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The measurement of isotopic abundances and ratio variations of plutonium can provide important information about the sources and behaviours of radiogenic isotopes in the environment. The detection of ultra-trace isotopes of plutonium is increasing interest in the scientific literature for the determination of soil erosion rates due to their long retention times in the environment. The characteristics of plutonium within the environment make it an ideal tracer for the determination of soil redistribution rates and its robustness presents the opportunity to replace more commonly used radioisotopes such as 137Cesium and 210Lead. However, ultra-trace analysis of plutonium (fg g−1) presents analytical challenges which must be overcome in a variety of soil types. Inductively Coupled Plasma Mass Spectrometry has proven valuable for detection of plutonium in a range of environmental samples. However, severe polyatomic interferences from uranium isotopes significantly limits its application. Due to the improvements in detection sensitivity and reaction cell technology, inductively coupled plasma tandem mass spectrometry, which is also commonly referred to as triple quadrupole inductively coupled plasma tandem mass spectrometry (ICP-MS/MS), has emerged as an exceptional tool for ultra-trace elemental analysis of plutonium isotopes in environmental samples overcoming the limitations of standard quadrupole ICP-MS such as limited sensitivity and cost of analysis. In this review, common methods reported in the literature for the separation and subsequent detection of plutonium isotopes are compared to recent advances in analysis using ICP-MS/MS technology. Graphical Abstract

Health disparities exist in incidence, treatment, and survival of esophageal and gastric cancer based on socioeconomic and minority racial/ethnic group status. How socioeconomic and minority status affect access and utilization of precision oncology in foregut malignancies is not well understood. Based on other cancer types, multiple intrinsic and extrinsic factors influence utilization of cancer genetic testing, participation in precision oncology clinical trials, and access to molecularly targeted therapies. As precision oncology becomes more common in the treatment of foregut malignancies, health equity will require ongoing identification of sources of disparities and proposal of practical solutions.

Soil erosion accelerated by poor agricultural practices, land degradation, deprived infrastructure development and other anthropogenic activities has important implications for nutrient cycling, land and lake productivity, loss of livelihoods and ecosystem services, as well as socioeconomic disruption. Enhanced knowledge of dynamic factors influencing soil erosion is critical for policymakers engaged in land use decision-making. This study presents the first spatio-temporal assessment of soil erosion risk modelling in the Winam Gulf, Kenya using the Revised Universal Soil Loss Equation (RUSLE) within a geospatial framework at a monthly resolution between January 2017 and June 2020. Dynamic rainfall erosivity and land cover management factors were derived from existing datasets to determine their effect on average monthly soil loss by water erosion. By assessing soil erosion rates with enhanced temporal resolution, it is possible to provide greater knowledge regarding months that are particularly susceptible to soil erosion and can better inform future strategies for targeted mitigation measures. Whilst the pseudo monthly average soil loss was calculated (0.80 t ha−1 month−1), the application of this value would lead to misrepresentation of monthly soil loss throughout the year. Our results indicate that the highest erosion rates occur between February and April (average 0.95 t ha−1 month−1). In contrast, between May and August, there is a significantly reduced risk (average 0.72 t ha−1 month−1) due to the low rainfall erosivity and increased vegetation cover as a result of the long rainy season. The mean annual gross soil loss by water erosion in the Winam Gulf catchment amounts to 10.71 Mt year−1, with a mean soil loss rate of 9.63 t ha−1 year−1. These findings highlight the need to consider dynamic factors within the RUSLE model and can prove vital for identifying areas of high erosion risk for future targeted investigation and conservation action.

