tbuckley/cabot-search huggingface dataset:
Treatment of childhood glial tumors with cisplatin and irinotecan
Authors: J. Mora, O. Cruz, A. Parareda, A. Guillen, R. Puy, S. Massaguer, C. de Torres, G. Garcia, J. M. Costa
Journal: Journal of Clinical Oncology (2009)

10062 Background: Childhood glial tumors are heterogeneous neoplasias for which non-surgical management is controversial. After a pilot study suggesting that irinotecan/cisplatin (I/C) may be effective in children (Mora et al, Neuro Oncol 2007), we initiated a phase II prospective trial with the aim of avoiding radiation therapy for low grade's (LG) and improve outcome for high grade's (HG). Methods: The indication for adjuvant therapy was based upon histology, the extent of surgical resection, and the presence of clinical or neuroradiological signs of progression. Weekly Irinotecan (50 mg/m2 and 65 mg/m2 the last 2 cycles) and Cisplatin (30 mg/m2) for four consecutive weeks (1 cycle), and a total of 4 cycles was used. Results: From January 2004 to December 2007, 30 children aged 6 months to 17 years were treated, 21 at diagnosis, 7 at progression and 2 at relapse. Fourteen tumors were WHO grades I-II gliomas (LGG), 10 grade III (6 gliomas, 2 anaplastic ependymomas and 2 AT/RT), and 6 had no biopsy (3 brainstem (BST) and 3 optic-pathway tumors (OPT)). Two patients had type-1 neurofibromatosis and OPT. Primary sites included: 4 supratentorial, 8 BST, 9 OPT, 2 cerebellar, and 7 spinal. Prior to the I/C regimen, gross total resection was performed in 7 and biopsy in 14 tumors; 9 patients received chemotherapy and 5 radiotherapy. All but 6 patients, 2 because of C allergy and 4 BST because of progression, completed the protocol, with no grade 3–4 side effects. Vomiting was the main side effect. Twenty (90%) of 22 patients with evaluable clinical symptoms had a complete and rapid response, with objective functional recovery. With a median follow-up of 25 months, 14 (47%) patients had a complete/partial response (7 out of 10 HG), 10 (40%) had stable disease (8 out of 14 LG), and 6 (20%) progressed (all BST). Five patients died of disease, all BST. Twenty-five (83%) patients remain progression-free, median 27 months from protocol entry. Conclusions: Seventy percent objective response rate for HG and avoidance of radiotherapy for 93% of LG was obtained using the I/C regimen. Remarkable fast clinical responses and functional recoveries occurred. No significant financial relationships to disclose.
Abstract 18415: Beta-trace Protein and Beta-2-microglobulin are Independent Predictors of All-cause and Cardiovascular Mortality in US Adults
Authors: Ching-Lung Chrung, Bernard M Cheung
Journal: Circulation (2012)

Background: Beta-trace protein (BTP) and beta-2-microglobulin (B2M) are novel markers of renal dysfunction associated with cardiovascular disease. We evaluated their relationship with all-cause and cardiovascular mortality in a representative sample of US adults. Methods: 6,642 participants aged 20 or above were included in the Third National Health and Nutrition Examination Survey. They were recruited from 1988 to 1994 and followed up through 2006. Multivariate Cox regression analysis was used, with adjustment for age, race/ethnicity, sex, education, smoking, physical activity, BMI, diabetes, hypertension, hypertriglyceridemia, low HDL, serum uric acid, C-reactive protein, vitamin D, total cholesterol, blood urea nitrogen, hemoglobin, white blood cell count and eGFR. Results: The mean (95% CI) serum BTP and B2M levels were 0.581 mg/L (0.571-0.592) and 1.93 mg/L (1.89-1.97) respectively. Within an average 12.1 years follow-up, 2,540 all-cause and 1,157 cardiovascular deaths occurred. The multivariate adjusted hazard ratios comparing the lowest BTP quartile with the highest quartile were 1.43 (95% CI: 1.11-1.83; P-trend=0.007) for all-cause mortality, and 1.53 (95% CI: 1.11-2.11; P-trend&lt;0.001) for cardiovascular mortality. The multivariate adjusted hazard ratios comparing the lowest with the highest B2M quartile were 2.30 (95% CI: 1.68-3.15; P-trend&lt;0.001) for all-cause mortality, and 1.91 (95% CI: 1.03-3.55; P-trend=0.006) for cardiovascular mortality. Similar results were obtained when BTP and B2M were analyzed as continuous variables, in the subgroup with eGFR≥60 (n=4,066), or with further adjustment of LDL in the subgroup with LDL measurements (n=3,099). Conclusion: We have identified serum BTP and B2M as novel and significant predictors of all-cause and cardiovascular mortality in the general population.
Anemia in chronic obstructive pulmonary disease
Authors: Tadeusz Przybylowski, Renata Rubinsztajn, Krzysztof Karwat, Marta Maskey-Warzechowska, Ryszarda Chazan
Journal: European Respiratory Journal (2012)

