tbuckley/cabot-search huggingface dataset:
Screening for chemotherapy-induced reactivation of hepatitis B virus infection: An institutional experience
Authors: A. S. Bertolini, O. Fusco, E. Berardi, F. Malugani, M. Fiumanò, A. Doria, S. Pedroncelli, V. Filipazzi, D. Dalu, E. Menatti
Journal: Journal of Clinical Oncology (2008)

20563 Background: In patients with a hepatitis B history (HBV), chemotherapy (CT) can allow the reactivation of HBV, by suppression of the immune system. New-onset HBV may result in varying degrees of hepatocellular injury. Risk factors are detectable hepatitis B surface antigen (HBsAg), pre-CT HBV DNA level, antibodies to hepatitis B core antigen (anti-HBc), treatment with corticosteroids, young age, male gender and lymphoma or breast cancer diagnosis. Lamivudine prophylaxis is recommended to reduce the incidence and severity of hepatitis in this context. Methods: Since October 2006 we tested for HBV infection all pts candidate to CT. The protocol has three sequential levels: HBV markers evaluation; HBV DNA testing in pts HBsAg+ or HBsAg negative but anti-HBc ± anti-HBs positive and with high risk of immune depression; Lamivudine prophylaxis for pts HBsAg+ or HBsAg negative but with detectable HBV DNA. Results: We have screened 301 pts with CT program ongoing:189 (63%) pts were negative for markers of previous HBV infection; on the contrary 112 (37%) had markers positive. Seventeen (15%) of these were HBsAg+, 12 (11%) for anti-HBs alone and 83 (74%) for anti-HBc ± anti-HBs. HBV DNA was tested in all pts HBsAg+ and in 30 of 81 pts with positive markers and high risk of immune depression. HBV DNA was detected in all HBsAg+ pts, while in any of those HBsAg negative but with positive markers. For the last level 15 HBV DNA+ pts were treated by Lamivudine prophylaxis. In 12/15 HBV DNA had negativized within the first three months, in 2/15 the viremia level decreased, and only 1 patient, affected by non-Hodgkin’s lymphoma, experienced HBV reactivation. This patient was resistant to prophylactic therapy. Lamivudine was replaced by Adefovir therapy, but the level of viremia did not change significantly. Conclusions: Our study underlines the need to carefully investigate pts which undergo CT. They should be screened for the presence of markers of chronic hepatitis B infection or previous HBV infection, because they must be considered for Lamivudine prophylaxis use. Finally, the prophylactic use of Lamivudine in inactive HBV carriers with hemato-oncological malignancy prevents interruptions in their treatment for primary disease as a result of HBV reactivation. No significant financial relationships to disclose.
A dose finding pharmacokinetic study of the tumor-targeting human L19-IL2 monoclonal antibody-cytokine fusion protein in patients with advanced solid tumors
Authors: G. Curigliano, G. Spitaleri, T. De Pas, C. Noberasco, L. Giovannoni, H. Menssen, L. Zardi, A. Milani, D. Neri, F. de Braud
Journal: Journal of Clinical Oncology (2007)

3057 Background: L19-IL2 is a tumor targeting immunocytokine constituted by a single chain Fragment variable format directed against ED-B domain of fibronectin and the human cytokine interleukin-2 (IL-2). It has striking anticancer activity in preclinical models. We evaluated safety, pharmacokinetic profile (PK) and activity of L19-IL2 in advanced cancer patients. Patients and Methods: Five cohorts of patients with recurrent/refractory solid tumors received a dose escalation intravenous infusion of L19-IL2 (5, 10, 15, 22.5 e 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 21 days. Serum samples for PK assessment, immunophenotyping and assays for detection of human antifusion protein antibodies to L19 (HAFA) were collected at screening and on day 1, 3, 5 and 10 of each cycle. Results: Eighteen solid cancer patients were enrolled from 11/05 to 9/06 (6 colorectal and 3 renal cell cancer (RCC) patients, 3 with melanoma, and 1 neuroendocrine tumor, thymic carcinoma, biliary tract carcinoma, breast cancer, peritoneal mesothelioma and parotid gland carcinoma). Median age was 49 years (range 35–69), 14 patients were male and 4 female. All patients were evaluable for safety and activity. The maximum tolerated dose was determined to be 22.5 Mio IU IL-2 equivalent. Drug-related dose-limiting toxicities at 30 Mio IU L19-IL2 were hypotension requiring vaso-pressor support and acute renal failure. Treatment-related deaths did not occur, and all toxicities were reversible. Five patients achieved stable disease (RCC, n=3; biliary tract carcinoma, n=1; peritoneal mesothelioma, n=1). All other patients progressed. Immunophenotyping disclosed IL2-typical transient activation of T-cell subsets. Very preliminary data showed a weak induction of HAFA at day 10 in 5 patients. These data could not be confirmed by competition ELISA experiments. Conclusions: Up to 22.5 Mio IU IL2 equivalent of L19-IL2 can be safely administered to advanced solid cancer patients in an outpatient setting. Some evidence of clinical activity in patients susceptible to immunomodulatory therapy (RCC) was found. All observed toxicity was mild and reversible. An expanded study at recommended dose in RCC patients is currently ongoing. [Table: see text]
Lymphedema is common among post-operative cancer survivors
Authors: J. N. Cormier, L. Davidson, Y. Xing, W. J. Evans, J. M. Armer
Journal: Journal of Clinical Oncology (2006)