In a 2019 editorial entitled ‘The Society for Environmental Geochemistry and Health (SEGH): building for the future’ (Watts et al. 2019), SEGH President Dr Michael Watts and all current board members outlined their aspirations and initiatives for the Society’s expansion into the new decade and beyond. Central to these efforts was the establishment of a dedicated group of early career researchers (ECRs) within SEGH to foster interaction, collaboration, mentorship and ultimately the expansion of this demographic. SEGH defines ECRs as undergraduate or postgraduate (Masters/PhD) students or as scientists having received their highest degree (BSc, MSc or PhD) within the past 5 years. ECRs currently make up approximately 20% of SEGH memberships, and nurturing growth at grassroots level is a critical strategy in preserving the Society’s long-term future if it is to remain relevant in an ever more competitive research landscape. With this in mind, ECR representatives currently sitting on the board took the initiative to follow up the 2019 editorial from an ECR perspective, with contributions made exclusively by members of this group. Drawing from personal experiences, we focus on key aspects of SEGH as a society and a community, but more importantly as a wider discipline and career path. We highlight the unique selling points of SEGH membership to ECRs, while voicing our wishes for improvement with the overall aim of promoting the society, and the society’s core values. Our hope is that we can attract more ECRs to our diverse community and enhance the experience of our current members.

Peptoids, N-substituted glycine oligomers, are a class of diverse and sequence-specific peptidomimetics with wide-ranging applications. Advancing the functional repertoire of peptoids to emulate native peptide and protein functions requires engineering peptoids that adopt regular secondary and tertiary structures. An understanding of how changes to peptoid sequence change structural features, particularly in water-soluble systems, is underdeveloped. To address this knowledge gap, five 15-residue water-soluble peptoids that include naphthalene-functionalized side chains were designed, prepared, and subjected to a structural study using a palette of techniques. Peptoid sequence designs were based on a putative amphiphilic helix peptoid bearing structure-promoting (S)-N-(1-naphthylethyl)glycine residues whose self-association in water has been studied previously. New peptoid variants reported here include sequence changes that influenced peptoid conformational flexibility, functional group patterning (amphiphilicity), and hydrophobicity. Peptoid structures were evaluated and compared using circular dichroism spectroscopy, fluorescence spectroscopy, and size exclusion chromatography. Spectral data confirmed that sequence changes alter peptoids' degree of assembly and the organization of self-assembled structures in aqueous solutions. Insights gained in these studies will inform the design of new water-soluble peptoids with regular structural features, including desirable higher-order (tertiary and quaternary) structural features.

Studies that identify a new supramolecular host for the highly toxic and prevalent carcinogen benzo[a]pyrene (BP) are reported here. By monitoring changes to absorption and fluorescence spectra, the interaction between BP and two peptoids (N-substituted glycine oligomers) of different length and self-association propensities were compared. Peptoid length and solvent choice influence spectral features. Observed trends support that peptoid self-association in aqueous solution generates a hydrophobic core to which BP can associate.

In this study, we provide a quantitative description of the adsorption of water-soluble N-substituted glycine oligomers (peptoids) to supported lipid bilayers that mimic mammalian plasma membranes. We prepared a small array of systematically varied peptoid sequences ranging in length from 3 to 15 residues. Using the nonlinear optical method second harmonic generation (SHG), we directly monitored adsorption of aqueous solutions of 3- and 15-residue peptoids to phospholipid membranes of varying physical phase, cholesterol content, and head group charge in physiologically relevant pH buffer conditions without the use of extrinsic labels. Equilibrium binding constants and relative surface coverages of adsorbed peptoids were determined from fits to the Langmuir model. Three- and 15-residue peptoids did not interact with cholesterol-containing lipids or charged lipids in the same manner, suggesting that a peptoid’s adsorption mechanism changes with sequence length. In a comparison of four three-residue peptoids...

This article shows how to apply the qualitative definition of IPLs within the setting of a process hazard analysis (PHA) to get most of the gain from Layer of Protection Analysis (LOPA) without doing a LOPA (without using numerical values). The article includes an implementation path to develop PHA leader competencies to guide the qualitative approach. We also show the way we use a PHA team to identify when a SIF is needed and to select the proper target safety integrity level (SIL). This portion of the SIL evaluation and the identification and labeling of the IPLs during the PHA/hazard and operability analysis (HAZOP) does not take any longer than a normal PHA/HAZOP, once the right habits are established. Note that this approach eliminates the need for a separate SIL Evaluation Study to identify the SIFs and select the target SIL. Finally, the article ties together these two specific topics, along with the topic of making risk judgments, to show there is less than 5% need to go beyond HAZOP, and less than 0.01% need to go beyond LOPA. © 2016 American Institute of Chemical Engineers Process Saf Prog 35: 349–359, 2016

