bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional metamorphism of the Appalachian Humber zone of Gaspé Peninsula: 40Ar/39Ar evidence for crustal thickening during the Taconian orogeny
Authors: Pincivy Alix , Malo Michel , Ruffet Gilles , Tremblay Alain , Sacks Paul E
Published: March 2003

Geochronological studies on the timing of deformation and metamorphism along the Laurentian margin have shown that the ages of metamorphic events change along-strike within the Newfoundland  southern Quebec segment of the Canadian Appalachians. The Gaspé Peninsula is located at mid-point of the two extremities of this segment. New single-grain laser 40Ar/39Ar plateau ages solely reflect latest MiddleLate Ordovician metamorphism. Samples taken within the internal Humber zone in the Shickshock Group rocks yield 40Ar/39Ar muscovite and hornblende ages ranging from 457 to 454 Ma. Samples from the Amphibolite du Diable, the metamorphic sole of the Mont Albert ophiolite, yield 40Ar/39Ar muscovite and hornblende ages ranging from 459 to 457 Ma. Ordovician ages of the internal Humber zone are consistent with 40Ar/39Ar ages from southern Quebec and are interpreted as the result of the emplacement onto the margin of both the ophiolite and its metamorphic sole.
The Nastapoka drift belt, eastern Hudson Bay: implications of a stillstand of the QuebecLabrador ice margin in the Tyrrell Sea at 8 ka BP
Authors: Lajeunesse Patrick , Allard Michel
Published: March 2003

During deglaciation of eastern Hudson Bay, the western margin of the QuébecLabrador sector of the Laurentide Ice Sheet came to a stillstand about 8 14C ka BP along the Nastapoka Hills, a series of topographic highs along the bay. These hills are the northward continuation of the eastern Hudson Bay cuesta system. It left a drift belt consisting of ice-contact submarine fans along the western slopes of the hills, small frontal moraines on hilltops, and grounding-line deposits on sills between the hills. Geomorphological, sedimentary, and radiometric evidence suggest that the stillstand responsible for deposition of the Nastapoka drift belt was either entirely or partly synchronous with the deposition of the Sakami moraine farther south. There was a period when these two morainic systems marked a continuous ice margin. These stillstands occurred due to reduction of ablation at the ice margin. In the Nastapoka Hills, ablation slowed down when the ice margin was anchored on higher relief and stood at a regional break of slope that grounded the ice margin and reduced water depth at the ice terminus, therefore, putting an end to intensive calving. In eastern James Bay and southeastern Hudson Bay, stabilization of the ice margin was caused by a reequilibrium of the ice terminus after a rapid drop of water level due to the drainage of Glacial Lake Ojibway. The new data improves the resolution of the position ice margin in eastern Hudson Bay at 8 ka BP.
Tectonometamorphic evolution of the Acatlan Complex eclogites (southern Mexico)
Authors: Meza-Figueroa Diana , Ruiz Joaquin , Talavera-Mendoza Oscar , Ortega-Gutierrez Fernando
Published: March 2003

The Acatlan Complex of southern Mexico is linked to the evolution of the AppalachianCaledonian chains and records events related to the Taconian, Acadian, and Alleghanian orogenies of northeastern North America. Mafic eclogites and garnet amphibolites from two selected localities are used to partially reconstruct the tectonometamorphic evolution of this complex. Eclogites contain garnet (almandine) + CaNa pyroxene + phengitic mica + zoisiteclinozoisite + quartz ± CaNa amphibole (barroisite, katophorite) ± albitic plagioclase ± rutile. Phase and textural relationships, thermobarometric determinations, and available radiometric ages indicate that eclogite-facies metamorphism took place during the Ordovician at temperatures around 560 ± 60°C and pressures between 11 and 15 kbar (1 kbar = 100 MPa). Eclogites underwent widespread retrogression to epidote-amphibolite then greenschist facies during exhumation, most probably during Devonian times. Epidoteamphibolite facies include the critical assemblage calcic pyroxene + calcic amphibole (magnesiohornblende and pargasite) + muscovite + garnet + plagioclase + epidote ± quartz, whereas greenschist facies is defined by the assemblage actinolite + albitic plagioclase + epidote + chlorite. Thermobarometric data suggest that retrogression occurred at temperatures between 510 ± 20°C and 300 ± 25°C and pressures ranging from 6 to 3.5 kbar. The obtained PT (pressuretemperature) path suggest that the Acatlan Complex evolved in a more complex continental collisional setting, including intraoceanic arcs, than shown in previously proposed models.
New biostratigraphic data from the Lower Jurassic Fernie Formation in the subsurface of west-central Alberta and their stratigraphic implications
Authors: Asgar-Deen Michèle , Hall Russell , Craig Jim , Riediger Cynthia
Published: March 2003

Geophysical gamma-ray log responses and examination of cores from select wells of the lower Fernie Formation document important correlations of several new lithologic units recognized in the subsurface of west-central Alberta. Ammonite faunas and coccolith floras recovered from these cores are illustrated and provide new ages for several of these units, requiring a revision of their correlation with surface stratigraphy of the west-central Alberta foothills. The organic-rich, fine-grained west-central Alberta subsurface lower Fernie Formation sediments are Hettangian to late Toarcian in age and are, therefore, correlative with outcrops of unnamed basal Fernie strata of northeastern British Columbia, Nordegg Member cherty limestones of the Cadomin and Nordegg areas, and with the Red Deer Member and Poker Chip Shale at outcrop in west-central Alberta.
Late Ordovician platform foundering, its paleoceanography and burial, as preserved in separate (eastern Michigan Basin, Ottawa Embayment) basins, southern Ontario
Authors: Sharma Sajal , Dix George R , Riva J FV
Published: March 2003