18524 Background: Lymphedema (LE) is associated with the surgical treatment of a number of tumors and is a serious long-term condition with significant medical, economic, and quality of life consequences. Early detection and management are critical to preventing LE progression and complications. We examined the literature to ascertain the incidence and identify factors associated with an increased postoperative risk for LE. Methods: We systematically reviewed the oncology literature (1972–2005) to identify studies that examined postoperative LE. Data pertaining to the type of malignancy, the surgical procedure performed, the criteria used to define LE, and the median follow-up time were extracted. The incidence of LE was summarized using weighted averages. Results: We identified a total of 122 reports of postoperative LE (N = 24,095 patients), which were broken down by cancer type as follows: breast cancer (n = 45), melanoma (n = 31), gynecologic (GYN) malignancies (n = 30), genitourinary (GU) malignancies (prostate n = 6, penile n = 6, bladder n = 2), and sarcoma (n = 2). When only prospective studies (n = 74, 61%) were considered, the incidence of LE following axillary node dissection (AND) in patients with breast cancer was 19% compared with 8% following AND for melanoma. The incidence of lower extremity LE following inguinofemoral and/or pelvic lymph node dissection for melanoma was 30% compared with 24%, 14%, and 20% for GYN malignancies, GU malignancies and sarcomas. The relative risk of postoperative lower extremity LE increased two-fold in patients who received radiation therapy. Methods of measuring LE included extremity circumference (n = 17 studies) with various defined thresholds (&gt;1 cm [n = 8], &gt;2 cm [n = 7], and &gt;3 cm [n = 2]). Fourteen studies used volume measurements, while the remainder used an ad hoc clinical grading method. The lowest incidence of LE was seen in studies with the shortest follow-up. Conclusions: LE is a common condition resulting from the surgical treatment of a number of different malignancies. To enhance the quality of postoperative care in cancer survivors, objective LE measurement and symptom assessment should be part of standard practice during both early and long-term follow-up. No significant financial relationships to disclose.
Abstract 17938: Sub-valve and Valvar Pathology Predict Post-operative Valve Failure After Primum Repair
Authors: Timothy Colen, Nee Scze Khoo, Joseph Atallah, David B Ross, Ivan M Rebeyka, Luis Quinonez, Jeffrey F Smallhorn
Journal: Circulation (2012)

Background Atrioventricular valve regurgitation (AVVR) is the most common reason for reoperation after primum defect repair. Descriptions of pre-operative (pre-op) anatomical risk factors predictin...
A first-in-human phase Ia open-label dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the humanized monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) administered intravenously in patients with advanced solid tumors.
Authors: L. S. Rosen, M. S. Gordon, S. Bai, P. Hegde, J. Fredrickson, D. S. Chen, I. Chang, R. P. Funke, G. S. Chandler, L. Naumovski, P. N. Munster
Journal: Journal of Clinical Oncology (2011)