Anemia is frequently associated with many chronic diseases and can be responsible for weakness, fatigue, impaired mood, deficits in cognitive function and decreased quality of life. Anemia is also common in COPD and is associated with higher comorbidity, mortality, and costs of care, its prevalence in COPD patients is estimated at 13 to 23%.  The aim of our study was to evaluate the prevalence of anemia in COPD patients and analyze its relationship with functional status.  Methods.  Study group consisted of 132 patients (37% F), at mean age 68.2±9 years with post-bronchodilator FEV1 57.1±19.2% of predicted. Anemia was defined by hemoglobin concentration   Results  Anemia was diagnosed in 24 (18.2%) patients: 4 female and 20 male patients (p  Conclusions: Anemia in COPD is more prevalent in males and can effect up to 20% of patients. It does not seem to depend on the severity of disease, however, it significantly reduces exercise capacity of patients.
Tamoxifen and exemestane (E) in combination as neoadjuvant treatment of hormone sensitive post-menopausal breast cancer women: Clinical efficacy and effects on tumor pathology and immunopathology
Authors: F. Dalenc, M. Lacroix-Triki, S. Serone-Vivien, G. Ferron, C. Couteau, L. Gladieff, T. Maudelonde, H. Roché
Journal: Journal of Clinical Oncology (2004)

9666 Background: Neoadjuvant therapy with T or aromatase inhibitors shown tumor responses and provides the opportunity to monitor tumors therapy effects. In vivo models suggest additive benefit of E with T. Purpose : We investigate combining treatment (E+T) in a phase II study to evaluate clinical (cl R) and pathological responses (pR), safety, tumor biological modifications : ER, PR, Her2, Bcl2, clived CK18, MIB1, cycline D1, aromatase activity, 17 β-estradiol and overall estrogenic activity of serum. Methods: 15 patients (pt) with ER+ and/or PR+ breast tumor received 4–5 months(m) of E 25 mg and T 20 mg daily before surgery. E began 8 days before combination. Serum was collected at D0, D8, 2 and 4 m and tumor tissue before treatment and surgery.Results:Pt characteristics : median age 74 years [60–80]; median clinical tumors size 6 cm [3–10]; median ultrasound 2.9 cm [1.4–6.8]; TNM : 6 T3, 3 T4b, 6 T4c; 7 N0, 6 N1, 2 N2; 2 M1. Pathology : 11 ductal, 2 lobular, 2 mucinous; 10 EE (Elston /Ellis) grade II, 5 gr III; 15 ER+, 12 PR+, 2 Her-2 +++ (IHC). Cl R: 4/15 (26%) PR, 10/15 (66%) SD, 1/15 (6%) PD at 4 m. No grade 3 / 4 toxicities. 1 pt stopped treatment at 3.3 m (ischemic cerebro-vascular injury). Breast conservative surgery achieved in 2/14 pt. pR classified to Chevallier : 10/14 ( 71,4%) grade 3, 4/14 ( 28,6% )gr 4 and Sotaloff : 7/14 ( 50%) T-B, 3/14 ( 21,4%) T-C and 4/14 (28,6%) T-D; 5/13 (38,5%) N-B, 2/13 ( 15,4%) N-C, 6/13 ( 46,1%) N-D, 1 NE. Treatment immunopathologic changes are summarised below and compared with pR. Others biological results and pharmakokinetics of drugs will be presented. Conclusions: Our study confirmed moderate efficacy on ER+ breast tumors in post-menopausal women with E+T as neoadjuvant therapy. E+T demonstrated anti-proliferative effects in tumours, cytotoxic effects on ER+ clones, anti-estrogenic effects . No significant financial relationships to disclose.
Systemic high-dose ara-C for the treatment of meningeal leukemia in adult acute lymphoblastic leukemia and non-Hodgkin's lymphoma.
Authors: E Morra, M Lazzarino, D Inverardi, E Brusamolino, E Orlandi, A Canevari, G Pagnucco, C Bernasconi
Journal: Journal of Clinical Oncology (1986)