Comparison of litho-, bio-, and chemostratigraphy in two cores from the northeastern margin of the Michigan Basin (Manitoulin Island) and from within the Ottawa Embayment (eastern Ontario) identifies interbasinal differences of Late Ordovician platform foundering linked to Taconic orogenesis. Graptolite biostratigraphy defines an east-to-west younging (late Edenian to early Maysvillian) of platform burial. A regional unconformity likely caps the platform succession. In both basins, an increased supply of mafic material appears during the final stages of platform collapse, with the accumulation of organic-rich (<8%), petroliferous shales (Collingwood Member  Michigan Basin; Eastview Member  Ottawa Embayment). Both units preserve evidence for deposition coincident with increased dysoxic to possible anoxic bottom-water conditions, but the Collingwood Member accumulated under a relatively stable paleoceanographic environment. Rhythmic interbedding with platform limestone in eastern Ontario, combined with evidence for fluctuating paleoproductivity, suggests the depositional environment of the Eastview Member was more sensitive to higher order controls affiliated with tectonic, oceanographic, and (or) sea level variation. Such interbasinal differences likely reflect a greater rate of subsidence in the Manitoulin region transforming platform sedimentation to a distal ramp facies. In eastern Ontario, a lesser rate of subsidence maintained a shallower water, but open margin, setting. Burial of the Upper Ordovician platform, as preserved in eastern Ontario, occurred during peak dysoxic conditions, with deposition of a hemipelagic facies (Billings Formation) that marks the peak supply of clay-size mafic-derived sediment. Bottom-water ventilation occurred only with appearance of abundant Taconic-derived distal turbidites. An equivalent hemipelagic facies appears to be absent from the Manitoulin region. However, equivalent resedimented deposits are represented by the Blue Mountain Formation.
Cross-strike potential-field anomalies in the Canadian Cordillera
Authors: Cook Frederick A , Lynn C Elissa , Hall Kevin W
Published: March 2003

Application of bandpass and directional filtering to potential-field maps of western Canada has led to the discovery of regionally extensive anomalies crossing the northwest strike of Cordilleran structures. The most prominent of these, the SteamboatFraser trend, is a northsouth-striking feature that projects from the foreland belt in northeastern British Columbia, where it becomes subparallel to anomalies east of the Mackenzie Mountains, southward to the northern limit of the Fraser River strike-slip fault, a distance of about 600 km. Within the hinterland of the Cordillera, the trend appears to spatially correlate with the margins of some Tertiary volcanics. The northeasternmost, and thus most cratonward, Tertiary volcanics are located on the northern projection of the trend. The trend may thus be interpreted as either late, post-orogenic intrusives (e.g., dikes and related volcanic rocks) that are only partially exposed, as pre-orogenic (pre-Mesozoic) features (e.g., faults, dikes) in the crust that were overridden by the Cordilleran thrust sheets, or a combination of these. Although it is not possible to determine which of these (pre- or post-orogenic) is appropriate for the trend, the eventual choice has important implications for the structure and evolution of this part of the Cordillera. If the source of the anomalies is pre-orogenic, a major implication is that Precambrian Shield rocks would be present at depth beneath the southern Canadian Cordillera as far west as the Fraser River fault. Alternatively, if the source is post-orogenic, it represents an anomalously linear feature that has no obvious expression on the surface other than a poorly defined spatial correlation with the margins of some Tertiary volcanics.
Dunes and associated sand transport in a tidally influenced sand-bed channel: Fraser River, British Columbia
Authors: Villard P V , Church M
Published: March 2003

Dunes form annually on the sand bed of the tidally influenced South Arm of Fraser River, British Columbia. Bathymetric surveys along the center of the main channel throughout a snow-melt freshet provided measurements of dune geometry and migration. Dune length, height, and steepness all increase with river discharge. However, lag between the highest flow conditions and development of the largest, steepest dunes reflects the influence of antecedent flow conditions on dune geometry. Population averages of dune height and steepness ratio change more rapidly than dune length, whilst coefficients of variation of dune height, length, and steepness ratio indicate high variability in dune geometry within the estuarine reach during periods of dune growth and decay. Unlike dune geometry, dune migration rates display little lag with flow conditions. The largest coefficients of variation for dune migration occur during periods of rapid change in discharge and tidal fall, corresponding to the onset of rapid change in dune geometry on both rising and falling limbs. Migration rate estimates and geometry measurements are used to estimate associated sand transport. In the absence of hydraulic measurements in the estuary, Mission and Hope discharges are adopted to drive simple statistical models of sand transport as a function of discharge and tidal fall. The models cover 6570% of the transport, and tidal fall is only marginally significant. Comparison with historical direct measurements indicates that the dune-associated transport coincides with bed-load transport in the estuary, and arguments are made that it constitutes the preponderance of all bed-material transport.
Seismotectonic characteristics of the Lower St. Lawrence Seismic Zone, Quebec: insights from geology, magnetics, gravity, and seismics
Authors: Lamontagne Maurice , Keating Pierre , Perreault Serge
Published: March 2003

