bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of sulfadoxine-pyrimethamine in Tanzania after two years as first-line drug for uncomplicated malaria: assessment protocol and implication for treatment policy strategies
Authors: Mugittu Kefas , Abdulla Salim , Falk Nicole , Masanja Honorati , Felger Ingrid , Mshinda Hassan , Beck Hans-Peter , Genton Blaise
Published: November 2005

Background

Systematic surveillance for resistant malaria shows high level of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine (SP) across eastern and southern parts of Africa. This study assessed in vivo SP efficacy after two years of use as an interim first-line drug in Tanzania, and determined the rates of treatment failures obtained after 14 and 28 days of follow-up.

Methods

The study was conducted in the Ipinda, Mlimba and Mkuranga health facilities in Tanzania. Children aged 6–59 months presenting with raised temperature associated exclusively with P. falciparum (1,000–100,000 parasites per μl) were treated with standard dose of SP. Treatment responses were classified according to the World Health Organization (WHO) definition as Adequate Clinical and Parasitological Response (ACPR), Early Treatment Failure (ETF), Late Clinical Failure (LCF) and Late Parasitological Failure (LPF) on day 14 and day 28.

Results

Overall 196 (85.2%) of 230 patients had ACPR on day 14 but only 116 (50.9%) on day 28 (57.7% after excluding new infections by parasite genotyping). Altogether 21 (9.1%) and 13 (5.7%) of the 230 patients assessed up to day 14 and 39 (17.1%) and 55 (24.1%) of the 228 followed up to day 28 had clinical and parasitological failure, respectively.

Conclusion

These findings indicate that SP has low therapeutic value in Tanzania. The recommendation of changing first line treatment to artemether + lumefantrine combination therapy from early next year is, therefore, highly justified. These findings further stress that, for long half-life drugs such as SP, establishment of cut-off points for policy change in high transmission areas should consider both clinical and parasitological responses beyond day 14.
Protein-protein interactions of the hyperthermophilic archaeon Pyrococcus horikoshiiOT3
Authors: Usui Kengo , Katayama Shintaro , Kanamori-Katayama Mutsumi , Ogawa Chihiro , Kai Chikatoshi , Okada Makiko , Kawai Jun , Arakawa Takahiro , Carninci Piero , Itoh Masayoshi , Takio Koji , Miyano Masashi , Kidoaki Satoru , Matsuda Takehisa , Hayashizaki Yoshihide , Suzuki Harukazu
Published: November 2005

Background

Although 2,061 proteins of Pyrococcus horikoshii OT3, a hyperthermophilic archaeon, have been predicted from the recently completed genome sequence, the majority of proteins show no similarity to those from other organisms and are thus hypothetical proteins of unknown function. Because most proteins operate as parts of complexes to regulate biological processes, we systematically analyzed protein-protein interactions in Pyrococcus using the mammalian two-hybrid system to determine the function of the hypothetical proteins.

Results

We examined 960 soluble proteins from Pyrococcus and selected 107 interactions based on luciferase reporter activity, which was then evaluated using a computational approach to assess the reliability of the interactions. We also analyzed the expression of the assay samples by western blot, and a few interactions by in vitro pull-down assays. We identified 11 hetero-interactions that we considered to be located at the same operon, as observed in Helicobacter pylori. We annotated and classified proteins in the selected interactions according to their orthologous proteins. Many enzyme proteins showed self-interactions, similar to those seen in other organisms.

Conclusion

We found 13 unannotated proteins that interacted with annotated proteins; this information is useful for predicting the functions of the hypothetical Pyrococcus proteins from the annotations of their interacting partners. Among the heterogeneous interactions, proteins were more likely to interact with proteins within the same ortholog class than with proteins of different classes. The analysis described here can provide global insights into the biological features of the protein-protein interactions in P. horikoshii.
Three-dimensional seismic-while-drilling (SWD) migration in the angular frequency domain
Authors: Rocca Fabio , Vassallo Massimiliano , Bernasconi Giancarlo
Published: November 2005