Considering the good penetration of systemic high-dose ara-C (HDara-C) into the CNS, we used this approach for treating overt meningeal leukemia, either isolated or with concurrent extraneurologic disease, in 15 adults with high-risk acute lymphoblastic leukemia (ALL), one adult with lymphoid blast crisis of chronic granulocytic leukemia (LBC-CGL), and four adults with poor-prognosis non-Hodgkin's lymphoma (NHL). Treatment consisted of ara-C, 3 g/m2 every 12 hours by three-hour infusion for eight doses followed by a second course of four doses on day 21. Remitters received consolidation with monthly courses of HDara-C for four doses. Additional systemic multi-drug reinduction therapy and direct CNS treatment with intrathecal methotrexate (IT MTX) and cranial irradiation (CRT) was administered to the three remitters last treated. Thirteen of 20 patients (65%) achieved complete remission (CR): seven of seven patients with isolated meningeal leukemia and six of 13 patients with concurrent CNS and bone marrow disease. Of the remaining seven patients, five had a complete CSF clearing with persistent marrow disease. In all cases there was prompt resolution of neurologic signs and symptoms. The median duration of CR was 5 months (range 2 to 8 months). The most significant toxicity seen was myelosuppression, which was predictable and manageable. Nonhematologic toxicity was generally acceptable and included moderate nausea and vomiting, diarrhea, drug fever, transient liver dysfunction, and dermatitis. No cases of CNS toxicity occurred. There were no treatment-related deaths. Disease-free survival was limited by marrow relapse, either isolated or with concurrent CNS disease. No instances of isolated meningeal relapse occurred. These results obtained in a poor-risk subset of patients indicate that HDara-C is an effective treatment for the induction of remission in ALL and NHL with meningeal leukemia. Therefore, HDara-C should be considered for inclusion in multiagent consolidation programs for patients at high risk for CNS disease.
Evolutionary expansion of Mhc class I loci in the mole-rat, Spalax ehrenbergi.
Authors: V Vincek, D Nizetić, M Golubić, F Figueroa, E Nevo, J Klein
Journal: Molecular Biology and Evolution (1987)

A cosmid genomic library was prepared from a single individual of the rodent Spalax ehrenbergi, the mole rat, captured in Israel. The library was screened with a mouse probe hybridizing with all mouse class I major-histocompatibility-complex (Mhc) genes; the cross-hybridizing clones were isolated; and their restriction maps were prepared using five enzymes. A total of 93 class I-bearing clones could be identified in the library. Forty-five of these clones showed partial overlaps and could be arranged into 14 clusters. Eleven of these clusters could be shown to contain two class I genes each; the remaining clusters, as well as most of the non-overlapping clones, each contained one class I gene. After the elimination of clones with possible cloning artifacts and of clones that may carry allelic forms of a given gene in the heterozygous animal, the total number of class I loci identified in Spalax is approximately 65. The high number of loci probably arose from the duplication of either the entire class I set or the different class I families. The high number of gene copies might represent a means of selecting different functional genes from the family in different mammalian orders. Three of the approximately 65 Spalax class I genes cross-hybridize with a probe specific for the mouse K, D, and L genes; two of these genes are in the same cluster. These three elements might possibly be the functional class I genes of the mole rat.
Colonies Formed in Agar From Human Breast Cancer and Their Identification as T-Lymphocytes&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: S Asano, T E Mandel
Journal: JNCI Journal of the National Cancer Institute (1981)

