tbuckley/cabot-search huggingface dataset:
Plasma pharmacokinetics of uracil after an oral uracil challenge dose for dihydropyrimidine dehydrogenase (DPD) phenotyping
Authors: J. G. Maring, B. N. Oonk, E. G. E. De Vries, G. A. P. Hospers
Journal: Journal of Clinical Oncology (2004)

2120 Background: The initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU) is DPD, catalyzing the reduction of 5-FU into 5,6-dihydrofluorouracil. In patients with DPD enzyme deficiency, 5-FU chemotherapy is associated with severe, life-threatening toxicity. The current pharmacokinetic study was performed within the scope of the development of an oral, Uracil Challenge Test for DPD phenotyping in patients scheduled to receive 5-FU. Methods: The pharmacokinetics of uracil and its metabolite 5,6-dihydrouracil (DHU) were studied after oral administration of an uracil challenge dose in 12 human volunteers. The volunteers ingested 500 mg/m2 uracil as an oral solution on an empty stomach. Blood sampling was carried out on t = 15, 30, 45, 60, 80, 100, 120, 150, 180, 210 and 240 min after oral intake. Uracil and DHU were quantified in plasma by high performance liquid chromatography. DPD activity in peripheral blood mononuclear (PBM) cells was measured for reference DPD values. Results: All volunteers (6 male and 6 female, age 27–53) had DPD activities within normal range and normal liver- and renal function parameters. After oral ingestion, uracil was rapidly absorbed from the intestinal tract in all subjects. The mean Cmax was (mean ± SD) 14.8 ± 4.2 mg/L (range 11.4–22.2) and was reached at t = 0.47 ± 0.11 hr (range 0.35–0.70 hr) after ingestion. The mean distribution volume was 30.2 ± 10.8 L (range 14.4–46.2 L). The area under the curve (AUC), calculated with the trapezoid rule, was 15.9 ± 5.1 mg.hr/L (range 10.9–26.1 mg.h/L) and the mean uracil clearance rate was 61.0 ± 16.5 L/hr (range 39.0–84.8 L/hr). Conclusions: After oral ingestion, uracil is rapidly absorbed from the gastrointestinal tract and subsequently rapidly metabolized into DHU in humans with normal DPD activity. The oral Uracil Challenge Test is currently investigated in previously characterized, partially DPD deficient patients to determine its use in pre-chemotherapy DPD-phenotyping. No significant financial relationships to disclose.
Correlation between preoperative T1 breast cancer staging and final pathologic analysis.
Authors: J. S. Gass, D. L. Wiggins, D. S. Dizon
Journal: Journal of Clinical Oncology (2011)

101 Background: Contemporary breast surgery is exploring less invasive techniques for the treatment of breast cancer and recent approaches such as ablative therapy have shown promise in early trials. Caution is required prior to adopting of these techniques, however, as ablative treatment may hinder interpretation of final pathology, which might impact adjuvant recommendations. To address this concern, we evaluated the concordance between preoperative core needle biopsy and postoperative final pathology, to determine whether the biopsy findings predicted final pathology. Methods: A retrospective chart review was performed of women diagnosed with breast cancers less than 2 cm on radiographic evaluation between 1997 and 2004. Concordance between preoperative assessment (by imaging and core needle biopsy) and final pathology results was analyzed based on tumor size, grade, lymphovascular space invasion, and in situ component. Kappa analysis was performed to characterize agreement. Results: We identified 56 women from our institution for analysis. The median age was 56 (range, 38-94) and the majority had presented with an abnormal mammogram (61%). The vast majority also underwent breast-conserving surgery (95%). Agreement was moderately accurate between preoperative and final assessment of grade (weighted κ 0.536) and size (weighted κ 0.464). It was not accurate in the assessment of lymphovascular invasion (weighted κ 0.123) and the presence of DCIS (weighted κ 0.197). Conclusions: Information from preoperative evaluation is insufficiently accurate for the evaluation of breast tumors, which may be important for adjuvant decision making. This information must be taken in to account when assessing new technologies, which may impact on the assessment of histologic criteria in excised breast cancers.
Allergic Reactions to Dipyrone: Immediate and Non-Immediate Responses
Authors: Inmaculada Doña, Francisca Gómez, Tahia D. Fernandez, Adriana Ariza, Arturo Ruiz, Maria Isabel Sánchez Rivas, Cristina De Leyva, Maria Isabel Montañez, Antonio Guzman, Miguel Blanca, Maria J. Torres
Journal: Journal of Allergy and Clinical Immunology (2016)
Lack of Carcinogenic Activity and Metabolic Fate of Fluorenylacetamides in Monkeys&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;
Authors: Helen M. Dyer, Margaret G. Kelly, Roger W. O'Gara
Journal: JNCI Journal of the National Cancer Institute (1966)