Drawing from a career from 1963 through 2016 in the chemical and process industries, this article will describe some informal practices of process safety elements observed during the Master-Apprentice era of the 1960s. The article will trace the development of incident investigation, Process Hazard Analysis, and Fault Tree Analysis tools used by the author. It will touch on safety instrumented systems and the development of Layer of Protection Analysis to determine how strong the safety instrumented functions should be. © 2015 American Institute of Chemical Engineers Process Saf Prog 35: 8–12, 2016

A desire to replicate the structural and functional complexity of proteins with structured, sequence-specific oligomers motivates study of the structural features of water-soluble peptoids (N-substituted glycine oligomers). Understanding the molecular-level details of peptoid self-assembly in water is essential to advance peptoids' application as novel materials. Peptoid 1, an amphiphilic, putatively helical peptoid previously studied in our laboratory, shows evidence of self-association in aqueous solution. In this work, we evaluate how changes to aqueous solution conditions influence the self-association of 1. We report that changes to pH influence the fluorescence and CD spectroscopic features as well as the peptoid's interaction with a solvatochromic fluorophore and its apparent size as estimated by size exclusion chromatography. Addition of guanidine hydrochloride and ammonium sulfate also modulate spectroscopic features of the peptoid, its interaction with a solvatochromic fluorophore, and its elution in size exclusion chromatography. These data suggest that the ordering of the self-assembly changes in response to pH and with solvent additives and is more ordered at higher pH and in the presence of guanidine hydrochloride. The deeper understanding of the self-association of 1 afforded by these studies informs the design of new stimuli-responsive peptoids with stable tertiary or quaternary structures.

The synthesis and fluorescence spectroscopy studies of 21 peptoids, including 19 new tripeptoids, are described. Insight into sequence features that influence biophysical properties in the presence and absence of unilamellar lipid vesicles is provided. Concomitantly, we highlight the educational value of training undergraduates in multidisciplinary research using peptoid science.

Peptoids are versatile peptidomimetic molecules with wide‐ranging applications from drug discovery to materials science. An understanding of peptoid sequence features that contribute to both their three‐dimensional structures and their interactions with lipids will expand functions of peptoids in varied fields. Furthermore, these topics capture the enthusiasm of undergraduate students who prepare and study diverse peptoids in laboratory coursework and/or in faculty led research. Here, we present the synthesis and study of 21 peptoids with varied functionality, including 19 tripeptoids and 2 longer oligomers. We observed differences in fluorescence spectral features for 10 of the tripeptoids that correlated with peptoid flexibility and relative positioning of chromophores. Interactions of representative peptoids with sonicated glycerophospholipid vesicles were also evaluated using fluorescence spectroscopy. We observed evidence of conformational changes effected by lipids for select peptoids. We also summarize our experiences engaging students in peptoid‐based projects to advance both research and undergraduate educational objectives in parallel.

Professional athletes may suddenly find themselves well off, but often their spending, saving, and gifting goals pull them in many directions simultaneously. Systematic, quantitative wealth planning that matches objectives with individual circumstances is critical in defining, evaluating, and realizing the athlete’s financial blueprint. The preferred methodology is combining behavioral goals-based investing with the efficiency of “modern portfolio theory,” which can reinforce each other symbiotically: The key is to separate core-capital requirements—what the athlete will need to support his lifestyle—from excess capital, which can be put to discretionary uses. Working with an advisory team of professionals that includes an investment expert will increase the likelihood of the athlete satisfying both his needs and wants—or, conversely, deferring some of his goals until certain milestones are met.