Seismic depth migration back-propagates seismic data in the correct depth position using information about the velocity of the medium. Usually, Kirchhoff summation is the preferred migration procedure for seismic-while-drilling (SWD) data because it can handle virtually any configuration of sources and receivers and one can compensate for irregular spatial sampling of the array elements (receivers and sources). Under the assumption of a depth-varying velocity model, with receivers arranged along a horizontal circumference and sources placed along the central vertical axis, we reformulate the Kirchhoff summation in the angular frequency domain. In this way, the migration procedure becomes very efficient because the migrated volume is obtained by an inverse Fourier transform of the weighted data. The algorithm is suitable for 3D SWD acquisitions when the aforementioned hypothesis holds. We show migration tests on SWD synthetic data, and we derive solutions to reduce the migration artifacts and to control aliasing. The procedure is also applied on a real 3D SWD data set. The result compares satisfactorily with the seismic stack section obtained from surface reflection data and with the results from traditional Kirchhoff migration.
Analysis of depth resolution in potential-field inversion
Authors: Fedi Maurizio , Hansen Per Christian , Paoletti Valeria
Published: November 2005

We study the inversion of potential fields and evaluate the degree of depth resolution achievable for a given problem. To this end, we introduce a powerful new tool: the depth-resolution plot (DRP). The DRP allows a theoretical study of how much the depth resolution in a potential-field inversion is influenced by the way the problem is discretized and regularized. The DRP also allows a careful study of the influence of various kinds of ambiguities, such as those from data errors or of a purely algebraic nature. The achievable depth resolution is related to the given discretization, regularization, and data noise level. We compute DRP by means of singular-value decomposition (SVD) or its generalization (GSVD), depending on the particular regularization method chosen. To illustrate the use of the DRP, we assume a source volume of specified depth and horizontal extent in which the solution is piecewise constant within a 3D grid of blocks. We consider various linear regularization terms in a Tikhonov (damped least-squares) formulation, some based on using higher-order derivatives in the objective function. DRPs are illustrated for both synthetic and real data. Our analysis shows that if the algebraic ambiguity is not too large and a suitable smoothing norm is used, some depth resolution can be obtained without resorting to any subjective choice of depth weighting.
Using airborne thermal infrared imagery and helicopter EM conductivity to locate mine pools and discharges in the Kettle Creek watershed, north-central Pennsylvania
Authors: Love Erica , Hammack Richard , Harbert William , Sams James , Veloski Garret , Ackman Terry
Published: November 2005

The Kettle Creek watershed contains 50–100-year-old surface and underground coal mines that are a continuing source of acid mine drainage (AMD). To characterize the mining-altered hydrology of this watershed, an airborne reconnaissance was conducted in 2002 using airborne thermal infrared imagery (TIR) and helicopter-mounted electromagnetic (HEM) surveys. TIR uses the temperature differential between surface water and groundwater to locate areas where groundwater emerges at the surface. TIR anomalies located in the survey included seeps and springs, as well as mine discharges. In a follow-up ground investigation, hand-held GPS units were used to locate 103 of the TIR anomalies. Of the sites investigated, 26 correlated with known mine discharges, whereas 27 were previously unknown. Seven known mine discharges previously obscured from TIR imagery were documented. HEM surveys were used to delineate the groundwater table and also to locate mine pools, mine discharges, and groundwater recharge zones. These surveys located 12 source regions and flow paths for acidic, metal-containing (conductive) mine drainage; areas containing acid-generating mine spoil; and areas of groundwater recharge and discharge, as well as identifying potential mine discharges previously obscured from TIR imagery by nondeciduous vegetation. Follow-up ground-based electromagnetic surveys verified the results of the HEM survey. Our study suggests that airborne reconnaissance can make the remediation of large watersheds more efficient by focusing expensive ground surveys on small target areas.
Historical development of the gravity method in exploration
Authors: Nabighian M. N. , Ander M. E. , Grauch V. J. S. , Hansen R. O. , LaFehr T. R. , Li Y. , Pearson W. C. , Peirce J. W. , Phillips J. D. , Ruder M. E.
Published: November 2005