The estuary of the St. Lawrence River between Baie-Comeau and Sept-Îles is an area where 50 to 100 earthquakes are detected yearly. This study defines the major lineaments of the Precambrian basement and compares them with mapped faults where possible, and examines their possible correlation with the local earthquakes. Onshore, aerial photographs, remote sensing images, and field mapping are used to identify the geological structures of the Precambrian basement, while offshore, they are interpreted from potential field (magnetic, gravity) and a published synthesis of seismic reflection profiles. The Precambrian basement dips towards the southeast under the Appalachian nappes with normal faults with kilometre-scale throw and eastwest or ENEWSW strikes. Onshore, a system of normal brittle faults with a complex history of movements crosscuts both the Precambrian basement and the overlying Ordovician sedimentary cover. Most earthquakes occur beneath the St. Lawrence River at focal depths between about 7 and 25 km that place them well within the Precambrian Shield. In the Lower St. Lawrence Seismic Zone, the trend of the normal faults that changes from SWNE to mostly eastwest, and lateral density anomalies possibly enhance the local stress level. It is also suggested that local faults could be weak because of crustal fluids at depth, possibly under hydrostatic pressure, or to fault gouge, which leads to a lower coefficient of friction. It is possible that the region was intensely fractured by the emplacement of the Sept-Iles layered igneous complex.
Lower Paleozoic configuration of the Quebec reentrant based on improved along-strike paleogeography
Authors: Cousineau Pierre A , Longuépée Hugues
Published: March 2003

An improved paleogeography of the Quebec reentrant has been achieved by examining the nature and distribution of major sediment buildups within this reentrant. The Quebec reentrant has one side produced by rift faults and one side by a major transform fault. The Oak Hill Group was deposited near a triple-rift zone. Clastic sediments of this group formed a large delta that was fed by a major river flowing in the rift valley of the Ottawa graben. The delta must have prograded on a gentle slope platform. No other thick deltaic deposits are known towards the northeast. Instead, facies analyses favor the existence of a promontory near Québec. Still farther to the northeast, the Saguenay graben was not the product of a triple-rift junction. However, it served to funnel sediments to a deep-sea fan, and the adjacent platform was narrow with a steep slope. The lateral distribution of sediments from the Ordovician Taconic orogeny can be explained by this improved paleogeographic reconstruction. The configuration of the Quebec reentrant required the arc to move into the reentrant. The Taconian tectonic wedge progressively accreted the thick sediment buildups that were the Oak Hill delta and the Bas-du-Fleuve deep-sea fan. This allowed them to act as new barriers to orogenic sediment dispersal as the orogeny proceeded.
Synthesis of Nanosize Gd2 O 3 : Eu Phosphor Particles with High Luminescence Efficiency under Ultraviolet Light
Authors: Kang Y. C. , Roh H. S. , Kim E. J. , Park H. D.
Published: March 2003

To synthesize nanosize

Gd

2

O

3

:
Eu

phosphor particles with high luminescence efficiency under UV light, organic additives such as citric acid and ethylene glycol and

Na

2

CO

3

flux were introduced in large-scale spray pyrolysis.

Gd

2

O

3

:
Eu

phosphor particles prepared from solution with polymeric precursors such as citric acid and ethylene glycol had micrometer size and spherical shape. However, particles prepared from polymeric precursor solution with

Na

2

CO

3

flux were nanosize and had nonaggregation characteristics. The as-prepared spherical particles with micrometer size turned into nanosized particles during post-treatment by recrystallization process. The nanosized

Gd

2

O

3

:
Eu

phosphor particles showed high brightness under 254 nm UV light. The photoluminescence (PL) intensity of the particles prepared from polymeric precursor solution with

Na

2

CO

3

flux material and post-treated at 1050°C, which are nanosize and have nonaggregation characteristics, was identical to 109% of that of the

Y

2

O

3

:
Eu

commercial product. The particles post-treated at 1150°C had a PL intensity 34% higher than the commercial product while showing aggregated characteristics. © 2003 The Electrochemical Society. All rights reserved.
The influence of glycosaminoglycans and crosslinking agents on the phenotype of hepatocytes cultured on collagen gels
Authors: Kataropoulou Margarita , Henderson Catherine , Grant Helen
Published: March 2003

The use of primary hepatocyte cultures as in vitro models for studying xenobiotic metabolism and toxicity is limited by the loss of liver-specific differentiated functions with time in culture and the inability of the cells to proliferate. The aim of this study was to investigate the effect of incorporating 20% chondroitin-6-sulphate (Ch6SO4), a glycosaminoglycan (GAG), into collagen gels (0.3% w/v) and crosslinking the gels with either 1-ethyl-3-(3-di methylaminopropyl) carbodiimide (EDAC) or 1,6-diaminohexane (DAH) on the expression of glutathione-Stransferases (GSTs) and the activity of cytochrome P450 in hepatocytes cultured for 48 hours and 7 days. Hepatocytes were isolated from male Sprague–Dawley rats by collagenase perfusion. Cell homogenates were immunoblotted against class α and π GST subunits. To measure cytochrome P450 activity, testosterone hydroxylation was assessed. Viability of the cultured cells was assessed by confocal laser scanning microscopy using the vital stain carboxyfluorescein diacetate (CFDA). Cells cultured on gels crosslinked with EDAC were dead by 48 hours as judged by lack of CFDA-derived fluorescence and absence of GST bands on the immunoblots. The viability and morphology of the cells were unaffected by any of the other components of the substrata tested. Expression of GSTs indicated that the hepatocyte phenotype was stable for at least 48 hours. The addition of GAG did not improve the phenotype at either 48 hours or 7 days in culture, but the combination of GAG and DAH crosslinking improved GST expression in the 7-day cultures. However, the hepatocyte cytochrome P450 activity did not show any improvement on any of the gels. The combination of GAG and DAH crosslinking provided the most stable substratum environment in terms of GST expression in hepatocytes.
Self-limiting cerebellar ataxia following organophosphate poisoning
Authors: Fonseka M MD , Medagoda K , Tillakaratna Y , Gunatilake S B , de Silva H J
Published: March 2003