During the past 4 years, N-2-fluorenylacetamide (2-FAA) and N,N'-2,7-fluorenylenebisacetamide (2,7-FAA) were administered orally to 16 macaque monkeys each, and the copper chelate of N-hydroxy-2-FAA(Cu-N-OH-2-FAA) was injected subcutaneously into 9 monkeys. With few exceptions, the animals were less than 24 hours old when initially exposed to the fluorenylacetamides. Histologic changes in the livers of monkeys fed 2-FAA and 2,7-FAA were relatively slight, and no tumors or hyperplastic nodules have been seen. Cysts and foreign-body granulomas formed at the site of repeated subcutaneous injections of Cu-N-OH-2-FAA. The metabolism of 2-FAA and 2,7-FAA was studied in 4 young male rhesus monkeys. Experiments with C14-labeled compounds showed that 2-FAA is excreted rapidly (72 hours) when given either orally or intra-peritoneally (97% in urine and 3% in feces). Eighty-seven percent of the urinary metabolites were identified by chromatography as 7-hydroxy-2-FAA (76-92% in conjugated form) and the rest as free amines (1.4%) and a mixture of N-OH-2-FAA and 2-FAA (3.7–6.4%). 2,7-FAA, when given orally, is excreted rapidly in the feces. Ninety-eight percent is recoverable, unmetabolized, from the feces within 1 week and 1.65 percent is present in the urine as metabolized material. When given intraperitoneally, however, the excretion is slower and is chiefly in the urine (65% the 1st week and 87% in 3 weeks). Only 13 percent of the compound was recovered from the feces in 22 days (1 O% in the 1st week). Potential metabolites of 2,7-FAA are not yet available for identification of the radioactive materials separated by chromatography. The possible relation of the metabolic behavior of these two fluorenyl compounds to their failure to show any carcinogenic effect after 1 to 3½ years of feeding is discussed.
Role of Amadori-modified nonenzymatically glycated serum proteins in the pathogenesis of diabetic nephropathy.
Authors: M P Cohen, F N Ziyadeh
Journal: Journal of the American Society of Nephrology (1996)

Accelerated nonenzymatic glycation in diabetes, resulting in Amadori-modified proteins and the later-developing advanced glycation end-products, has been mechanistically linked to the pathogenesis of diabetic nephropathy. Recent focus on putative AGE-induced pathophysiology has shifted attention from the possible role of Amadori-modified proteins in the development of diabetic complications. Ample experimental evidence has demonstrated that Amadori-modified serum proteins adversely affect renal glomerular capillary function, structure, and metabolism. Previous studies from the laboratories of this study's authors have shown that human serum containing diabetic concentrations of albumin modified by Amadori-glucose adducts inhibits the replication of murine mesangial cells in culture and stimulates the production and gene expression of type IV collagen. Monoclonal antibodies (A717) specific for Amadori-glycated albumin prevent these abnormalities. In other studies, it has also been shown that in vivo administration of A717 (Fab fragments) retards the progression of diabetic nephropathy in diabetic db/db mice. Neutralizing the effects of the elevated circulating glycated albumin concentration is associated with reduction in proteinuria and mesangial matrix expansion, and prevention of the overexpression of mRNA encoding type IV collagen and fibronectin in the renal cortex. The renoprotective effects of A717 are independent of any change in blood glucose concentrations. These studies implicate Amadori-modified glycated albumin in the pathogenesis of diabetic nephropathy. It is proposed in this study that abrogating the biologic effects of increased glycated albumin in diabetes has novel therapeutic potential in the management of diabetic renal complications.
Deletion of Interstitial Genes between <i>TMPRSS2</i> and <i>ERG</i> Promotes Prostate Cancer Progression
Authors: Douglas E. Linn, Kathryn L. Penney, Roderick T. Bronson, Lorelei A. Mucci, Zhe Li
Journal: Cancer Research (2016)