2614 Background: Epidermal growth factor-like domain 7 (EGFL7), is a vascular-restricted, tumor selective, extracellular matrix protein that promotes endothelial cell adhesion, survival and re-growth. Anti-EGFL7 (MEGF0444A) is a huMAb that targets and inhibits the adhesive and pro-survival activities of EGFL7 on endothelial cells. Anti-EGFL7 prolongs survival of mice bearing invasive pancreatic islet tumors driven by the large T antigen, and reduces vascular density and perfusion in the tumors. The combination of anti-EGFL7 with an anti-vascular endothelial growth factor antibody had significantly more potent anti-tumor activity than either agent alone. Methods: This was a Phase Ia, open-label, 3+3 dose-escalation study to evaluate the safety, tolerability and PK of MEGF0444A, administered intravenously (IV) every 3 weeks, in patients (pts) with advanced solid tumors. PD markers including levels of circulating progenitor cells (CPC) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) were assessed. Results: Thirty pts were enrolled in 5 dose-escalation and 2 dose-expansion cohorts. The highest planned dose of 15 mg/kg, also the maximum administered dose, was reached without dose-limiting toxicities (DLTs) within the 21-day DLT window. Ten serious and 8 non-serious adverse events >= Grade 3 in severity were reported, none of which were attributed to study drug. Infusion-related reactions were rare. MEGF0444A demonstrated linear PK typical of IgG1 monoclonal antibodies. There were no tumor responses and most patients progressed by end of cycle 4. Enumeration of CPC levels showed a decrease in a subset of pts within 15 days of MEGF0444A therapy. DCE-MRI results were suggestive of anti-angiogenic activity in select pts. Conclusions: MEGF0444A was well tolerated and has good PK properties. Potential vascular targeting by MEGF0444A is suggested by changes in CPC levels and DCE-MRI. MEGF0444A is currently being investigated in combination with bevacizumab and chemotherapy in a Phase Ib clinical trial.
Correlation between Egr-1 and gelsolin expression in human breast cancer tissues
Authors: Ruochun Huang, Weimin Yang, Ruo-Pan Huang
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2862 

The development of malignant tumors is the result of sequential genetic and epigenetic lesions that lead to alterations in a number of gene expressions, which are primarily controlled by transcription factors. A growing body of evidence suggests that early growth response-1 (Egr-1), a transcription factor, may function as a tumor suppressor. To gain more evidence to support the role of Egr-1 in the suppression of cancer cell growth, we examined the expression of Egr-1 in human breast cancer tissues. Our data showed that all normal mammary tissues expressed high levels of Egr-1, while most of the breast cancer tissues expressed very small amounts of Egr-1. The expression pattern of Egr-1 in human breast cancer tissues is highly correlated with gelsolin expression. Induction of Egr-1 by serum stimulation accompanies the increase of gelsolin expression. While in cells lacking the induction of Egr-1 in response to serum stimulation, gelsolin expression remained unchanged. Furthermore, gelsolin promoter activity was profoundly reduced in Egr-1 null mouse embryonic fibroblasts comparing with Egr-1 wild type mouse embryonic fibroblasts. Our results suggest that Egr-1 may be an important breast cancer marker and that there exists a potential new pathway involved in Egr-1 and gelsolin leading to breast cancer cell progression.
Abstract 15811: A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias
Authors: Sridharan Rajamani, Gongxin Liu, Lufei Hu, Wei Wang, Arvinder K Dhalla, Luiz Belardinelli
Journal: Circulation (2012)

Background -  Slowly inactivating or late sodium current (late I Na ) in the mammalian ventricle is pro-arrhythmic. Inhibition of it is a strategy to suppress afterdepolarizations and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. This study introduces GS-458967, a potent and selective inhibitor of late I Na , and demonstrates its effectiveness to suppress ventricular arrhythmias.   Methods and Results -  The effects of GS-458967 to inhibit cardiac late I Na  versus other ion currents were determined using rabbit isolated ventricular myocytes and perfused hearts. Anti-arrhythmic actions of GS-458967 were characterized in  ex vivo  and  in vivo  models of reduced repolarization reserve and ischemia. GS-458967 inhibited late I Na  in ventricular myocytes with an IC 50  of 0.13 µM and did not prolong action potential duration or the QRS interval (surrogates for inhibitions of I Kr  and peak I Na ) in rabbit heart. GS-458967 prevented and reversed proarrhythmic effects (afterdepolarizations, torsades de pointes) of the late I Na  enhancer ATX-II (Figure 1A) and the I Kr  inhibitors E-4031 (isolated heart) and clofilium ( in vivo ). GS-458967 was many-fold more potent and selective to inhibit late I Na , and more effective to reduce arrhythmias in myocytes, isolated hearts and intact rabbits than either flecainide or ranolazine. GS-458967 suppressed cardiac arrhythmias caused by acute ischemia (ligation of the left circumflex coronary artery) in the anesthetized rabbit, whereas flecainide increased ischemia-induced ventricular arrhythmias and mortality (Figure 1B).  Conclusions -  Our results establish a role of late I Na  in mammalian ventricular rhythm disturbances and demonstrate that a selective inhibitor of this current is not proarrhythmic and is superior to flecainide or ranolazine for suppression of ventricular arrhythmias in experimental models.
Co-occurrence of extended spectrum β lactamase and MCR-1 encoding genes on plasmids
Authors: Marisa Haenni, Laurent Poirel, Nicolas Kieffer, Pierre Châtre, Estelle Saras, Véronique Métayer, Romain Dumoulin, Patrice Nordmann, Jean-Yves Madec
Journal: The Lancet Infectious Diseases (2016)
Chronic myeloid leukemia (CML) with e1a2 BCR-ABL fusion transcript type: Analysis of characteristics, outcomes, and prognostic significance
Authors: D. Verma, H. Kantarjian, D. Jones, G. Borthakur, G. Garcia-Manero, D. A. Thomas, S. Verstovsek, M. Rios, J. Cortes
Journal: Journal of Clinical Oncology (2009)