The gravity method was the first geophysical technique to be used in oil and gas exploration. Despite being eclipsed by seismology, it has continued to be an important and sometimes crucial constraint in a number of exploration areas. In oil exploration the gravity method is particularly applicable in salt provinces, overthrust and foothills belts, underexplored basins, and targets of interest that underlie high-velocity zones. The gravity method is used frequently in mining applications to map subsurface geology and to directly calculate ore reserves for some massive sulfide orebodies. There is also a modest increase in the use of gravity techniques in specialized investigations for shallow targets. Gravimeters have undergone continuous improvement during the past 25 years, particularly in their ability to function in a dynamic environment. This and the advent of global positioning systems (GPS) have led to a marked improvement in the quality of marine gravity and have transformed airborne gravity from a regional technique to a prospect-level exploration tool that is particularly applicable in remote areas or transition zones that are otherwise inaccessible. Recently, moving-platform gravity gradiometers have become available and promise to play an important role in future exploration. Data reduction, filtering, and visualization, together with low-cost, powerful personal computers and color graphics, have transformed the interpretation of gravity data. The state of the art is illustrated with three case histories: 3D modeling of gravity data to map aquifers in the Albuquerque Basin, the use of marine gravity gradiometry combined with 3D seismic data to map salt keels in the Gulf of Mexico, and the use of airborne gravity gradiometry in exploration for kimberlites in Canada.
Endocarditis and ulnar artery aneurysm as presenting features of antiphospholipid syndrome and polyarteritis nodosa
Authors: Egan A C , Caleyachetty R , Sabharwal T , Harper B , Tomlinson M , Kirkham B , Hughes G RV , D’Cruz D
Published: November 2005

Antiphospholipid syndrome in association with vasculitis is highlighted in this report. The combination of thrombotic and inflammatory processes resulted in endocarditis, aneurysm formation and thrombosis. To our knowledge this is the first presentation of a large vessel aneurysm in these conditions. Anticoagulation and immunosuppression are the treatment modalities of choice.
Lateralized cognitive dysfunction in patients with systemic lupus erythematosus
Authors: Glanz B I , Schur P H , Lew R A , Khoshbin S
Published: November 2005

This study was designed to determine whether there is a lateralized pattern of cognitive dysfunction in patients with systemic lupus erythematosus (SLE). Fifty right-handed patients with SLE, but no history of cerebrovascular disease participated in the study. Thirty right-handed healthy subjects matched for age and education served as controls. SLE and healthy control subjects underwent a three-hour neuropsychological evaluation designed to measure attention, memory, visual spatial skills, verbal skills reasoning, psychomotor speed, and motor function. A cognitive disability index was created to identify cognitive impairment. Percentile tables based on the performance of all subjects were constructed for 20 component scores. Any subject with five or more component scores below the 25th percentile was designated impaired. Using this criterion, cognitive impairment was identified in 50% of patients with SLE and 20% of healthy controls. Patients with SLE were impaired on measures of psychomotor speed/fluency, verbal speed/fluency and verbal memory. This pattern of performance on neuropsycholgical testing was consistent with left hemisphere brain dysfunction. The observed deficits were not clearly attributable to vascular lesions and suggest immune-mediated effects on specific brain regions in a subgroup of patients with SLE.
Histologic Effects of Laser‐assisted Topical Anesthesia in a Porcine Model
Authors: Singer Daniel D. , Singer Adam J. , McClain Steve A. , Tortora George
Published: November 2005