Single cell suspensions prepared from human breast cancer specimens by collagenase digestion were cultured in soft agar with phytohemagglutinin-stimulated human lymphocyte-conditioned medium (PHA-LCM). In 6 of 10 different tumors, PHA-LCM-dependent clonal growth was develop. After 12-14 days of incubation, two morphologic types of colony containing 20-500 cells were recognized. Both were composed of lymphocytes of T-cell nature, as judged by cell morphology in smears, cytochemical properties, capacity to form rosettes with sheep erythrocytes, and electron microscopic appearances. Contamination of the tumor cell suspensions by blood could be excluded as a source of the colony-forming lymphocytes, and the incidence of colony-forming cells correlated well with the degree of lymphocyte infiltration of the tumors. Some of the colonies in agar were expanded further in liquid culture in the continuous presence of PHA-LCM. These clones were apparently high in proliferating capacity as compared with the proliferating activity of peripheral T-cell clones obtained from normal blood. These clones were considered to be highly activated T-lymphocytes and to be stimulated to grow in vitro by the T-cell growth factor contained in PHA-LCM. The direct cloning and expansion of such activated T-lymphocytes infiltrating the tumors will be useful for studies on the functional characteristics of these cells.
Pentoxifylline During Steroid Window At Induction To Remission Increases Apoptosis In Childhood Acute Lymphoblastic Leukemia
Authors: Oscar Gonzalez-Ramella, Jimenez-Lopez Xochiquetzatl, Sergio Gallegos-Castorena, Pablo Ortiz-Lazareno, Jose Manuel Lerma-Diaz, Georgina Hernandez-Flores, Fernando Sanchez-Zubieta, Alejandro Bravo-Cuellar
Journal: Blood (2013)
Prognostic impact of bone marrow CD138 immunohistochemistry (IHC) prior to autologous stem cell transplant (ASCT) for multiple myeloma (MM)
Authors: M. C. Foster, R. Christensen, J. Egan, J. Whitley, W. K. Chiu, J. Serody, D. Gabriel, A. Ivanova, C. H. Dunphy, T. C. Shea
Journal: Journal of Clinical Oncology (2009)

8600 Background: Low bone marrow plasma cell (BMPC) burden prior to ASCT for MM is associated with favorable outcomes, but is usually determined by morphologic evaluation of marrow aspirates, a method subject to variability in sampling and interpretation. It is unknown if CD138 IHC, a more sensitive measure of BMPC, predicts progression-free survival (PFS), overall survival (OS) or post-ASCT response. Methods: Consecutive patients (n=93) who underwent single ASCT for MM from 2001 to 2008 and had available, stainable bone marrow core biopsies (BMB) obtained &lt;90 days prior to ASCT were included in this single-center retrospective cohort study. BMB and/or clot CD138 IHC staining were reviewed by blinded hematopathologists. Post-ASCT response, PFS, and OS were determined using the International Myeloma Working Group uniform response criteria. Results: Patients were highly cytoreduced prior to ASCT, with 50.5% of pts having 0–5%, 21.5% having 6–10%, 20.4% having 11–20%, and 7.5% having &gt;20% BMPC by CD138 analysis. BMPC% by CD138 IHC correlated with aspirate BMPC% [Pearson correlation coefficient=0.48, 95%CI (0.30, 0.63)]. In 12.6% of patients, BMPC% by CD138 IHC was ≥10% more than the aspirate count. Patients with ≤5% BMPC were more likely to achieve or maintain a CR or VGPR at initial post-ASCT restaging than those with &gt;5% BMPC: Odds Ratio (95% CI) 6.91 (2.12, 22.57), p=. 0005 (chi-squared). With median follow up of 15.4 months for the ≤5% BMPC group and 19.3 months for the &gt;5% BMPC group, 34/93 patients have progressed or died, with no difference between groups. By Kaplan-Meier analysis, PFS was similar regardless of BMPC [3 year estimated PFS (95%CI): ≤5%BMPC, 49.9% (29.4, 70.4) vs. &gt;5%BMPC, 45.5% (26.7, 64.3); HR=1.24 (0.62, 2.49), p=.55, log-rank]. There was no difference in OS [3 year estimated OS (95%CI): ≤5%BMPC, 71.0% (49.7, 92.3) vs. &gt;5%BMPC, 81.8% (66.2, 97.4); HR=0.61 (0.21, 1.78), p=.36, log-rank]. Conclusions: Detection of ≤5% BMPC by CD138 IHC prior to ASCT predicts attainment or maintenance of post-transplant CR/VGPR and correlates with plasma cell morphology. Differences in PFS or OS may emerge with additional follow-up, or if more patients with a higher content of residual plasma cells were transplanted. [Table: see text]
Phase I study of XMT-1001 given IV every 3 weeks to patients with advanced solid tumors.
Authors: E. A. Sausville, L. E. Garbo, G. J. Weiss, D. Shkolny, A. V. Yurkovetskiy, C. Bethune, R. K. Ramanathan, R. J. Fram
Journal: Journal of Clinical Oncology (2010)