7030 Background: The most common BCR-ABL fusion transcripts in CML are e13a2 (b2a2) and e14a2 (b3a2). Rarely, other transcripts like e1a2 are seen. Currently, there is no published series of data on efficacy of imatinib or other tyrosine kinase inhibitors (TKIs) in CML with e1a2. Methods: We analyzed records of 1,292 CML patients treated with TKI at our institution between January 2000 and November 2008. Results: 14 CML patients with e1a2 transcripts were identified, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Median age at diagnosis was 60 (range 28–86) years, median follow-up 39.5 (range 2–109) months. Of the 9 in CP, 3 received interferon and then imatinib after interferon failure, 6 received TKI as first-line therapy (5 imatinib, 1 nilotinib): 5 achieved CHR only, 1 CCyR, 1 MCyR, 1 PCyR, and 1 did not respond to imatinib. 5 patients (2 post-interferon failure - 1 in CHR, 1 in PCyR; 3 frontline imatinib - 1 in CHR, 1 in CCyR, 1 non-responder) progressed to advanced phases (3 myeloid BP, 1 lymphoid BP, 1 AP) at a median 48 (range 4–92) months after CML diagnosis; with only 1 alive and in CMR after allogeneic SCT. AP patient received various TKIs sequentially and achieved only CHR with disappearance of clonal evolution. BP patients received Hyper-CVAD+imatinib/dasatinib or idarubicin+Ara-C; 2 did not respond, 1 had CCyR lasting 12 months with Hyper-CVAD+Imatinib and 1 had CMR after allogeneic SCT lasting 2 months. In all 14 patients, cytogenetic responses lasted 1–9 months before being lost and none (except 2) achieved MMR or CMR on imatinib or other TKI therapy. Six patients (5 CP, 1 AP) were alive at a median 39 (range 2–85) months after initial diagnosis: 4 with CHR (2 on imatinib, 1 nilotinib, 1 bosutinib), 1 with MCyR on imatinib, and 1 with CMR after allogeneic SCT. Conclusions: CML with e1a2 BCR-ABL fusion transcripts is rare and is associated with an inferior outcome to therapy with TKI, with responses being usually short-lived. These patients need to be identified as high-risk patients and monitored closely for efficacy during therapy with TKI. No significant financial relationships to disclose.
Evaluation of a urea/lactic acid-based topical keratolytic agent (ULABTKA) for prevention of capecitabine-induced hand and foot syndrome (HFS): NCCTG trial N05C5.
Authors: S. L. Wolf, R. Qin, S. P. Menon, K. M. Rowland, J. W. Kugler, P. J. Flynn, D. Christian, D. Satele, J. L. Berenberg, C. L. Loprinzi
Journal: Journal of Clinical Oncology (2010)