TMPRSS2-ERG gene fusions that occur frequently in human prostate cancers can be generated either through insertional chromosomal rearrangement or by intrachromosomal deletion. Genetically, a key difference between these two mechanisms is that the latter results in deletion of a ∼3-Mb interstitial region containing genes with unexplored roles in prostate cancer. In this study, we characterized two mouse models recapitulating TMPRSS2-ERG insertion or deletion events in the background of prostate-specific PTEN deficiency. We found that only the mice that lacked the interstitial region developed prostate adenocarcinomas marked by poor differentiation and epithelial-to-mesenchymal transition. Mechanistic investigations identified several interstitial genes, including Ets2 and Bace2, whose reduced expression correlated in the gene homologs in human prostate cancer with biochemical relapse and lethal disease. Accordingly, PTEN-deficient mice with prostate-specific knockout of Ets2 exhibited marked progression of prostate adenocarcinomas that was partly attributed to activation of MAPK signaling. Collectively, our findings established that Ets2 is a tumor suppressor gene in prostate cancer, and its loss along with other genes within the TMPRSS2-ERG interstitial region contributes to disease progression. Cancer Res; 76(7); 1869-81. ©2016 AACR.
Open technique has lower evidence of complications
Authors: D M Richards, J Hill, N A Scott, J Bancewicz, M. Irving
Journal: BMJ (1995)

EDITOR,--We disagree with Andy Adam's comments regarding the drawbacks of an open surgical technique for placing long term central venous catheters. It is our practice to place such catheters by using an open cutdown technique under local anaesthesia. We mainly use the cephalic vein, with fluoroscopic screening to ensure correct positioning. With this technique more than 800 catheters have been inserted over the past 10 years, for parenteral nutrition, antibiotics, and chemotherapy. The incidence …
Abstract 15847: Detection of Stress-Induced Myocardial Ischemia by Imaging Using Novel Spectroscopic Analysis of Pre-Exercise 12-Lead ECG
Authors: Gordon L Fung, Barbara J Drew, Elias H Botvinick, Wei-min B Chiu, Gabriel I Cook, Bill Chiu
Journal: Circulation (2012)

Under conventional interpretation, the resting ECG is a required but nondiagnostic step in ischemia screening and evaluation. We hypothesize that spectroscopic analysis for microdamage in materials...
Caffeic acid phenethyl ester (CAPE) as a preventive agent in preclinical model of breast cancer
Authors: Jing Wu, Lori Horton, Maarten Bosland, Jerzy Karkoszka, Krystyna Frenkel
Journal: Cancer Research (2007)

4202  Breast cancer (BCa) therapies cause serious side-effects, hence, an agent inhibiting human BCa growth at nontoxic doses could be useful in treating patients. CAPE is produced by honeybees as a part of propolis, which protects beehives from infections. CAPE, a potent anti-inflammatory agent, causes apoptosis in tumor cells and affects cell cycle, NF-κB, p53, NOS, NQO1, cytokines, and products of other genes required for normal cell functioning. Our goal is to test in a nude mouse xenograft model the hypothesis that CAPE can act as preventive, therapeutic, or adjuvant to a standard BCa therapy. Since estrogen receptor (ER)-α confers a pronounced effect on BCa progression, MCF-7 [ER(+)] & MDA-MB-231 (MDA-231) [ER(-)] were used as model tumor cells and their in vitro responses to CAPE compared to those of controls [MCF-12A, ER(+), and MCF-10A, ER(-)]. Our in vitro results showed that 0.5-5 µM CAPE inhibits MDA-231 cell growth dose- and time-dependently (30.6%±6.9; p  In in vivo studies, Balb/c female nude mice were tested for responses to the dietary non-toxic doses of 10, 50, and 250 nmol CAPE/mouse/day. Mice pre-implanted with E2 were injected with MCF-7 cells in both flanks and fed either regular or one of the three CAPE-containing diets. The half-way through (about one month) results show that CAPE diets caused an overall dose- and time-dependent decreases in rates of tumor growth, as assessed by tumor volume. The most consistent effects were evident using 50 nmol CAPE-containing diet, which caused statistically significant decline in growth of large tumors 19, 26, and 32 days after cell implantation, with 26% (p=0.003), 29% (p=0.014), and 43% (p=0.015) decreases in tumor volume, respectively. The same type of experiments will be performed using MDA-231 cells, but without external E2. In conclusion, the results of both in vitro and xenograft model preclinical studies strongly suggest that CAPE could become useful as a preventive, therapeutic, or adjuvant modality after testing it in clinical phase 1&2 trials. [Study was supported in part by grants from the Susan Komen Foundation. [(BCTR0600476) & NIEHS (ES00260)]
Management of interstitial lung disease associated with connective tissue disease
Authors: Stephen C Mathai, Sonye K Danoff
Journal: BMJ (2016)