Adults with primary malignant glioma have an unacceptably poor outcome. Although temozolomide plus radiotherapy improves survival of newly diagnosed glioblastoma multiforme (GBM) patients,1 most patients develop tumor progression within 1 – 2 years. Outcome following recurrence is poor.2 Most tumors recur at or adjacent to the site of origin, indicating that failure to eradicate local tumor growth is a major factor contributing to poor outcome.3 For this reason, we have focused on augmenting local control to improve overall outcome by administering tumor-associated radiolabeled monoclonal antibodies (mAbs) directly into spontaneous tumor cysts, surgically created resection cavities (SCRCs), the intrathecal space, and solid tumors.4–8 Tenascin, an extracellular matrix hexabrachion glycoprotein, is expressed ubiquitously in several cancers, including high-grade gliomas, but not in normal brain.9,10 mAb 81C6, a murine isotype 2b immunoglobulin G (IgG2b) that binds to an alternatively spliced region of tenascin,9–12 reacts specifically with tenascin-expressing tumors.13 When labeled with 131I, 81C6 delays tumor growth and prolongs survival in flank and intracranial human xenograft models.14,15 An initial human experience demonstrated the specificity of 131I-labeled murine 81C6 (131I-81C6) mAb compared to 125I-labeled nonspecific IgG2b mAb but also revealed limited intratumor penetration following intravenous or intraarterial administration.16 Hence, subsequent studies incorporated administration into an SCRC, tumor cyst, or intrathecal space. Prior phase I studies established the maximum tolerated dose (MTD) of 131I-81C6 injected into the SCRC of patients with newly diagnosed and recurrent malignant brain tumors to be 120 mCi and 100 mCi, respectively.7,8 Phase II studies demonstrated that patients treated with 131I-81C6 had favorable overall survival compared to established historical controls.4,5 Based on constraints of our U.S. Food and Drug Administration (FDA)-approved phase I and II studies, patients received a “fixed” dose of 131I-81C6 in which the administered level of radioactivity was the same among groups of patients. As a result of this design, 131I dosages were not adjusted to compensate for patient-specific variables such as SCRC volume and SCRC residence time. Dosimetry of patients treated on these studies revealed a wide range of radiation absorbed doses at the SCRC margin. Moreover, outcome correlated with delivered radiation dose to the SCRC. Specifically, patients who received less than 44 Gy were more likely to develop recurrent tumor, whereas those who received significantly more than 44 Gy were more likely to develop radionecrosis. Therefore, a 44-Gy boost to the SCRC margin was considered optimal.17 We now report a pilot study using a novel, patient-specific dosing strategy of 131I-81C6 designed to achieve a 44-Gy boost to the 2-cm SCRC margin in adults with newly diagnosed malignant gliomas.

The classic reference from CCPS “Inherently Safer Chemical Processes, A Life Cycle Approach”, 1st edition, 1996, was updated in 2006–2007. The goal of this book is to influence the future state of chemical process evolution by illustrating and emphasizing the merits of integrating process research, development, and design into a comprehensive process that balances safety, capital, and environmental concerns throughout the life cycle of the process. The authors hope that this book will influence the next generation of engineers and chemists as well as current practitioners and managers in the field of chemical processing. Lessons learned since the first edition of the CCPS® inherent safety concept book in 1996, combined with the fact that inherently safer design (ISD) is becoming more widely accepted prompted CCPS® to update the book. Also, since 1996, several jurisdictions have mandated consideration of ISD for certain facilities, and such requirements have been proposed at the Federal level in the United States. In particular, there is a need for more guidance, especially in practical, step-wise approaches to conduct inherently safer studies. This new edition builds on the first edition with the same philosophy but clarifies the concept with recent research and thoughts of practitioners, added examples, added more industry methods, security issues, and a discussion on regulatory issues. A key feature of the new book is the clarification of the meaning of ISD by setting the 1st and 2nd orders of ISD. This is distinguished from layers of protection and other traditional process safety concepts. Numerous added examples and checklists make this a very practical guide and a good edition to the library of anyone involved in process risk management. © 2008 American Institute of Chemical Engineers Process Saf Prog, 2008

Purpose: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available salvage therapy. This study was conducted to determine if the combination of a novel antiangiogenic therapy, bevacizumab, and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma. Experimental Design: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m2, whereas patients not taking enzyme-inducing antiepileptic drugs received 125 mg/m2. Toxicity and response were assessed. Results: Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients). The median progression-free survival was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was 72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli, and one patient had an arterial ischemic stroke. Conclusions: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.