Deliberate self-harm by ingestion of organophosphate insecticides is a common health problem in Sri Lanka. The poisoning results in an initial life-threatening cholinergic crisis and several intermediate and late neurological and psychiatric manifestations. A patient who developed self-limiting cerebellar signs 8 days after ingestion of dimethoate, an organophosphorous insecticide, is reported on.
Human Kallikrein 6 (hK6): A New Potential Serum Biomarker for Diagnosis and Prognosis of Ovarian Carcinoma
Authors: Diamandis Eleftherios P. , Scorilas Andreas , Fracchioli Stefano , van Gramberen Marleen , de Bruijn Henk , Henrik Alfthan , Soosaipillai Antoninus , Grass Linda , Yousef George M. , Stenman Ulf-Hakan , Massobrio Marco , van der Zee Ate GJ , Vergote Ignace , Katsaros Dionyssios
Published: March 2003

Purpose: The discovery of new ovarian cancer biomarkers that are suitable for early disease diagnosis and prognosis may ultimately lead to improved patient management and outcomes.

Patients and Methods: We measured, by immunoassay, human kallikrein 6 (hK6) concentration in serum of 97 apparently healthy women, 141 women with benign abdominal diseases, and 146 women with histologically proven primary ovarian carcinoma. We then calculated the diagnostic sensitivity and specificity of this test and examined the association of serum hK6 concentration with various clinicopathologic variables and patient survival.

Results: Serum hK6 concentration between normal and benign disease patients was not different (mean, 2.9 and 3.1 μg/L, respectively). However, hK6 in presurgical serum of ovarian cancer patients was highly elevated (mean, 6.8 μg/L; P < .001). Serum hK6 decreased after surgery (to a mean of 3.9 μg/L) in 68% of patients. The diagnostic sensitivity of serum hK6 at 90% and 95% specificity is 52% and 47%, respectively, in the whole patient population. For early stage disease (stage I or II), sensitivity is approximately 21% to 26%. When combined with CA-125, at 90% specificity, sensitivity increases to 72% (for all patients) and to 42% in stage I or II disease. Serum hK6 concentration correlates moderately with CA-125 and is higher in patients with late-stage, higher-grade disease and in patients with serous histotype. Preoperative serum hK6 concentration is a powerful predictor of disease-free and overall survival in both univariate and multivariate analyses.

Conclusions: Serum hK6 concentration seems to be a new biomarker for ovarian carcinoma and may have value for disease diagnosis and prognosis.
Immunotherapy of Advanced Breast Cancer With a Heterophilic Ganglioside (NeuGcGM3) Cancer Vaccine
Authors: Carr Adriana , Rodríguez Edmundo , del Carmen Arango María , Camacho Rolando , Osorio Marta , Gabri Mariano , Carrillo Guido , Valdés Zolidina , Bebelagua Yanín , Pérez Rolando , Fernández Luis Enrique
Published: March 2003

Purpose: A heterophilic ganglioside cancer vaccine was developed by combining NeuGcGM3 with the outer membrane protein complex of Neisseria meningitidis to form very small size proteoliposomes (VSSP). A phase I clinical trial was performed to determine safety and immunogenicity of this vaccine.

Patients and Methods: Stage III to IV breast cancer patients received up to 15 (200 μg) doses of the vaccine by intramuscular injection. The first five doses (induction phase) were given at 2-week intervals, with the remaining treatment (maintenance) administered on a monthly basis.

Results: Twenty-one patients, 11 of whom had metastatic disease, were included. Main toxicities included erythema and induration at the injection site, sometimes associated with mild pain, and low-grade fever (World Health Organization grades 1 and 2). All treated patients who completed the induction phase developed anti-NeuGcGM3 antibody titers between 1:1,280 and 1:164,000 immunoglobulin G (IgG), and 1:640 and 1:164,000 IgM. Noteworthy specific IgA antibodies were induced by vaccination in all stage III patients and in three stage IV patients. Serum antibody levels were higher in the stage III patients, with the larger increases observed after week 32. The antiganglioside IgG subclasses were mainly IgG1 and IgG3. Hyperimmune sera increased complement-mediated cytotoxicity versus P3X63 myeloma cells and a marked IgG differential reactivity against human mammary ductal carcinoma samples.

Conclusion: NeuGcGM3/VSSP/Montanide ISA 51 is an unusual immunogenic ganglioside vaccine and also seems to be safe in this small trial. Immunologic surrogates of activity indicate that this reagent warrants further investigation.
Phase I Clinical and Pharmacology Study of Clofarabine in Patients With Solid and Hematologic Cancers
Authors: Kantarjian Hagop M. , Gandhi Varsha , Kozuch Peter , Faderl Stefan , Giles Francis , Cortes Jorge , O’Brien Susan , Ibrahim Nuhad , Khuri Fadlo , Du Min , Rios Mary Beth , Jeha Sima , McLaughlin Peter , Plunkett William , Keating Michael
Published: March 2003

Purpose: To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia.