The lung is a common site of complications of systemic connective tissue disease (CTD), and lung involvement can present in several ways. Interstitial lung disease (ILD) and pulmonary hypertension are the most common lung manifestations in CTD. Although it is generally thought that interstitial lung disease develops later on in CTD it is often the initial presentation ("lung dominant" CTD). ILD can be present in most types of CTD, including rheumatoid arthritis, scleroderma, systemic lupus erythematosus, polymyositis or dermatomyositis, Sjögren's syndrome, and mixed connective tissue disease. Despite similarities in clinical and pathologic presentation, the prognosis and treatment of CTD associated ILD (CTD-ILD) can differ greatly from that of other forms of ILD, such as idiopathic pulmonary fibrosis. Pulmonary hypertension (PH) can present as a primary vasculopathy in pulmonary arterial hypertension or in association with ILD (PH-ILD). Therefore, detailed history, physical examination, targeted serologic testing, and, occasionally, lung biopsy are needed to diagnose CTD-ILD, whereas both non-invasive and invasive assessments of pulmonary hemodynamics are needed to diagnose pulmonary hypertension. Immunosuppression is the mainstay of treatment for ILD, although data from randomized controlled trials (RCTs) to support specific treatments are lacking. Furthermore, treatment strategies vary according to the clinical situation—for example, the treatment of a patient newly diagnosed as having CTD-ILD differs from that of someone with an acute exacerbation of the disease. Immunosuppression is indicated only in select cases of pulmonary arterial hypertension related to CTD; more commonly, selective pulmonary vasodilators are used. For both diseases, comorbidities such as sleep disordered breathing, symptoms of dyspnea, and cough should be evaluated and treated. Lung transplantation should be considered in patients with advanced disease but is not always feasible because of other manifestations of CTD and comorbidities. Clinical trials of novel therapies including immunosuppressive therapies are needed to inform best treatment strategies.
Brief Communication: In Vitro Growth Promotion of Rat Leukemia L5222 Cells in the Presence of 2-MercaptoethanoI2
Authors: Natalie Pourreau-Schneider
Journal: JNCI Journal of the National Cancer Institute (1975)

Propagation of the transplantable acute rat leukemia L5222 in vitro was highly dependent on the reducing agent 2-mercaptoethanol (2-Me). Maximum growth promotion was obtained in the simultaneous presence of 1.25–2.5×10−4m 2-Me and 30% fetal bovine serum in enriched tissue culture medium NCTC 135. A short exposure to the reducing agent insured growth of the leukemia cells for 5 days, but extended culture necessitated constant presence of the thiol. After 2–8 days of culture, inoculation of the cell suspension produced widespread leukemia in inbred BD IX rats.
Orthotopic liver transplantation for hepatocellular car- cinoma after successful downstaging: results from the Belgian multicentre cohort
Authors: J. Schreiber, J Lerut, C Verslype, H Van Vlierberghe, Lucidi, Olivier Detry, L Vanghia, F Puleo, E Trépo, ME Inostroza, H Poels, R Troisi, Jean Delwaide, SM Francque, Donckier, C Moreno
Journal: Hepatology (2014)
Randomized phase II trial of sorafenib (SO) with temsirolimus (TEM) or tipifarnib (TIPI) in metastatic melanoma: Southwest Oncology Group Trial S0438.
Authors: K. A. Margolin, J. Moon, L. E. Flaherty, C. D. Lao, W. L. Akerley, J. A. Sosman, J. M. Kirkwood, V. K. Sondak
Journal: Journal of Clinical Oncology (2010)

8502 Background: BRAF and N-RAS mutations occur in 50% and 15%-20% of melanomas, respectively, while lack of functional PTEN enhances PI3 kinase/AKT/mTOR pathway signaling. Combinations that presumably inhibit parallel or sequential steps may overcome resistance to single agents. This randomized phase II trial tested 2 such combinations—SO plus TEM or TIPI—as first-line therapy of advanced melanoma. Methods: To assess the objective response (OR) rate and progression-free survival (PFS), patients (pts) with previously untreated non-ocular metastatic melanoma were randomized to (arm A) SO 200 mg po bid plus TEM 25 mg iv weekly, or (arm B) SO 400 mg po qam and 200 mg po qpm continuously plus TIPI 100 mg po days 1-21 q28 days in 2-stage accrual. After the first 30 pts in each arm, ≥ 3 responses or ≥ 9 patients progression-free at > 4 months were required to proceed to stage 2, adding 25 pts. Dose adjustments (1 or both drugs) were based on reported agent-specific toxicities. Results: In stage 1, 48 pts enrolled on arm A, 45 evaluable for PFS and 44 for response. In Arm A, stage I partial response (PR) = 2 pts, 4-mo PFS = 11 pts, Arm A then accrued to stage 2, total 67 pts; the final results will be reported. In stage I, 42 pts enrolled on Arm B, 41 evaluable for PFS and response with 1 PR and 4-mo PFS = 8 pts. Arm B was then closed. Toxicity was predominantly diarrhea, rash, hyperlipidemia and fatigue. Serious toxicity: fatal interstitial pneumonitis, gastrointestinal bleed, hypokalemia, left ventricular dysfunction and pulmonary dysfunction (1 pt each in arm A), and grade 4 hyperlipidemia (1 pt in arm B). Conclusions: These combinations appear to show insufficient activity, possibly due to poor pathway inhibition at tolerated doses. It was later reported that SO is inactive against BRAF and modestly inhibits several other cellular kinases. Molecularly targeted combinations that block parallel signaling pathways, including MAP kinase and others, may still hold promise in melanoma. Successful combination Rx will depend on drugs with improved therapeutic index in pts selected by tumor genotype. No significant financial relationships to disclose.
Facial surgeons call for review of two week cancer referral system
Authors: Jacqui Wise
Journal: BMJ (2016)