Objectives: A handheld laser device that removes the stratum corneum, the major barrier to transdermal absorption, has recently been approved to assist with topical anesthesia before painful procedures such as intravenous cannulation. The authors assessed the cutaneous histomorphologic effects of the laser device and the ability of the laser‐treated skin to resist infection in a porcine model. Methods: This was a blinded, randomized animal experiment using isoflurane‐anesthetized young domestic pigs. The ventral surface of the animals was irradiated multiple times with a lightweight, portable erbium yttrium‐aluminum‐garnet unit or a sham laser. One third of the wounds were inoculated with a Staphylococcus aureus suspension. The treated areas were then covered with a dry dressing, and full‐thickness biopsy specimens of the treated areas were obtained immediately after treatment and at three, seven, ten, and 14 days for blinded histopathologic evaluation using hematoxylin and eosin staining and electron microscopy. Quantitative bacterial counts were obtained at three days in wounds exposed to bacteria. Main outcomes were quantitative bacterial counts, presence of cellular necrosis, epidermal integrity, and dermal scarring. Data analysis was conducted with descriptive statistics. Results: Laser irradiation resulted in immediate disruption of the cornified layer of the skin and necrosis of the stratum spinosum in all treated areas. There were also focal areas of vacuolar alteration of the basal one third of the epidermis. There was no evidence of any damage to the basement membrane or the underlying dermis. At three days, the epidermis had healed and there was evidence of epidermal hyperplasia and hyperkeratosis that was completely resolved by 14 days. There were no infections and no scarring. Sham laser had no histomorphologic effects on the skin. There was no bacterial growth from all sham laser–treated wounds challenged with bacteria. Three of 20 (15%; 95% confidence interval = 0% to 31%) laser‐irradiated wounds that were challenged with bacteria grew between 280,000 and 1,600,000 colony‐forming units/g. Conclusions: Laser irradiation results in ablation of the stratum corneum and a superficial burn to the epidermis that heals by three to 14 days without any scarring or infection in pigs. Challenging laser‐irradiated cutaneous wounds with a large bacterial inoculum resulted in bacterial growth in a minority of wounds.
Factors Associated with Failure of Noninvasive Positive Pressure Ventilation in the Emergency Department
Authors: Merlani Paolo G. , Pasquina Patrick , Granier Jean Max , Treggiari Miriam , Rutschmann Olivier , Ricou Bara
Published: November 2005

Objectives: To determine the factors associated with failure of noninvasive positive pressure ventilation (NPPV) in patients presenting with acute respiratory failure to the emergency department (ED). Methods: The authors retrospectively analyzed patients admitted to the ED for acute respiratory failure (defined as a PaCO2 level >45 mm Hg, and pH ≤ 7.35 or a PaO2/FiO2 ratio < 250 mm Hg) and who were treated with NPPV. NPPV was delivered routinely according to an institutional protocol. Failure of NPPV was defined as the requirement of endotracheal intubation at any time. Results: A total of 104 patients were included. NPPV failed in 31% (32/104), and the mortality was significantly higher in this group (12/32 [44%]) compared with patients who were not intubated (2/72 [3%]) (p < 0.0001). Factors associated with failure of NPPV were Glasgow Coma Scale score < 13 at ED admission (odds ratio [OR], 3.67; 95% confidence interval [CI] = 1.33 to 10.07), pH ≤ 7.35 (OR, 3.23; 95% CI = 1.25 to 8.31), and respiratory rate (RR) ≥20 min−1 (OR, 3.86; 95% CI = 1.33 to 11.17) after one hour of NPPV. The negative predictive value for NPPV failure was 86% (95% CI = 70% to 95%) for RR ≥20 min−1. In the multivariate analysis, pH ≤ 7.35 and RR ≥20 min−1 after one hour of NPPV were independently associated with NPPV failure (adjusted ORs, 3.51; 95% CI = 1.29 to 9.62 and 3.55; 95% CI = 1.13 to 11.20, respectively). Conclusions: Patients with pH ≤ 7.35 and an RR ≥20 min−1 after one hour of NPPV had an increased risk of subsequent endotracheal intubation.
Changing Opioid Use for Right Lower Quadrant Abdominal Pain in the Emergency Department
Authors: Neighbor Martha L. , Baird Carina H. , Kohn Michael A.
Published: November 2005