Patients and Methods: The initial part of the study defined the MTD and DLT in solid tumors. The second part of the study defined the MTD and DLT in acute leukemia.

Results: The starting dose of clofarabine (15 mg/m2) was myelosuppressive, requiring several dose de-escalations to 2 mg/m2, the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m2, with several escalations to 55 mg/m2. The DLT was reversible hepatotoxicity at 55 mg/m2. The recommended dose for acute leukemia phase II studies was 40 mg/m2. Among 32 treated patients with acute leukemia, two achieved a complete response and three had a marrow complete response without platelet recovery (hematologic improvement), for an overall response rate of 16%. At 40 mg/m2, the median plasma clofarabine level was 1.5 μmol/L (range, 0.42 to 3.2 μmol/L; n = 7). Cellular and plasma pharmacokinetic studies suggested dose proportionality but showed a wide variation in intracellular concentrations of clofarabine triphosphate.

Conclusion: This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m2 for solid tumors, the DLT being myelosuppression; and 40 mg/m2 for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.
Role of DNA Mismatch Repair Defects in the Pathogenesis of Human Cancer
Authors: Peltomäki Päivi
Published: March 2003

The DNA mismatch repair (MMR) system is necessary for the maintenance of genomic stability. In a broad sense, all main functions of the MMR system, including the correction of biosynthetic errors, DNA damage surveillance, and prevention of recombination between nonidentical sequences serve this important purpose. Failure to accomplish these functions may lead to cancer. It is therefore not surprising that inherited defects in the MMR system underlie one of the most prevalent cancer syndromes in humans, hereditary nonpolyposis colon cancer (HNPCC). In addition, acquired defects of the same system may account for 15% to 25%, or even a higher percentage, of sporadic cancers of different organs of the “HNPCC spectrum,” including the colon and rectum, uterine endometrium, stomach, and ovaries. Recent studies indicate that the MMR genes may be involved in the pathogenesis of even a broader spectrum of tumors in one way or another. An updated review of the different features of the human MMR system will be provided, with the emphasis on their implications in cancer development.
Invasion Factors uPA/PAI-1 and HER2 Status Provide Independent and Complementary Information on Patient Outcome in Node-Negative Breast Cancer
Authors: Zemzoum Iris , Kates Ronald E. , Ross Jeffrey S. , Dettmar Peer , Dutta Moshumi , Henrichs Cordula , Yurdseven Suna , Höfler Heinz , Kiechle Marion , Schmitt Manfred , Harbeck Nadia
Published: March 2003

Purpose: The independent clinical relevance of invasion factors urokinase-type plasminogen activator (uPA)/PAI-1 and HER2 status was evaluated in lymph node-negative breast cancer patients (N = 118) without adjuvant systemic therapy after long-term follow-up of more than 10 years (median, 126 months).

Patients and Methods: Levels of uPA and its inhibitor PAI-1 were prospectively measured by enzyme-linked immunosorbent assay in primary tumor tissue extracts. HER2 gene amplification (HER2_AMP) was evaluated by fluorescence in situ hybridization (FISH; Ventana Medical Systems HER-2/neu probe; Tucson, AZ), and HER2 protein overexpression (HER2_EXP) was evaluated by immunohistochemistry (IHC; Oncogene Science antibody Ab-3; Cambridge, MA) on parallel-cut formalin-fixed paraffin-embedded tissue sections.

Results: uPA/PAI-1 was high (either one or both factors were high) in 44% of the tumors. HER2_AMP was detected by FISH in 33% of the patients, and HER2_EXP was found by IHC in 44% of the patients. In a multivariate analysis of established and tumor-biologic prognostic factors, uPA/PAI-1 was the only independent prognostic factor for disease-free survival ([DFS]; P < .001; relative risk [RR], 8.3; 95% confidence interval [CI], 3.4 to 20.4). Although HER2_AMP and HER2_EXP did not reach significance for DFS, they were significant for overall survival (OS), even in multivariate analysis (HER2_AMP: P = .004; RR, 3.7; 95% CI, 1.5 to 9.2; HER2_EXP: P = .009; RR, 3.4; 95% CI, 1.4 to 8.7).

Conclusion: After long-term follow-up, uPA/PAI-1 levels in primary tumor tissue reliably and strongly indicate an aggressive course of disease in lymph node-negative breast cancer independent of HER2 status. The particular prognostic effect of HER2 status on OS may reflect its ability to predict resistance to systemic therapy.
Early Detection of Response to Radiation Therapy in Patients With Brain Malignancies Using Conventional and High b-Value Diffusion-Weighted Magnetic Resonance Imaging
Authors: Mardor Yael , Pfeffer Raphael , Spiegelmann Roberto , Roth Yiftach , Maier Stephan E. , Nissim Ouzi , Berger Raanan , Glicksman Ami , Baram Jacob , Orenstein Arie , Cohen Jack S. , Tichler Thomas
Published: March 2003

Purpose: To study the feasibility of using diffusion-weighted magnetic resonance imaging (DWMRI), which is sensitive to the diffusion of water molecules in tissues, for detection of early tumor response to radiation therapy; and to evaluate the additional information obtained from high DWMRI, which is more sensitive to low-mobility water molecules (such as intracellular or bound water), in increasing the sensitivity to response.

Patients and Methods: Standard MRI and DWMRI were acquired before and at regular intervals after initiating radiation therapy for 10 malignant brain lesions in eight patients.