e13121 Background: XMT-1001 is a water soluble macromolecular conjugate of camptothecin (CPT). In this novel CPT prodrug, CPT is conjugated with a 70 kDa biodegradable hydrophilic polyacetal, poly (1-hydroxymethylethylene hydroxymethylformal). XMT-1001 has an improved therapeutic window compared with irinotecan in human tumor xenograft models, providing a compelling rationale for its clinical development. Methods: This is a dose-escalation study of XMT-1001 given as an IV infusion once every 3 weeks. The objectives are to determine the maximum tolerated dose (MTD) and assess safety and pharmacokinetics (PK) of XMT-1001. Three patients (pts) are entered at each dose level, with expansion to 6 pts if there is dose-limiting toxicity. Analyses of plasma and urine were performed for XMT-1001 (conjugated CPT), 2 major drug release products, and for unconjugated (free) CPT. Results: To date, 54 pts have received 160 cycles of XMT-1001 at dose levels from 1.0 to 113 mg CPT equivalents (eq.)/m2. Two pts had Gr 3 infusion reactions to study drug. After the introduction of clinical trial material with an improved formulation, no infusion reactions suggestive of hypersensitivity have occurred (33 pts, 98 cycles). No hemorrhagic cystitis or ≥ Gr 3 diarrhea was noted. Gr 2-4 neutropenia occurred in 3 pts treated at 85 mg CPT eq. /m2. Stable disease was observed in 14 of 50 evaluable pts with the following tumor types and doses in mg CPT eq./m2: sarcoma (85 mg/m2, 6 wks), NSCLC (1.0 mg/m2, 6 wks; 20.5 mg/m2, 36 wks; 36.3 mg/m2, 18 wks), nasopharyngeal (36.3 mg/m2, 12 wks), ovarian (4.9 mg/m2, 12 wks), pancreas (4.9 mg/m2, 36 wks), appendiceal (7.3 mg/m2, 12 wks), bile duct (9.1 mg/m2, 18 wks), basal cell (11.6 mg/m2, 6 wks), colon (15.4 mg/m2, 18 wks), gastric (20.5 mg/m2, 12 wks), prostate (85 mg/m2, 6 wks), and rectal (27.3 mg/m2, 6 wks). Tumor shrinkage was noted in a pt with colon cancer at the 15.4 mg/m2 dose level. The exposure to XMT-1001 and its release products, as measured by Cmax and AUC, demonstrated dose proportional increases with respect to dose of XMT-1001. Levels of free CPT in urine have been low. Conclusions: XMT-1001 can be given safely to patients; XMT-1001 has a favorable PK profile; and prolonged stable disease ≥ 12 wks was seen in 9 pts at doses below the MTD. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Mersana Pharmaceuticals Mersana Pharmaceuticals, Mersana Therapeutics, Inc. Mersana Therapeutics, Inc.
Sunitinib (SU) response in imatinib-resistant (IM-R) GIST correlates with <i>KIT</i> and <i>PDGFRA</i> mutation status
Authors: M. C. Heinrich, R. G. Maki, C. L. Corless, C. R. Antonescu, J. A. Fletcher, C. D. Fletcher, X. Huang, C. M. Baum, G. D. Demetri
Journal: Journal of Clinical Oncology (2006)