Objectives: To compare the use of opioid analgesia in the treatment of emergency department patients with acute right lower quadrant (RLQ) abdominal pain between 1998 and 2003 and to explore the relationship between opioid use and abdominal computed tomography (CT) scanning. Methods: This was a retrospective cohort study of patients presenting in 1998 and 2003 to an urban emergency department with a triage complaint of RLQ pain. The authors abstracted use and timing of abdominal CT scanning and opioid analgesia. Other predictor variables were patient demographics. Risk ratio for receiving opioids with CT scan versus without CT scan, stratifying by year, were calculated. Proportional‐hazards analysis was used to control for time in the emergency department. Results: Of the 187 patients seen in 1998, 38 (20%) underwent CT scanning and 43 (23%) received opioids. Of the 137 patients seen in 2003, 77 (56%) underwent CT scanning and 72 (53%) received opioids. In 1998, the risk ratio for receiving opioids in patients who underwent CT scanning (vs. without) was 3.7 (95% confidence interval [CI] = 2.3 to 6.1); in 2003, it was 1.5 (95% CI = 1.0 to 2.1). Opioids were overwhelmingly given before CT scanning in those patients who received both (81% in 1998 and 98% in 2003). The mean time to administration of the first opioid dose in 1998 was 155 minutes and in 2003 was 94 minutes. The proportional‐hazards analysis confirmed a strong association between CT scanning and opioid administration in 1998 (relative hazard, 2.7; 95% CI = 1.5 to 5.1) and substantial attenuation of the association in 2003 (relative hazard, 1.3; 95% CI = 0.8 to 2.1). The hospitalization rate was not significantly different in 2003 (33%) versus 1998 (27%) (p = 0.28). The risk ratio of receiving opioids in admitted patients was 2.8 (95% CI = 1.7 to 4.6) in 1998 and 2.0 (95% CI = 1.5 to 2.7) in 2003. Conclusions: Opioid administration to patients with RLQ pain has dramatically increased between 1998 and 2003. During these five years, the number of patients receiving opioids more than doubled and the time to first administration of opioids decreased by one hour. The authors show that this cannot be attributed to an increased use of CT scanning.
Identification of Depression in an Inner‐city Population Using a Simple Screen
Authors: Haughey Marianne T. , Calderon Yvette , Torres Sandra , Nazario Steven , Bijur Polly
Published: November 2005

Objectives: The purpose of this study was to compare a brief screening tool with physicians' usual practice in detecting depressive symptoms in patients presenting with somatic complaints to an inner‐city emergency department. Depression is a major cause of morbidity and mortality in the United States. Underprivileged patients who rely on emergency departments for primary care remain at risk for undetected depression. Methods: This prospective observational study included all patients older than 18 years presenting to an urgent care clinic staffed by emergency physicians in an urban public hospital during an eight‐week period. Clinically unstable patients and those with a chief complaint of depression were excluded. After consenting, patients completed a previously validated two‐question screening tool for depression. Patients identified as having depressive symptoms were referred to social workers for evaluation for possible psychiatric intervention. Results: Of the 226 patients enrolled, 55% (124/226; 95% confidence interval [CI] = 48% to 61%) screened positive for depressive symptoms. Physicians identified 14% (31/226; 95% CI = 10% to 19%) as having depressive symptoms. The κ value was 0.22 (95% CI = 0.14 to 0.29). All patients but one identified as positive by the physicians screened positive on the screening tool. Patients who screened positive were referred to social workers. The physicians failed to identify 19 of the patients who needed further psychiatric care. Conclusions: Depressive symptoms are common among patients in urgent care settings with somatic complaints. A simple screening tool identified more patients for further evaluation than does physicians' usual practice.
Phase I/IIa Study of Cetuximab With Gemcitabine Plus Carboplatin in Patients With Chemotherapy-Naïve Advanced Non–Small-Cell Lung Cancer
Authors: Robert Francisco , Blumenschein George , Herbst Roy S. , Fossella Frank V. , Tseng Jennifer , Saleh Mansoor N. , Needle Michael
Published: November 2005

Purpose

This multicenter, open-label, phase I/IIa study was undertaken to establish the safety/toxicity profile of cetuximab in combination with gemcitabine and carboplatin in patients with chemotherapy-naïve, epidermal growth factor receptor–positive, stage IV non–small-cell lung cancer. Secondary objectives were to gather preliminary evidence of efficacy including tumor response rate, time to progression, and overall survival.

Patients and Methods

Thirty-five patients received a total of 264 3-week cycles of treatment with cetuximab, carboplatin, and gemcitabine. An initial dose of cetuximab 400 mg/m2intravenously was administered the first week, followed by weekly doses of 250 mg/m2. Carboplatin (area under the curve = 5, day 1) and gemcitabine 1,000 mg/m2on days 1 and 8 were administered every 3 weeks. Patients were evaluated for tumor response after every two cycles of therapy.