Results: One week posttherapy, three of six responding lesions showed an increase in the conventional DWMRI parameters. Another three responding lesions showed no change. Four nonresponding lesions showed a decrease or no change. The early change in the diffusion parameters was enhanced by using high DWMRI. When high DWMRI was used, all responding lesions showed increase in the diffusion parameter and all nonresponding lesions showed no change or decrease. Response was determined by standard MRI 7 weeks posttherapy. The changes in the diffusion parameters measured 1 week after initiating treatment were correlated with later tumor response or no response (P < .006). This correlation was increased to P < .0006 when high DWMRI was used.

Conclusion: The significant correlation between changes in diffusion parameters 1 week after initiating treatment and later tumor response or no response suggests the feasibility of using DWMRI for early, noninvasive prediction of tumor response. The ability to predict response may enable early termination of treatment in nonresponding patients, prevent additional toxicity, and allow for early changes in treatment.
Randomized Controlled Trial Comparing Oral Doxifluridine Plus Oral Cyclophosphamide With Doxifluridine Alone in Women With Node-Positive Breast Cancer After Primary Surgery
Authors: Tominaga Takeshi , Koyama Hiroki , Toge Tetsuya , Miura Shigeto , Sugimachi Keizo , Yamaguchi Susumu , Hirata Koichi , Monden Yasumasa , Nomura Yasuo , Toi Masakazu , Kimijima Izo , Noguchi Shinzaburo , Sonoo Hiroshi , Asaishi Kazuaki , Ikeda Tadashi , Morimoto Tadaoki , Ota Jun , Ohashi Yasuo , Abe Osahiko
Published: March 2003

Purpose: We compared the therapeutic usefulness of doxifluridine (5′-DFUR) alone and a combination of 5′-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy.

Patients and Methods: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5′-DFUR alone or 5′-DFUR plus CPM. All patients initially received 5′-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5′-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5′-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5′-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups.

Results: Of the 1,088 eligible women, 546 were assigned to receive 5′-DFUR alone and 542 were assigned to receive 5′-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5′-DFUR plus CPM than in those who received 5′-DFUR alone (log-rank test, P = .021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5′-DFUR group and 32.3% of patients (175 of 542) in the 5′-DFUR plus CPM group (χ2 test, P < .001).

Conclusion: Combination therapy with 5′-DFUR plus CPM is more effective in preventing recurrence than 5′-DFUR alone.
Effect of Number of Lymph Nodes Sampled on Outcome in Patients With Stage I Non–Small-Cell Lung Cancer
Authors: Gajra Ajeet , Newman Nancy , Gamble Gary P. , Kohman Leslie J. , Graziano Stephen L.
Published: March 2003

Purpose: We postulate that surgical sampling and pathologic evaluation of lymph nodes of surgical specimens from patients with stage I non–small-cell lung cancer (NSCLC) can have an effect on the time to recurrence and survival of these patients.

Patients and Methods: We analyzed data on 442 patients with stage I NSCLC who were treated with surgical resection and some form of lymph node sampling. Associations between total lymph nodes sampled and disease-free survival (DFS) and overall survival (OS) were investigated. The effect of total lymph node stations sampled and the surgical techniques (random lymph node sampling, systematic sampling [SS], or complete mediastinal lymph node dissection [MLND]) on DFS and OS was also studied. Complete MLND and SS were defined as dissection or sampling of levels 4, 7, and 10 for right-sided lesions and levels 5 or 6 and 7 for left-sided lesions.

Results: Patients were divided into quartiles on the basis of total number of lymph nodes sampled. Improved DFS and OS were associated with greater number of lymph nodes sampled. SS and MLND were associated with improved survival compared with random lymph node sampling. The total number of lymph nodes sampled maintained strong significance in the multivariate analysis.

Conclusion: These results indicate that examining a greater number of lymph nodes in patients with stage I NSCLC treated with resection increases the likelihood of proper staging and affects patient outcome. Such information is important not only for therapy and prognosis of individuals but also for identifying those who may benefit from adjuvant therapy.
General Quality of Life 2 Years Following Treatment for Prostate Cancer: What Influences Outcomes? Results From the Prostate Cancer Outcomes Study
Authors: Penson David F. , Feng Ziding , Kuniyuki Alan , McClerran Dale , Albertsen Peter C. , Deapen Dennis , Gilliland Frank , Hoffman Richard , Stephenson Robert A. , Potosky Arnold L. , Stanford Janet L.
Published: March 2003

Purpose: The goal of this study was to determine the relationship between primary treatment, urinary dysfunction, sexual dysfunction, and general health-related quality of life (HRQOL) in prostate cancer.

Methods: A sample of men with newly diagnosed prostate cancer between 1994 and 1995 was randomly selected from six population-based Surveillance, Epidemiology, and End Results registries. A baseline survey was completed by 2,306 men within 6 to 12 months of diagnosis, and these men also completed a follow-up HRQOL survey 2 years after diagnosis. Logistic regression models were used to determine whether primary treatment, urinary dysfunction, and sexual dysfunction were independently associated with general HRQOL outcomes approximately 2 years after diagnosis as measured by the Medical Outcomes Study 36-item Short Form Health Survey. The magnitude of this effect was estimated using least square means models.

Results: After adjustment for potential confounders, primary treatment was not associated with 2-year general HRQOL outcomes in men with prostate cancer. Urinary function and bother were independently associated with worse general HRQOL in all domains. Sexual function and bother were also independently associated with worse general HRQOL, although the relationship was not as strong as in the urinary domains.

