 2,615 women with primary DCIS from NSABP B-17 and B-24 (randomized from 1985 to 1994) were included. Median follow-up was &gt; 12 yrs. In B-17 treatment was lumpectomy (LO, 403) or lumpectomy with whole breast irradiation (LRT, 410). In B-24 patients received LRT (901) or LRT plus TAM [901]. Hazard ratio and cumulative incidence of IBTR were examined by treatment. Mortality hazard was evaluated in relation to prior IBTR. Results: IBTR was a first failure in 465 patients (243 invasive, 222 noninvasive). The 12 year cumulative incidence of all IBTRs was 32.9% for LO, 15.8% LRT, and 12.5% LRT+TAM. RT significantly reduced I-IBTR (LRT/LO hazard ratio (HR) = 0.39; 95% confidence interval (CI) =0.26 to 0.59). TAM conferred additional benefit on I-IBTR (LRT+TAM/LRT HR=0.68; 95% CI= 0.48 to 0.97). Overall mortality was low. Women with I-IBTR had a two-fold greater mortality risk relative to those without I-IBTR (HR=2.08; 95% CI = 1.46 to 2.98). The effect was greater for LRT patients (HR=3.04; 95% CI= 1.92 to 4.84) than for LO patients (HR=1.17; 95% CI = 0.57 to 2.39). For LRT+TAM patients, the effect was similar to that for LRT patients HR=1.91; 95% CI= 0.76 to 4.78). Conclusions: As in cases of I- IBTR after an invasive index tumor, the occurrence of an I-IBTR with a DCIS index tumor, particularly after RT, confers increased risk for subsequent mortality. No significant financial relationships to disclose.
Long-Term Hemodialysis. The Management of the Patient with Chronic Renal Failure.
Authors: Donald Macrae, -Constantine Hampers
Journal: Annals of Internal Medicine (1974)

In addition, it is too large and not designed to give the "core" of neuropathology taught in about 30 hours of instruction in a medical school.Moreover, it lacks teach- ing method in its approach.As descriptive neuropathology, it has great merit.This, along with its excellent reference source and its illustra- tions, should make it very useful as a reference text.
Maintenance chemotherapy in patients with non-squamous non-small cell lung cancer (NSCLC).
Authors: A. Belalcazar, E. S. Santos, J. E. Gomez, E. Lopez, L. E. Raez
Journal: Journal of Clinical Oncology (2010)

e18146 Background: Maintenance chemotherapy (MCX) has been accepted for non-squamous NSCLC patients (pts) due to overall survival advantage. However, the best MCX (by efficacy and cost) is not yet defined. Prior studies have established the role of pemetrexed (Pem) or bevacizumab (B) as MCX, however, there is not enough data about the combination or the role of single agent Pem as MCX after first-line chemotherapy (FCX) with Pem. The objectives of this study were to evaluate the efficacy of Pem single agent or in combination as MCX for NSCLC pts who have received Pem as FCX. Methods: A retrospective review from January 2008 to November 2009 focused on stage IIIB/IV NSCLC pts who have received or are planned to receive MCX with single agent Pem or in combination (as part of FCX or second line); those whose MCX is part of FCX must also have Pem as FCX. Results: We had19 pts with a median age: 60 years (range, 34-77), 10 males, 11 Hispanic, 6 White, 2 African-American, 17 had adenocarcinoma, 13 had received at least 1 cycle of MCX (median number of MCX cycles: 5; range: 1-18). All chemotherapy regimens were frontline unless otherwise specified: 16 carboplatin/Pem/B (1 pt received it as second line), 1 cisplatin/Pem/B, 1 carboplatin/Pem, and 1 Pem/B (as second line). The best response after completion of FCX (n = 13) was: 2 PR and 11 SD. Eleven of 13 pts on MCX also received Pem as FCX; 12 of these pt. received Pem/B combination and 1 Pem alone as MCX regimen. Two pts on MCX developed grade 3-4 adverse events: fatigue, anemia and thrombocytopenia. One of them died with pneumonia during Pem MCX without disease progression. After a median follow up of 7 months (range: 5-13), no progression of disease has been reported on those pts on MCX. Conclusions: Carboplatin/Pem/B is becoming a common regimen used as FCX followed by MCX Pem/B in eligible patients with non-squamous NSCLC. As MCX, Pem/B is well tolerated with most AEs being grade 1-2. A longer follow up will take place. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Lilly
Pharmacodynamic biomarkers of anti-NRP1 activity in phase I, dose-escalating clinical trials as a single agent and combined with bevacizumab.
Authors: Y. Yan, J. Li, J. Wu, Y. Xin, J. Aimi, H. Xiang, A. Bagri, R. K. Brachmann, D. S. Chen, P. Hegde
Journal: Journal of Clinical Oncology (2010)