Results

The most frequently reported adverse events related to cetuximab included an acne-like rash (88.6%), dry skin (34.3%), asthenia and skin disorders (31.4%), mucositis/stomatitis (25.7%), fever/chills (20%), and nausea/vomiting (17.1%). The majority of these toxicities were mild to moderate. One patient withdrew from the study because of a grade 3 allergic reaction. Myelosuppression was the most frequently observed toxicity related to chemotherapy. Responses among 35 assessable patients included 10 partial responses (28.6%). Twenty-one patients had stable disease. The median time to progression was 165 days, and the median overall survival was 310 days.

Conclusion

The combination of cetuximab, carboplatin, and gemcitabine was well tolerated with an acceptable toxicity profile. Most grade 3 adverse events were attributable to chemotherapy. The response rate and median survival are encouraging and warrant additional investigation.
Mammography, Breast Ultrasound, and Magnetic Resonance Imaging for Surveillance of Women at High Familial Risk for Breast Cancer
Authors: Kuhl Christiane K. , Schrading Simone , Leutner Claudia C. , Morakkabati-Spitz Nuschin , Wardelmann Eva , Fimmers Rolf , Kuhn Walther , Schild Hans H.
Published: November 2005

Purpose

To compare the effectiveness of mammography, breast ultrasound, and magnetic resonance imaging (MRI) for surveillance of women at increased familial risk for breast cancer (lifetime risk of 20% or more).

Patients and Methods

We conducted a surveillance cohort study of 529 asymptomatic women who, based on their family history and/or mutational analysis, were suspected or proven to carry a breast cancer susceptibility gene (BRCA). A total of 1,542 annual surveillance rounds were completed with a mean follow-up of 5.3 years. Diagnostic accuracies of the three imaging modalities used alone or in different combinations were compared.

Results

Forty-three breast cancers were identified in the total cohort (34 invasive, nine ductal carcinoma-in-situ). Overall sensitivity of diagnostic imaging was 93% (40 of 43 breast cancers); overall node-positive rate was 16%, and one interval cancer occurred (one of 43 cancers, or 2%). In the analysis by modality, sensitivity was low for mammography (33%) and ultrasound (40%) or the combination of both (49%). MRI offered a significantly higher sensitivity (91%). The sensitivity of mammography in the higher risk groups was 25%, compared with 100% for MRI. Specificity of MRI (97.2%) was equivalent to that of mammography (96.8%).

Conclusion

Mammography alone, and also mammography combined with breast ultrasound, seems insufficient for early diagnosis of breast cancer in women who are at increased familial risk with or without documented BRCA mutation. If MRI is used for surveillance, diagnosis of intraductal and invasive familial or hereditary cancer is achieved with a significantly higher sensitivity and at a more favorable stage.
Phase II Study of Oxaliplatin for Treatment of Patients With Mucosa-Associated Lymphoid Tissue Lymphoma
Authors: Raderer Markus , Wöhrer Stefan , Bartsch Rupert , Prager Gerald , Drach Johannes , Hejna Michael , Gaiger Alexander , Turetschek Karl , Jaeger Ulrich , Streubel Berthold , Zielinski Christoph C.
Published: November 2005

Purpose

Various chemotherapeutic regimens have been applied for treatment of mucosa-associated lymphoid tissue (MALT) lymphoma, but no standard regimen has been identified to date. In view of the activity of oxaliplatin (L-OHP) in various types of lymphoma, we performed a phase II study to evaluate the activity of L-OHP for treatment of MALT lymphoma. The primary objective of this study was to determine the objective response rate according to WHO standard criteria.

Patients and Methods

A total of 16 patients with MALT lymphoma of various sites of origin (four of the ocular adnexa, five of the salivary glands, three of the stomach, two of the lung, and one of the colon and the breast) were administered L-OHP at a dose of 130 mg/m2 infused during 2 hours every 3 weeks. Restaging was performed every two cycles; treatment was continued until complete remission (CR) or for a maximum of six cycles in responders.