Conclusion: Primary treatment is not associated with 2-year general HRQOL outcomes in prostate cancer. Although both sexual and urinary function and bother are associated with quality of life, men who are more bothered by their urination or impotence are more likely to report worse quality of life. This implies that future research should be directed toward finding ways to improve treatment-related outcomes or help patients better cope with their posttreatment urinary or sexual dysfunction.
Impact of Metaiodobenzylguanidine Scintigraphy on Assessing Response of High-Risk Neuroblastoma to Dose-Intensive Induction Chemotherapy
Authors: Kushner Brian H. , Yeh Samuel D.J. , Kramer Kim , Larson Steven M. , Cheung Nai-Kong V.
Published: March 2003

Purpose: The International Neuroblastoma Response Criteria (INRC) recommend, but do not make mandatory, metaiodobenzylguanidine (MIBG) scans. We present the first report on the effect of MIBG scans on the classification of response to dose-intensive induction therapy.

Patients and Methods: After dose-intensive induction and before consolidative therapy, 162 Memorial Sloan-Kettering Cancer Center (MSKCC) patients with high-risk neuroblastoma (NB) had MIBG scans (99 with 131I, 63 with 123I), computed tomography, 99mTc-bone scan, bone marrow (BM) tests, and urine catecholamine measurements. Induction included high-dose cyclophosphamide (140 mg/kg) plus other agents and high-dose cisplatin (200 mg/m2)/etoposide (600 mg/m2).

Results: In 90 patients treated with dose-intensive therapy from diagnosis at MSKCC, the use of MIBG scintigraphy increased the incomplete response numbers from 14 (15.5%) to 20 (22%), giving a complete remission/very good partial remission (CR/VGPR) rate of 78%. In 72 patients treated before referral to MSKCC for intensified therapy, MIBG findings changed the response classification of one patient; the CR/VGPR rate was 43%. MIBG scans showed no BM disease in 15 of 38 patients with histologically evident NB in BM but did show uptake consistent with BM involvement in five patients who had no NB observed in BM tests.

Conclusion: With the less effective therapy consequent to the intensification of induction only after initial exposure to standard-dose chemotherapy, MIBG scintigraphy merely confirms the findings of other staging modalities for detection of relatively widespread residual NB. However, when dose-intensive therapy is initiated at diagnosis, the reliable achievement of major disease responses makes extensive BM testing and MIBG scintigraphy prerequisites for accurate determination of disease status.
Clinical Outcome of Stage I/II Melanoma Patients After Selective Sentinel Lymph Node Dissection: Long-Term Follow-Up Results
Authors: Vuylsteke R.J.C.L.M. , van Leeuwen P.A.M. , Muller M.G. Statius , Gietema H.A. , Kragt D.R. , Meijer S.
Published: March 2003

Purpose: Although sentinel lymph node (SLN) status is part of the new American Joint Committee on Cancer staging system, there is no final proof that the SLN procedure in melanoma patients influences outcome of disease. This study investigated the accuracy of the SLN procedure and clinical outcome in melanoma patients after at least 60 months of follow-up.

Patients and Methods: Between 1993 and 1996, 209 patients with stage I/II cutaneous melanoma underwent selective SLN dissection by the triple technique. If the SLN contained metastatic disease, a completion lymphadenectomy was performed. Survival analyses were performed using the Kaplan-Meier approach. Factors associated with survival were analyzed using the Cox proportional hazards regression model.

Results: The success rate was 99.5%. Median follow-up was 72 months. Forty patients (19%) had a positive SLN. The false-negative rate was 9%. Five-year overall survival was 87% for the entire group and 92% and 67% for SLN-negative and SLN-positive patients (P < .0001), respectively. All patients with a positive SLN and a Breslow thickness ≤ 1.00 mm survived, and SLN-positive patients with a Breslow thickness less than 2.00 mm tend to have a better prognosis compared with SLN-negative patients with a Breslow thickness greater than 2.00 mm. SLN status (P = .002), Breslow thickness (P = .002), and lymphatic invasion (P = .0009) were all found to be independent prognostic factors for overall survival.

Conclusion: With a success rate of 99.5% and a false-negative rate of 9% after long-term follow-up, the triple-technique SLN procedure is a reliable and accurate method. Survival data seem promising, although a therapeutic effect is still questionable. As shown in this study, not all SLN-positive patients have a poor prognosis.
Granulosa Cell Tumor of the Ovary
Authors: Schumer Susan Tinsley , Cannistra Stephen A.
Published: March 2003