Facial surgeons have called for an urgent review of the two week fast track cancer referral system, saying that it is overwhelming the NHS and delaying access to treatment for patients who actually have head and neck cancer.

Their warning comes as a systematic review, published in the British Journal of Oral and Maxillofacial Surgery , showed that as few as 6.6% of fast track GP referrals for head and neck cancer turn out to be cancers.1 And a separate study in the same journal showed that the 2015 National Institute for Health and Care Excellence (NICE) referral guidelines for head and neck cancer were overly sensitive and not specific enough.2

The British Association of Oral and Maxillofacial Surgeons said that the two week referral system was not based on evidence. They also claimed that the problem was not confined to head and neck cancer because other studies had shown that, with breast, gastrointestinal, and colorectal cancer, the proportion of patients referred within two weeks who turn out to have cancer rarely exceeds 10%. …
Impact of induction chemotherapy and adjuvant radiation therapy on outcome after extrapleural pneumonectomy for malignant pleural mesothelioma
Authors: M. de Perrot, R. Feld, M. Anraku, A. Bezjak, R. Burkes, H. Roberts, J. Cho, A. Visbal, N. Leighl, S. Keshavjee, M. Johnston
Journal: Journal of Clinical Oncology (2007)

7708 Background: Examine the results of tri-modality therapy for malignant pleural mesothelioma (MPM). Methods: Protocol consisted of induction cisplatin-based chemotherapy, followed by extrapleural pneumonectomy (EPP) and adjuvant hemithoracic radiation therapy (RT) to 54 Gy. Results: A total of 60 patients were suitable candidates for tri-modality therapy between 01/2001 and 01/2007. Induction chemotherapy was administered to 56 patients; 4 patients underwent EPP without induction chemotherapy because of patient refusal (n=2), previous chemotherapy (n=1) and sarcomatoid MPM (n=1). Chemotherapy included vinorelbine/cisplatin (n=26), pemetrexed/cisplatin (n=26) and gemcitabine/cisplatin (n=4). EPP was performed in 47 patients; 13 patients did not undergo EPP because of tumor progression during chemotherapy (n=2), extensive chest wall involvement at surgery (n=6), or involvement of mediastinal lymph nodes at mediastinoscopy (n=5). Three patients (6%) died within 30 days of surgery. Pathological stage was II (n=6), III (n=35), and IV (n=6). Adjuvant RT was administered postoperatively to 36 patients and is ongoing in 5 patients; 6 patients did not receive adjuvant RT because of fatigue (n=5) or previous RT (n=1), and 4 patients did not complete RT up to 54 Gy. Overall survival for the 23 patients who completed the tri-modality therapy was 37% at 3 years with a median survival of 15 months. Eleven of the 23 patients had recurrence after a median of 8 months (range, 2–13 months). Recurrences were locoregional (n=2), in contralateral chest (n=3), abdomen (n=3), contralateral chest and abdomen (n=2), or pericardium (n=1). Among patients undergoing EPP, disease-free survival was longer in patients undergoing adjuvant high dose hemithoracic RT (p=0.07), in epithelial tumors (p=0.03), and in early stage (p=0.07). Overall survival was influenced by histology (p=0.007) and stage (p=0.05), but not by adjuvant high dose hemithoracic RT (p=0.5). The type of chemotherapy had no impact on disease-free and overall survival. Conclusions: Aggressive tri-modality therapy is feasible in selected patient with MPM. Adjuvant high dose hemithoracic RT can improve disease free survival and achieve good local control. No significant financial relationships to disclose.