Purpose: More brain tumor markers are required for prognosis and targeted therapy. We have identified and validated promising molecular therapeutic glioblastoma multiforme (GBM) targets: human transmembrane glycoprotein nonmetastatic melanoma protein B (GPNMBwt) and a splice variant form (GPNMBsv, a 12-amino-acid in-frame insertion in the extracellular domain). Experimental Design: We have done genetic and immunohistochemical evaluation of human GBM to determine incidence, distribution, and pattern of localization of GPNMB antigens in brain tumors as well as survival analyses. Results: Quantitative real-time PCR on 50 newly diagnosed GBM patient tumor samples indicated that 35 of 50 GBMs (70%) were positive for GPNMBwt+sv transcripts and 15 of 50 GBMs (30%) were positive for GPNMBsv transcripts. Normal brain samples expressed little or no GPNMB mRNA. We have isolated and characterized an anti-GPNMB polyclonal rabbit antiserum (2640) and two IgG2b monoclonal antibodies (mAb; G11 and U2). The binding affinity constants of the mAbs ranged from 0.27 × 108 to 9.6 × 108 M−1 measured by surface plasmon resonance with immobilized GPNMB, or 1.7 to 2.1 × 108 M−1 by Scatchard analyses with cell-expressed GPNMB. Immunohistochemical analysis detected GPNMB in a membranous and cytoplasmic pattern in 52 of 79 GBMs (66%), with focal perivascular reactivity in ∼27%. Quantitative flow cytometric analysis revealed GPNMB cell surface molecular density of 1.1 × 104 to 7.8 × 104 molecules per cell, levels sufficient for mAb targeting. Increased GPNMB mRNA levels correlated with elevated GPNMB protein expression in GBM biopsy samples. Univariate and multivariate analyses correlated expression of GPNMB with survival of 39 GBM patients using RNA expression and immunohistochemical data, establishing that patients with relatively high mRNA GPNMB transcript levels (wt+sv and wt), >3-fold over normal brain, as well as positive immunohistochemistry, have a significantly higher risk of death (hazard ratios, 3.0, 2.2, and 2.8, respectively). Conclusions: Increased mRNA and protein levels in GBM patient biopsy samples correlated with higher survival risk; as a detectable surface membrane protein in glioma cells, the data indicate that GPNMB is a potentially useful tumor-associated antigen and prognostic predictor for therapeutic approaches with malignant gliomas or any malignant tumor that expresses GPNMB.

Purpose To determine whether sentinel lymph node (LN) sampling (SLNS) could reduce the number of nodes required to characterize micrometastatic disease (MMD) in patients with potentially curable colon cancer. Patients and Methods Cancer and Leukemia Group B 80001 was a study to determine whether SLNS could identify a subset of LNs that predicted the status of the nodal basin for resectable colon cancer and, therefore, could be extensively evaluated for the presence of micrometastases. Patients enrolled onto this study underwent SLNS after injection of 1% isosulfan blue, and both sentinel nodes (SNs) and non-SNs obtained during primary tumor resection were sectioned at multiple levels and stained using anti–carcinoembryonic antigen and anticytokeratin antibodies. Results Using standard histopathology, SNs failed to predict the presence of nodal disease in 13 (54%) of 24 node-positive patients. Immunostains were performed for patients whose LNs were negative by standard histopathology. Depending on the immunohistochemical criteria used to assign LN positivity, SN examination resulted in either an unacceptably high false-positive rate (20%) or a low sensitivity for detection of MMD (40%). Conclusion By examining both SNs and non-SNs, this multi-institutional study showed that SNs did not accurately predict the presence of either conventionally defined nodal metastases or MMD. As a result, SLNS is not a useful technique for the study of MMD in patients with colon cancer.