Results

Sixty-five cycles were administered (median, four; range, two to six); toxicity consisted of transient sensory neuropathy in eight patients and nausea/emesis WHO grade 2 in two patients, whereas hematologic adverse effects (thrombocytopenia and leukocytopenia grade 2) occurred in only one patient each. Fifteen patients responded to chemotherapy, with nine achieving CR (56%), six (37.5%) achieving partial response, and one achieving stable disease; the median time to response was 4 months (range; 2 to 4 months).

Conclusion

These data suggest L-OHP is a highly active agent for treatment of MALT lymphoma. However, a longer follow-up is needed to judge whether these remissions are durable.
Patterns of Treatment Failure in Pediatric and Young Adult Patients With Hodgkin's Disease: Local Disease Control With Combined-Modality Therapy
Authors: Krasin Matthew J. , Rai Shesh N. , Kun Larry E. , Merchant Thomas E. , Metzger Monika L. , Kaste Sue C. , Howard Scott C. , Hudson Melissa M.
Published: November 2005

Purpose

Refinement in managing pediatric Hodgkin's disease (HD) requires understanding of factors associated with local treatment failure. This study defines the cumulative incidence (CI) of local failure (LF) and prognostic factors for pediatric patients treated for HD with combined-modality therapy (CMT).

Patients and Methods

We enrolled 195 patients onto two prospective studies at St Jude Children's Research Hospital between 1990 and 2000. Patients received CMT with chemotherapy (vinblastine, doxorubicin, methotrexate, and prednisone [VAMP]; vinblastine, etoposide, prednisone, and doxorubicin; or VAMP/cyclophosphamide, vincristine, and procarbazine) and involved-field radiation therapy delivered to initial site(s) of disease on the basis of early response. Sites of disease involvement, treatment, and sites of failure were confirmed from the patients' medical record, imaging, and radiotherapy treatment records. We estimated the overall survival, event-free survival, and CI of LF.

Results

With a median follow-up of 7.6 years, the CI of LF was 10.9% and 11.6% at 5 and 10 years, respectively. Twenty-seven (14%) of 195 patients experienced recurrence of HD, and 22 (81%) of those experienced LF. Bulky mediastinal disease greater than one third transthoracic diameter predicted a higher incidence of LF, but did not predict failure in the mediastinum. Male sex, low initial hemoglobin, and bulky mediastinal disease were prognostic indicators of LF. Attenuation of radiation dose to 15 Gy based on response provides excellent infield control.

Conclusion

CMT provides excellent local disease control in children and young adults with HD. LF remains a primary site of disease recurrence, with male sex, low initial hemoglobin, and bulky mediastinal disease predicting for LF.
Pathogenesis of Myelofibrosis With Myeloid Metaplasia
Authors: Tefferi Ayalew
Published: November 2005

The primary disease process in myelofibrosis with myeloid metaplasia (MMM) is clonal myeloproliferation with varying degrees of phenotypic differentiation. This is characteristically accompanied by secondary intramedullary collagen fibrosis, osteosclerosis, angiogenesis, and extramedullary hematopoiesis. Modern clonality studies have confirmed the multipotent stem-cell origin of the neoplastic process in MMM. The nature of the specific oncogenic mutation(s) is currently being unraveled with the recent discovery of an association between a somatic point mutation of JAK2 tyrosine kinase (V617F) and bcr/abl-negative myeloproliferative disorders, including MMM. The pathogenetic mechanisms that underlie the secondary bone marrow stromal changes in MMM are also incompletely understood. Mouse models of this latter disease aspect have been constructed by either in vivo overexpression of thrombopoietin (TPOhighmice) or megakaryocyte lineage restricted underexpression of the transcription factor GATA-1 (GATA-1lowmice). Gene knockout experiments using such animal models have suggested the essential role of hematopoietic cell-derived transforming growth factor beta1 in inducing bone marrow fibrosis and stromal cell–derived osteoprotegerin in promoting osteosclerosis. However, experimental myelofibrosis in mice does not recapitulate clonal myeloproliferation that is fundamental to human MMM. Other cytokines that are implicated in mediating myelofibrosis and angiogenesis in MMM include basic fibroblast, platelet-derived, and vascular endothelial growth factors. It is currently assumed that such cytokines are abnormally released from clonal megakaryocytes as a result of a pathologic interaction with neutrophils (eg, emperipolesis). This latter phenomenon, through neutrophil-derived elastase, could also underlie the abnormal peripheral-blood egress of myeloid progenitors in MMM.
Prognostic Relevance of Response Evaluation Using [18F]-2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography in Patients With Locally Advanced Non–Small-Cell Lung Cancer
Authors: Hoekstra Corneline J. , Stroobants Sigrid G. , Smit Egbert F. , Vansteenkiste Johan , van Tinteren Harm , Postmus Pieter E. , Golding Richard P. , Biesma Bonne , Schramel Frans J.H.M. , van Zandwijk Nico , Lammertsma Adriaan A. , Hoekstra Otto S.
Published: November 2005