e13551 Background: Neuropilin-1 (NRP1) is a receptor for multiple ligands including VEGF and semaphorins with broad expression on stromal cells, as well as a subset of tumor cells. In preclinical xenograft models, combining anti-NRP1 and anti-VEGF shows substantial antitumor activity. Anti-NRP1 is a fully human monoclonal antibody against NRP1 and is currently in phase I clinical trials. We explored the utility of circulating pharmacodynamic biomarkers from patient plasma in monitoring anti-NRP1 activity. Methods: Preclinically, in a dose ranging study in Cynomolgus monkeys, a panel of ninety distinct secreted plasma proteins, including VEGF, IL-8, sFlt1, sKDR, PlGF and bFGF, were evaluated as potential biomarkers of systemic inhibition of NRP1 signaling using ELISA based methods. PlGF was the only marker that demonstrated a desirable dynamic range to prompt serial evaluation as a potential biomarker of drug activity in the clinic. Results: A two-fold elevation in PlGF over baseline was observed as early as 24h in all patients from the dose of 5 mg/kg onwards in the single agent dose escalation trial. However, sustained elevation for 10 days or greater was observed at doses starting at 10 mg/kg. Increasing the dose of anti-NRP1 did not affect the magnitude of PlGF elevation but did increase the duration of elevation. The change in PlGF expression did not correlate strongly with PK parameters including AUC and Cmin. A dose dependent increase in sNRP1 was also observed in all patients, likely due to altered clearance associated with sNRP1:anti-NRP1 binding in circulation. Conclusions: Together, these data have allowed the translation of preclinical biology to humans and suggest PlGF as a biomarker of systemic pathway inhibition using anti-NRP1 in humans. PlGF levels are currently being evaluated in patients enrolled onto a phase Ib study of anti-NRP1 plus bevacizumab to determine if the combination of these two anti-angiogenesis agents will further potentiate the magnitude of PlGF elevation compared to either agent alone. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech
Outcome of poor prognostic phenotype non-Hodgkin lymphoma treatment among HIV-positive patients compared with HIV-negative counterparts in the HAART era: Experience from Hurlingham Oncology Clinic, Nairobi
Authors: N. A. Othieno-Abinya, H. O. Abwao, G. W. Kiarie
Journal: Journal of Clinical Oncology (2007)

18535 Background: In human immunedeficiency virus (HIV) related non-Hodgkin’s lymphoma (HIV-NHL) two interrelated life- threatening diseases are considered for treatment decision. Before highly active antiretroviral therapy (HAART), chemotherapy associated toxicity made it difficult for HIV-NHL patients to tolerate treatment. This has remarkably changed in the HAART era. These patients are best treated with standard protocols including: cyclophosphamde, doxorubicin, vincristine and prednisone (CHOP); rituximab-CHOP (R-CHOP): methotrexate, doxorubicin, cyclophosphamide, vincrstine, prednisone and bleomycin (MACOP-B). Methods: We reviewed records of patients with aggressive and highly aggressive phenotype NHLs aged 13 years and above, treated from June 1994 to May 2006. Information included demographic details, pathologic subtype, extent of disease, treatment, outcome. Results: Seventy-five patients - 43 M; 32 F. Age range 13–78 years, median 44.5. Thirty-two (42.7%) were HIV+, 32 (42.7%) HIV- and 11 (14.7%) HIV status undetermined. All HIV+ patients took HAART. Twenty-four (32%) were diffuse large B-cell, 7 (9.3%) transformed follicular, 3 (4%) Burkitt’s 32 (42.7%) only referred to as aggressive/highly aggressive and 9 (12%) others. Thirty-eight (50.7%) were in the high risk International Prognostic Index (IPI) category and 27 (36%) had IPI undetermined. Nine of 21 (42.9%) HIV+ patients had CD4+ cell counts &lt;100/ml. Treatments given upfront were: CHOP-35 patients (46.7%), MACOP-B-14 (18.7%), R-CHOP-11 (14.7%), and dropouts - 8 (10.7%). Seven of 32 (21.9%) HIV-NHL achieved complete remission (CR) vs 24 of 32 (75%) HIV-patients; highly significant (P&lt;0.0001). Five (15.6%) of HIV+ patients had treatment related deaths vs none in HIV- group (P&lt;0.00001). No significant correlation emerged between treatment outcome and IPI score (P= 0.22), or CD4+ cell counts (P = 0.15). HIV+ patients had a median follow-up of 5.5 months, mean of 9; those for HIV- patients were 17 and 30 months respectively; highly significant (P = 0.0036 and 0.0018 respectively). Conclusions: The outcome of treatment was significantly inferior among HIV+ patients. No significant financial relationships to disclose.
Retrospective study of clinical and radiographic risk factors associated with early onset, severe pulmonary hemorrhage in bevacizumab-treated patients with advanced non-small cell lung cancer (NSCLC)
Authors: A. B. Sandler, D. H. Johnson, J. Brahmer, J. H. Schiller, M. Ostland, R. Gray, S. Tran, I. Dimery
Journal: Journal of Clinical Oncology (2006)