Purpose: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent malignant glioma.Patients and Methods: Gefitinib and sirolimus were administered on a continuous daily dosing schedule at dose levels that were escalated in successive cohorts of malignant glioma patients at any recurrence who were stratified based on concurrent use of CYP3A-inducing anticonvulsants [enzyme-inducing antiepileptic drugs, (EIAED)]. Pharmacokinetic and archival tumor biomarker data were also assessed.Results: Thirty-four patients with progressive disease after prior radiation therapy and chemotherapy were enrolled, including 29 (85%) with glioblastoma multiforme and 5 (15%) with anaplastic glioma. The MTD was 500 mg of gefitinib plus 5 mg of sirolimus for patients not on EIAEDs and 1,000 mg of gefitinib plus 10 mg of sirolimus for patients on EIAEDs. DLTs included mucositis, diarrhea, rash, thrombocytopenia, and hypertriglyceridemia. Gefitinib exposure was not affected by sirolimus administration but was significantly lowered by concurrent EIAED use. Two patients (6%) achieved a partial radiographic response, and 13 patients (38%) achieved stable disease.Conclusion: We show that gefitinib plus sirolimus can be safely coadministered on a continuous, daily dosing schedule, and established the recommended dose level of these agents in combination for future phase 2 clinical trials.

This paper describes an actual incident investigation into unexpected premature failure of sealed diaphragm pressure transmitters in a chemical process. Some nontypical investigation tools from the CCPS Guidelines for Investigating Chemical Process Incidents (2nd edition) were used. A typical failure allowed a release of a corrosive process fluid with potential injury to personnel. The failures also required a shutdown of the process with loss of production. The cause of the problem was elusive; pressure transmitters from the same manufacturer had no problems in a similar process unit, although component designs differed between the two units. The investigation included confirmation of materials of construction, photographic and visual analyses of failed components, simulation of assembly of the pressure transmitter in the process and measurement of torque values, and brainstorming of possible failure mechanisms. Several hypotheses were tested using a fact-hypothesis matrix to determine most likely cause scenarios. Similarly, a matrix was used to illustrate which scenarios could be prevented by which corrective actions. The investigation included a root cause analysis tree to confirm cause scenarios. The paper discusses the incident investigation process, including diversity of skills on the investigation team, and how each of the tools was used. The paper also discusses the communication of the findings to operations. Language: en

Purpose To assess the efficacy and toxicity of intraresection cavity iodine-131–labeled murine antitenascin monoclonal antibody 81C6 (131I-m81C6) among recurrent malignant brain tumor patients. Patients and Methods In this phase II trial, 100 mCi of 131I-m81C6 was injected directly into the surgically created resection cavity (SCRC) of 43 patients with recurrent malignant glioma (glioblastoma multiforme [GBM], n = 33; anaplastic astrocytoma [AA], n = 6; anaplastic oligodendroglioma [AO], n = 2; gliosarcoma [GS], n = 1; and metastatic adenocarcinoma, n = 1) followed by chemotherapy. Results With a median follow-up of 172 weeks, 63% and 59% of patients with GBM/GS and AA/AO tumors were alive at 1 year. Median overall survival for patients with GBM/GS and AA/AO tumors was 64 and 99 weeks, respectively. Ten patients (23%) developed acute hematologic toxicity. Five patients (12%) developed acute reversible neurotoxicity. One patient (2%) developed irreversible neurotoxicity. No patients required reoperation for radionecrosis. Conclusion In this single-institution phase II study, administration of 100 mCi of 131I-m81C6 to recurrent malignant glioma patients followed by chemotherapy is associated with a median survival that is greater than that of historical controls treated with surgery plus iodine-125 brachytherapy. Furthermore, toxicity was acceptable. Administration of a fixed millicurie dose resulted in a wide range of absorbed radiation doses to the SCRC. We are now conducting a phase II trial, approved by the US Food and Drug Administration, using patient-specific 131I-m81C6 dosing, to deliver 44 Gy to the SCRC followed by standardized chemotherapy. A phase III multicenter trial with patient-specific dosing is planned.