9502 Background: IM resistance in advanced GIST represents a major clinical problem. SU (SU11248) is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities related to KIT, PDGFRs, VEGFRs, RET and FLT3 inhibition. SU has demonstrated efficacy in clinical trials of pts with IM-R GIST. Methods: This study examined the relationship between tumor kinase genotypes and SU clinical activity in 97 pts with metastatic IM-R GIST treated as part of a phase I/II trial. Tumors were imaged by CT or MRI for RECIST-defined response assessment. Tumor specimens were obtained prior to (n=76) and following (n=64) IM therapy and analyzed for primary or secondary KIT and PDGFRA mutations, respectively. Results: Clinical benefit (CB; defined as PR or SD &gt;6 months) with SU was observed for all major molecular GIST subtypes: KIT exon 11 (42 pts, CB 36%), KIT exon 9 (19 pts, CB 42%), PDGFRA (4 pts, CB 25%), no KIT or PDGFRA mutation (wild-type [WT]; 9 pts, CB 56%). Notably, the PR rate for GISTS with primary KIT exon 9 mutations was 37%, vs 5% for KIT exon 11 mutations (P=0.003). PFS and OS were significantly longer for pts with either a primary KIT exon 9 mutation or WT KIT/PDGFRA compared with pts with a KIT exon 11 mutation (exon 9 vs 11: PFS P=0.0007, OS P=0.005; WT vs exon 11: PFS P=0.03, OS P=0.01). Secondary KIT mutations (in exons 13, 14, 17 or 18) were found in 62% of GISTs with a primary KIT exon 11 mutation, but only in 16% with a primary KIT exon 9 mutation (P=0.002). No secondary mutations were found in GISTs lacking a primary KIT/PDGFRA mutation. Biochemical profiling of secondary kinase mutations revealed in-vitro sensitivity of KIT exon 13 and 14 mutations to SU, while secondary KIT exon 17 and 18 mutations were resistant to SU in vitro. These in-vitro results were consistent with clinical results: CB was observed in 65% of pts with secondary KIT mutations in exon 13 or 14 and in only 9% of pts with secondary KIT exon 17 or 18 mutations (P=0.006). Conclusions: Our findings suggest that, similar to prior results observed using imatinib, CB of SU following failure of IM treatment is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinase, the uncontrolled activity of which is a critical etiologic factor for GIST. [Table: see text]
Evolutionary change of restriction cleavage sites and phylogenetic inference for man and apes.
Authors: M Nei, F Tajima
Journal: Molecular Biology and Evolution (1985)

A mathematical theory for the evolutionary change of restriction endonuclease cleavage sites is developed, and the probabilities of various types of restriction-site changes are evaluated. A computer simulation is also conducted to study properties of the evolutionary change of restriction sites. These studies indicate that parsimony methods of constructing phylogenetic trees often make erroneous inferences about evolutionary changes of restriction sites unless the number of nucleotide substitutions per site is less than 0.01 for all branches of the tree. This introduces a systematic error in estimating the number of mutational changes for each branch and, consequently, in constructing phylogenetic trees. Therefore, parsimony methods should be used only in cases where nucleotide sequences are closely related. Reexamination of Ferris et al.'s data on restriction-site differences of mitochondrial DNAs does not support Templeton's conclusions regarding the phylogenetic tree for man and apes and the molecular clock hypothesis. Templeton's claim that Nei and Li's method of estimating the number of nucleotide substitutions per site is seriously affected by parallel losses and loss-gains of restriction sites is also unsupported.