Adult granulosa cell tumor (GCT) of the ovary is oftentimes a hormonally active, stromal cell neoplasm that is distinguished by its ability to secrete sex steroids such as estrogen. Patients may present with vaginal bleeding caused by endometrial hyperplasia or uterine cancer as a result of prolonged exposure to tumor-derived estrogen. In addition, GCT is a vascular tumor that may occasionally rupture and result in abdominal pain, hemoperitoneum, and hypotension, mimicking an ectopic pregnancy in younger patients. GCT is usually associated with a mass on pelvic examination that is subsequently confirmed on ultrasonography. Surgery is required for definitive tissue diagnosis, staging, and tumor debulking. In older women, a total abdominal hysterectomy and bilateral salpingooophorectomy are typically performed. In women of childbearing age, a more conservative unilateral salpingo-oophorectomy may be performed, assuming that careful staging reveals that the disease has not extended outside of the involved ovary and that a concomitant uterine cancer has been excluded. Survival of patients with GCT is generally excellent because most patients present with early-stage disease, although certain high-risk patient groups may be identified. Stage is the most important prognostic factor, with a higher risk of relapse being associated with stages II through IV disease. In addition, patients with stage I disease associated with features such as large tumor size, high mitotic index, or tumor rupture may also be at higher risk in some series. The value of postoperative adjuvant therapy for high-risk patients has not been investigated by prospective randomized trials, which are difficult to perform because of the rarity of this tumor. Nonetheless, the use of adjuvant chemotherapy or radiation has sometimes been associated with prolonged disease-free survival in patients with high-risk features. Because of the propensity of GCT to recur years after initial diagnosis, prolonged surveillance with serial physical examination and serum tumor markers such as estradiol and inhibin is reasonable.
Preoperative Concurrent Chemoradiotherapy in Locally Advanced Rectal Cancer With High-Dose Radiation and Oxaliplatin-Containing Regimen: The Lyon R0–04 Phase II Trial
Authors: Gérard Jean-Pierre , Chapet Olivier , Nemoz Chantal , Romestaing Pascale , Mornex Françoise , Coquard Régis , Barbet Nicolas , Atlan Dan , Adeleine Patrice , Freyer Gilles
Published: March 2003

Purpose: The combination of radiation, fluorouracil, and oxaliplatin in locally advanced rectal cancer has been shown to be feasible in a phase I trial. The purpose of this phase II trial was to assess tolerance and efficacy of this regimen in a preoperative setting.

Patients and Methods: Between May 2000 and October 2001, 40 operable patients were entered onto the study. Radiotherapy was delivered with a three-field technique to a dose of 50 Gy over 5 weeks with a concomitant boost approach. Two cycles of chemotherapy were given synchronously on weeks 1 and 5, with oxaliplatin 130 mg/m2 on day 1 followed by 5-day continuous infusion of fluorouracil 350 mg/m2 and l-folinic acid 100 mg/m2. Surgery was planned 5 weeks later.

Results: All patients completed treatment without modification except one who experienced grade 3/4 toxicity. Grade 3 toxicity was seen in seven patients. Surgery was performed in all patients after a mean interval time of 5 weeks. An objective clinical response was seen in 30 patients (75%). Sphincter-saving surgery was possible in 26 patients. No postoperative deaths occurred. In four patients (10%), a reoperation was necessary (anastomotic fistula, n = 2; pelvic abscess, n = 2). In six cases the operative specimen was sterilized (15%), and in 12 cases (30%), only few residual cells were detected.

Conclusion: Such a combined preoperative chemoradiotherapy and oxaliplatin-containing regimen is well tolerated with no increase in surgical toxicity. The good response rate observed warrants its use in further clinical trials.
Regulatory Approvals of Pediatric Oncology Drugs: Previous Experience and New Initiatives
Authors: Hirschfeld Steven , Ho Peter T.C. , Smith Malcolm , Pazdur Richard
Published: March 2003

Purpose: To review the Food and Drug Administration (FDA) experience with approvals of new drugs for pediatric oncology and to discuss new regulatory initiatives directed at pediatric oncology.

Methods: A retrospective review of FDA archival documents and the published literature.

Results: More than 100 drugs have been approved by the Division of Oncology Drug Products of the FDA for the treatment of malignancies. Only 15 have pediatric use information in their labeling, which is less than 50% of the drugs commonly used in the treatment of pediatric malignancies. In the past 20 years, there have been six submissions to the FDA for pediatric oncology indications. To illustrate principles of the approval process, each submission is discussed.

Conclusion: Potential reasons for a lack of New Drug Application submissions for pediatric oncology include the small pediatric oncology market compared with the adult oncology market and perceived barriers to performing studies in children. Reasons for failure to approve pediatric indications include small numbers of patients, lack of appropriate controls, and failure to demonstrate patient benefit. Approval criteria include the use of controlled trials, prospective data collection, and disease-appropriate end points. Regulatory initiatives to promote pediatric therapeutic development and product labeling are discussed.
Differential Patterns of Fos Induction in the Hypothalamus of the Rat Following Central Injections of Galanin-Like Peptide and Galanin
Authors: Fraley Gregory S. , Shimada Issei , Baumgartner James W. , Clifton Donald K. , Steiner Robert A.
Published: March 2003

Galanin and its newly discovered relative galanin-like peptide (GALP) are neuropeptides that are implicated in the neuroendocrine regulation of body weight and reproduction. GALP has been shown to bind in vitro to galanin receptor subtypes 1 and 2, but whether it has its own specific receptor(s) is unknown. We reasoned that if GALP acts through a receptor that is distinct from galanin receptors, then GALP should activate central pathways that are different from those activated by galanin. The purpose of this study was to determine whether galanin and GALP produce different patterns of neuronal activation within the hypothalamus. Quantitative analysis of Fos immunoreactivity showed that galanin induced a significantly greater number of Fos-positive nuclei in the paraventricular nucleus compared with GALP (P < 0.001); however, compared with galanin, GALP induced significantly more Fos-positive cells in the horizontal limb of the diagonal band of Broca, caudal preoptic area, arcuate nucleus, and median eminence (P < 0.05). These observations suggest that GALP and galanin act through different receptor-mediated pathways to exert their effects on the regulation of body weight and reproduction and identify target cells for GALP’s specific actions in the hypothalamus, including the preoptic area, paraventricular and arcuate nuclei, and the median eminence.