Purpose We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). Patients and Methods Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). Results Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. Conclusion Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

Objective and Summary Background Data: Sentinel lymph node (LN) sampling, a technique widely used to manage breast cancer and melanoma, seeks to select LNs that accurately predict regional node status and can be extensively examined to identify nodal metastatic disease not detected by standard histopathological staging. For patients with resectable colon cancer, improved identification of LN disease would significantly advance patient care by identifying patients likely to benefit from adjuvant therapy. This study, conducted by 25 surgeons at 13 institutions, examined whether sentinel node (SN) sampling accurately predicted LN status for patients with resectable colon cancer. Methods: SN sampling involved peritumor injection of 1% isosulfan blue, followed by identification of all LN visualized within 10 minutes. SN sampling was performed on 79 of 91 patients enrolled, followed by multilevel sectioning (MLS) of the nodes and examination by a single study pathologist. Results: By standard histopathology, 7 patients had primary disease that was either benign or not colon cancer and were therefore excluded from further studies. Of 72 colon cancer cases studied, 48 (66%) were node-negative and 24 (33%) contained nodal metastases. SNs were successfully located in 66 cases (92%) with an average of 2.1 nodes per patient. SNs were negative in 14 of 24 node-positive cases (58%). MLS revealed tumor in a SN in 1 of these cases, bringing the false-negative rate of SN examination to 54%. Conclusion: This multi-institutional study found that for patients with node-positive colon cancer, SN examination with MLS failed to predict nodal status in 54% of cases. We conclude that SN sampling with MLS, used alone, is unlikely to improve risk stratification for resectable colon cancer.

Introduction: Germ-line mutations of the APC gene are associated with familial adenomatous polyposis, and somatic mutations occur frequently in sporadic colorectal cancer. However, to abrogate APC function, both alleles must be inactivated. Recently, it has been demonstrated that epigenetic modification of the APC promoter influences APC silencing. Here we examined the influence of APC methylation on APC expression in tumors with and without LOH at the APC locus. Material and Methods: 137 sporadic colorectal cancer specimens were investigated for LOH at the 5q locus. The methylation status of the APC promoter was determined by methylation-specific PCR. APC expression was performed by immunohistochemistry. Results: APC expression was reduced or lost in 110 of 137 (80%) tumors and LOH at 5q was found in 13 of 132 (10%) tumors. There was no difference in 5q LOH between tumors with or without intact APC expression. Vice versa, there was no difference in the APC expression in tumors with 5q LOH. Aberrant APC p...

In preclinical studies, BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, plus CPT-11 (irinotecan) exhibits schedule-dependent, synergistic activity against malignant glioma (MG). We previously established the maximum tolerated dose of CPT-11 when administered for 4 consecutive weeks in combination with BCNU administered on the first day of each 6-week cycle. We now report a phase 2 trial of BCNU plus CPT-11 for patients with MG. In the current study, BCNU (100 mg/m2) was administered on day 1 of each 6-week cycle. CPT-11 was administered on days 1, 8, 15, and 22 at 225 mg/m2 for patients receiving CYP3A1- or CYP3A4-inducing anticonvulsants and at 125 mg/m2 for those not on these medications. Newly diagnosed patients received up to 3 cycles before radiotherapy, while recurrent patients received up to 8 cycles. The primary end point of this study was radiographic response, while time to progression and overall survival were also assessed. Seventy-six patients were treated, including 37 with newly diagnosed tumors and 39 with recurrent disease. Fifty-six had glioblastoma multiforme, 18 had anaplastic astrocytoma, and 2 had anaplastic oligodendroglioma. Toxicities (grade > or =3) included infections (13%), thromboses (12%), diarrhea (10%), and neutropenia (7%). Interstitial pneumonitis developed in 4 patients. Five newly diagnosed patients (14%; 95% CI, 5%-29%) achieved a radiographic response (1 complete response and 4 partial responses). Five patients with recurrent MG also achieved a response (1 complete response and 4 partial responses; 13%; 95% CI, 4%-27%). More than 40% of both newly diagnosed and recurrent patients achieved stable disease. Median time to progression was 11.3 weeks for recurrent glioblastoma multiforme patients and 16.9 weeks for recurrent anaplastic astrocytoma/ anaplastic oligodendroglioma patients. We conclude that the activity of BCNU plus CPT-11 for patients with MG appears comparable to that of CPT-11 alone and may be more toxic.