9017 Background: HFS is a dose-limiting toxicity of capecitabine, occurring in 43-71% of patients. No effective preventative treatment has been definitively demonstrated. Urea/lactic acid have hydrating and keratolytic properties. Pilot data suggest that they may prevent HFS. The purpose of this trial was to evaluate the prophylactic use of a ULABTKA for capecitabine-induced HFS. Methods: A randomized double-blind phase III trial evaluated 137 patients (pts) receiving their first ever cycle of capecitabine at a dose of either 2,000 or 2,500 mg/m2 per day for 14 days. Pts were randomized to a ULABTKA vs. a placebo cream, which was applied to the hands and feet BID for 21 days after the start of capecitabine. Pts completed a HFS Diary (HFSD) daily while applying the cream. HFS toxicity grade (CTCAE v 3.0) was also collected at baseline and at the end of each cycle. The primary endpoint was assessed by comparing the percentage of pts in each group who self-reported moderate severity (or worse) HFS during cycle 1 as measured by the HFSD. The planned 132 pts provided 80% power for detecting a moderate effect size of 18% difference with a two-sided Fisher's exact test at a 5% Type I significance level. Results: The percentage of pts with moderate or severe HFS was not different between the two arms, with 13.6% in the ULABTKA arm and 10.2% in the placebo arm (p % 0.768, using a Fisher's exact test). Maximum HFS severity frequency data and chi-square p-values from this cycle 1 are illustrated in the Table. Cycle 1 CTCAE skin toxicity was higher in the ULABTKA arm, but not significantly so (p % 0.82). No significant differences were observed in other toxicities between the two arms. Conclusions: These data do not support the efficacy of a ULABTKA cream for preventing symptoms of HFS in patients receiving capecitabine. HFS severity Location Hands Feet Combined (hands and feet) Urea Placebo Urea Placebo Urea Placebo None 35 (59%) 36 (74%) 38 (64%) 34 (69%) 32 (54%) 31 (63%) Mild 18 (31%) 11 (22%) 14 (24%) 10 (20%) 19 (32%) 13 (27%) Moderate 5 (9%) 1 (2%) 6 (10%) 3 (6%) 6 (10%) 3 (6%) Severe 1 (2%) 1 (2%) 1 (2%) 2 (4%) 2 (3%) 2 (4%) P value 0.324 0.727 0.747 No significant financial relationships to disclose.
Interaction between phenotypic oxidative DNA damage biomarker and polymorphic DNA repair genes in high-risk population for liver cancer
Authors: Yuntian Tang, Lili Tang, Zemin Wang, Changxia Shao, Jiahua Yu, Tianren Huang, Weimin Gao, Jia-Sheng Wang
Journal: Cancer Research (2008)

1893   Oxidative stress plays important roles in viral and chemical carcinogenesis. 8-hydroxy-29-deoxyguanosine (8-OHdG) is a phenotypic biomarker for oxidative DNA damage. Genetic polymorphism of DNA repair genes can modify DNA damage, which is a major category of biomarkers for susceptibility. To investigate the interaction between genotypic and phenotypic biomarkers, a cross-sectional study was carried out in 654 residents (412 males and 242 females) of southern Guangxi, one of the high-risk areas for liver cancer in China. DNA samples were extracted from peripheral leukocytes and polymorphic genotypes of hOGG1 and XRCC1 were determined by PCR-restriction fragment length polymorphism. Urinary 8-OHdG was measured by HPLC-electrocoularray detection and adjusted by the concentration of creatinine (creat). The median 8-OHdG level among all study subjects was 7.09 ng/mg creat, ranged 0.13-94.11 ng/mg creat. The median 8-OHdG level in females was 8.36 ng/mg creat ranged 0.18-94.11 ng/mg creat, which was significantly higher than the median 8-OHdG level in males (6.22 ng/mg creat ranged 0.13-61.20 ng/mg creat, p Ser/Ser  genotype had lower 8-OHdG level (median: 5.85 ng/mg creat) than those with heterozygous 326 Ser/Cys  or homozygous 326 Cys/Cys  (median: 7.49 ng/mg creat) (p=0.030, Wilcoxon rank-sum test). Same trend of 8-OHdG level in hOGG1 genotypes was found in females (p=0.040, Wilcoxon rank-sum test). Bivariate analysis also found that heterozygous and homozygous genotypes of hOGG1 (326 Cys ) could significantly increase 8-OHdG level in all study subjects (p=0.008, trend test). The median 8-OHdG level (6.79 ng/mg creat) in subjects with XRCC1 194 Arg/Arg  genotype was significantly lower than the median level, 7.73 ng/mg creat, in those with heterozygous 194 Arg/Trp  or homozygous 194 Trp/Trp  (p=0.032, Wilcoxon rank-sum test). Same trend of 8-OHdG level in XRCC1 genotypes was found in females (p=0.044, Wilcoxon rank-sum test). Furthermore, 8-OHdG level increased with the increased number of the combined genotypes among hOGG1 326 variant type ( Ser/Cys  or  Cys/Cys ) or XRCC1 194 variant type ( Arg/Trp  or  Trp/Trp ) (p=0.006, trend test), especially in females (p=0.006, trend test). Results from this study indicate that polymorphic DNA repair genes may impact expression or biological activity of DNA repair enzymes, especially if multiple polymorphisms occur, that may result in deficient DNA repair for oxidative DNA damage induced by viral and chemical carcinogens, and therefore, increase individual susceptibility to liver cancer. (Supported by the NCI research grant CA90997)