7068 Background: Bevacizumab (BV) added to chemotherapy prolongs survival in non-squamous NSCLC, but was uncommonly associated with serious pulmonary hemorrhage (PH) (Sandler A, et al, ASCO 2005). A retrospective study was conducted to potentially identify clinical or radiographic (CT) risk factors associated with early onset (&lt;150 days from initial treatment) PH. Methods: A broad search of the E4599 database for selected bleeding terms among BV-treated patients was conducted. Cases of PH were identified and adjudicated. Associations between baseline clinical factors and incidence of PH were evaluated in the full cohort of E4599 patients. In addition, a separate case-control analysis, using controls matched on age and sex, was conducted to evaluate baseline CT variables. Chest CTs were evaluated by blinded independent assessment of lesion location, cavitation, size of largest tumor or nodal mass, vascular involvement, presence of an endobronchial tumor, and total number of intra-thoracic lesions. Additional analyses were also conducted including cases of late-onset PH, post-baseline variables such as unconfirmed tumor response at 6 weeks (RECIST) and cavitation, and combined CT data from E4599 and an earlier Ph II trial. Results: Of 425 BV-treated pts, 10 cases of PH were identified. Of these, 7 were PH without additional complicating factors, and 6 were of early-onset. The cohort analysis of these 6 early-onset cases is presented ( table ). The case-control analysis on CT risk factors is ongoing. Conclusion: PH was an uncommon event, and based on this, no evidence was observed for an association between the baseline clinical variables and the incidence of early-onset events of PH without additional complicating factors. Conclusions for the CT variables evaluated will be presented. [Table: see text] [Table: see text]
Therapeutic implications for acquired resistance and heart toxicity using targeted therapy to erbB2
Authors: S. S. Bacus, J. Hill, N. Spector
Journal: Journal of Clinical Oncology (2006)

3084 Background: ErbB2 overexpression predicts for a poor prognosis in breast cancer making it an attractive therapeutic target. Molecules such as EGFR/ErbB2 tyrosine kinase inhibitors (TKI’s), lapatinib/GW2974 and antibodies such as trastuzumab are currently used in clinical trials. Clinical responses to TKI’s have been observed, but are short-lived. Our data elucidates the pathway of acquired resistance to TKI’s and the underlying pathway associated with cardiac toxicity after trastuzumab treatment. Finally, we show the clinical implications and the therapeutic approaches to overcome this. Methods: Immunostaining and Western Blot were performed for HER2, EGFR, ER, PR, Bcl-2, FOXO3a, ERRα, ERR, PGC-1α, p-AKT and pERK. AU565, MCF7, BT-474, MCF7/HER2 and AU/BCL2 were treated with ß-estradiol, tamoxifen citrate, GW2974 and trastuzumab. Results: We show that upregulation of ERα and ER-regulated genes contribute to the resistance to HER1/HER2 inhibitors. Although the ErbB2 pathway is inhibited by lapatinib, the dependence of tumor cell survival in resistant cancer cells switches from ErbB2 to ER pathway. By inhibiting ErbB2/P13/AKT signaling, the inhibitors upregulate FOXO3a, which upregulates ER and ER-regulated genes, such as BCL2, contributing to cellular resistance. We also show that this occurs in patients with ErbB2/EGFR overexpressing ER positive cancers treated with lapatinib. By combining EGFR/HER2 inhibitors or antibodies with interventions that down regulate ER activity or estrogen deprivation, we were able to delay ER-mediated resistance. In addition, we have shown that the genes associated with the fatty acid metabolic pathway are upregulated by trastuzumab, but not lapatinib. Conclusion: Our results show that activation of ER and ER-regulated genes (BCL2) that contributed to the development of resistance to ErbB inhibitors in AU and BT474 cells also occurred in patients treated by lapatinib whose breast cancers expressed a similar phenotype. Identifying the mechanisms involved in the development of resistance and toxicities to ErbB inhibitors will lead to rational therapeutic strategies and improve their efficacy. In addition, less cardiac toxicity is anticipated in patients treated with lapatinib. No significant financial relationships to disclose.
Cervical cancer and HPV vaccination: Knowledge and attitudes of adult women in Lusaka, Zambia.
Authors: F. Liu, B. Vwalika, M. R. Hacker, S. Allen, C. Awtrey
Journal: Journal of Clinical Oncology (2010)