To perform a detailed comparison of the in-house hospital costs of patients undergoing radical perineal prostatectomy (RPP) and radical retropubic prostatectomy (RRP) performed with or without bilateral staging lymph node dissection (BPLND) for localized prostate cancer.A retrospective cost review was done of a cohort of 402 consecutive radical prostatectomies performed at our institution during a 21-month period. The procedure was performed as RPP in 279 (69.4%) and RRP in 123 (30.6%) patients, of whom 10.4% and 61.8%, respectively, underwent BPLND under the same anesthesia. The hospital costs were evaluated for each patient using the categories of surgical, nursing, laboratory/transfusion, and pharmacy. Surgical costs were further subdivided into operating room, anesthesia, and recovery room costs. Univariate and multivariate statistical analyses were applied to identify predictors of procedure-related costs.The median hospital costs of patients undergoing RPP (7195 dollars, range 5052 dollars to 36,237 dollars) were substantially lower than those of patients undergoing RRP (9757 dollars, range 6935 dollars to 27,771 dollars; P = 0.001). The median costs for patients undergoing radical prostatectomy without BPLND were significantly lower in the RPP (7100 dollars, range 5052 dollars to 28,604 dollars) versus RRP (9169 dollars, range 6935 dollars to 16,705 dollars) patients (P = 0.001). The costs for RPP with BPLND (10,048 dollars, range 7529 dollars to 36,237 dollars) versus RRP with BPLND (9973 dollars, range 7658 dollars to 27,771 dollars) were not significantly different (P = 0.900). Patient age and nerve-preservation status did not significantly influence the procedure-related hospital costs.RPP may result in lower in-house costs per patient than RRP in those patients who do not require BPLND. Total hospital costs depend largely on the factors of operating room time, length of stay, and laboratory and transfusion requirements, which may vary among institutions.

Purpose To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. Patients and Methods This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. Results Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. Conclusion Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.

Runt domain transcription factors are important targets of TGF- superfamily proteins and play a crucial role in mammalian development. Three mammalian runt-related genes, RUNX1, RUNX2 and RUNX3, have been described. RUNX3 has been shown to be a putative tumor suppressor gene localized to chromosome 1p36, a region showing frequent loss of heterozygosity events in colon, gastric, breast and ovarian cancers. Because of the important role of TGFsignaling in the human colon, we hypothesized that RUNX3 may serve as a key tumor suppressor in human colon cancers and colon cancer-derived cell lines. We examined RUNX3 expression and the frequency of RUNX3 promoter hypermethylation in 17 colon cancer cell lines and 91 sporadic colorectal cancers. Semiquantitative analysis of RUNX3 transcripts was performed by RT-PCR and de novo methylation of the RUNX3 promoter was studied by a methylation-specific PCR (MSP) assay. Nineteen of 91 informative tumors (21%) and 11 of 17 (65%) colon cancer cell lines exhibited hypermethylation of the RUNX3 promoter. Interestingly, RUNX3 promoter hypermethylation was more common in tumors exhibiting high frequency of microsatellite instability (MSI-H) (33% of MSI-H vs. 12% of MSI-L/MSS tumors; p 0.012). Hypermethylation of the RUNX3 promoter correlated with loss of mRNA transcripts in all cell lines. RUNX3 promoter methylation was reversed and its expression restored in SW48 and HCT15 colon cancer cells after treatment with the demethylating agent 5-aza-2-deoxycytidine, indicating that loss of expression is caused by epigenetic inactivation in colon carcinogenesis. This is the first demonstration of frequent de novo hypermethylation of the RUNX3 promoter in sporadic colon cancers. The significant association of RUNX3 promoter hypermethylation with MSI-H colon cancers suggests that RUNX3 is a novel target of methylation, along with the hMLH1 gene, in the evolution of MSI-H colorectal cancers. © 2004 Wiley-Liss, Inc.