e12010 Background: Human papillomavirus (HPV) vaccination has the potential to greatly impact cervical cancer in developing countries, where screening and treatment resources are limited. Few studies have been conducted on the knowledge and attitudes of women in Africa regarding HPV vaccination. Zambia is a country in southeast Africa with the continent's second highest incidence of cervical cancer, approximately 30 cases/100,000 women per year. Methods: Women in medical clinics in Lusaka, Zambia were randomly selected to participate in a survey. After obtaining informed consent, trained nurses administered the questionnaires, which collected information on participants' knowledge of vaccines, cancer, cervical cancer, and potential acceptance of HPV vaccination. Results: Of 310 completed questionnaires, 98.7% of women knew of vaccines and over 99% had their children vaccinated. Over 70% of women had experience with a pelvic or speculum exam, and 68.7% of women believed doctor's visits for healthy people could be helpful. Among 227 women who had heard of cervical cancer, 23.3% had personally had an exam for cervical cancer. Regarding HPV vaccination, 96.1% and 98.1% of women would vaccinate themselves and their children respectively. Conclusions: Familiarity with vaccination is high among women in Lusaka, Zambia. Acceptance of HPV vaccination is potentially widespread. Introduction of HPV vaccination must be complemented by cervical cancer education and advocacy of screening visits. No significant financial relationships to disclose.
Vinflunine (VFL) as salvage chemotherapy in hormone-refractory prostate cancer (HRPC)
Authors: A. A. Meluch, D. R. Spigel, H. A. Burris, F. A. Greco, J. Gandhi, E. Crane, T. M. Markus, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2008)

16059 Background: Two randomized, phase III trials have demonstrated survival benefits for docetaxel-based chemotherapy in patients (pts) with HRPC. Though some pts retain sensitivity to this agent after completion of therapy, progression of their disease eventually occurs. To date, there is no second-line therapy with proven survival benefits. VFL is a novel vinca alkaloid with demonstrated preclinical antitumor activity in prostate cancer models, and clinical activity in several solid tumors including breast and bladder cancer. In this multicenter phase II trial, we evaluated VFL as salvage chemotherapy in HRPC. Methods: Eligibility criteria: progressive hormone-refractory metastatic or incurable localized prostate carcinoma; ECOG PS 0–2; prior docetaxel; ≤ 2 prior chemotherapy regimens; no prior anthracycline; adequate bone marrow, kidney and liver function; informed consent. All pts received: VFL 320 mg/m2 IV every 3 weeks (280 mg/m2 for pts ECOG PS 2, GFR < 60 cc/min, or prior pelvic RT). Pts were reevaluated after 2 cycles (6 weeks); responding/stable pts received 6 cycles. This study was designed to detect a response rate > 15%; 4 responses in the first 26 evaluable pts were necessary to proceed to the second stage. Results: Between May 2007 and November 2007, 35 pts were enrolled: median age, 75 years (range 52–86); ECOG 0/1/2, 6/26/3 pts; bone metastases, 33 pts (94%); measurable disease, 14 pts (40%); > 1 prior chemotherapy regimen, 23 pts (66%). Pts received VFL for a mean of 2.6 cycles (range 1–6). 27 pts were evaluable for PSA response: 1 pt had a partial response (4%), 9 pts (33%) had stable disease, and 17 pts (63%) had progression. The single PSA responder also had an objective PR. Eight pts were inevaluable (too early, 6; withdrew from study for personal reasons, 2). Most patients progressed rapidly; only 32% were progression-free at 3 months. Grade 3/4 toxicities included neutropenia (40%), fatigue (14%), dehydration (11%), anemia (9%), and abdominal pain/cramping (6%). No treatment-related deaths occurred. Conclusions: VFL has minimal activity in heavily pretreated pts with HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer, Genentech Bristol-Myers Squibb Bristol-Myers Squibb, Eli Lilly and Company, Genentech, GlaxoSmithKline, GPC Biotech, sanofi-aventis, SCRI