Purpose

The objective of this study was to determine the accuracy of (early) response measurements using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG PET) with respect to survival of patients with stage IIIA-N2 non–small-cell lung cancer (NSCLC) undergoing induction chemotherapy (IC), with a comparative analysis of PET methods.

Patients and Methods

In a prospective multicenter study, PET was performed in patients before IC and after one and three cycles. Computed tomography (CT) was performed before and after IC. Glucose consumption (metabolic rate of glucose [MRglu]) was measured using Patlak graphical analysis and correlated with simplified methods. Mediastinal lymph node (MLN) status was assessed visually. Cox proportional hazards analysis was used to determine the prognostic relevance of CT and PET measures of response with respect to survival.

Results

Complete PET data sets were available in 47 patients. Median survival was 21 months. MLN status after IC by PET predicted survival (hazard ratio [HR], 2.33; 95% CI, 1.04 to 5.22; P = .04) in contrast with CT (HR, 1.87; 95% CI, 0.81 to 4.30; P = .14). Residual MRglu after IC proved to be the best prognostic factor (HR, 1.95; 95% CI, 1.28 to 2.97; P = .002). Multivariate stepwise analysis showed that PET identified prognostically different strata in patients considered responsive according to CT. Residual MRglu after one cycle selected patients with different outcomes (HR, 2.04; 95% CI, 1.18 to 3.52; P = .01). Simplified quantitative 18FDG PET methods were correlated with Patlak graphical analysis during and after therapy (r ≥ 0.90).

Conclusion

18FDG PET has additional value over CT in monitoring response to IC in patients with stage IIIA-N2 NSCLC, and it seems feasible to predict survival early during IC. Simple semiquantitative and complex PET methods perform equally well.
Phase III Trial of Epirubicin Plus Paclitaxel Compared With Epirubicin Plus Cyclophosphamide As First-Line Chemotherapy for Metastatic Breast Cancer: United Kingdom National Cancer Research Institute Trial AB01
Authors: Langley Ruth E. , Carmichael James , Jones Alison L. , Cameron David A. , Qian Wendi , Uscinska Barbara , Howell Anthony , Parmar Mahesh
Published: November 2005

Purpose

To compare the effectiveness and tolerability of epirubicin and paclitaxel (EP) with epirubicin and cyclophosphamide (EC) as first-line chemotherapy for metastatic breast cancer (MBC).

Patients and Methods

Patients previously untreated with chemotherapy (except for adjuvant therapy) were randomly assigned to receive either EP (epirubicin 75 mg/m2 and paclitaxel 200 mg/m2) or EC (epirubicin 75 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously every 3 weeks for a maximum of six cycles. The primary outcome was progression-free survival; secondary outcome measures were overall survival, response rates, and toxicity.

Results

Between 1996 and 1999, 705 patients (353 EP patients and 352 EC patients) underwent random assignment. Patient characteristics were well matched between the two groups, and 71% of patients received six cycles of treatment. Objective response rates were 65% for the EP group and 55% for the EC group (P = .015). At the time of analysis, 641 patients (91%) had died. Median progression-free survival time was 7.0 months for the EP group and 7.1 months for the EC group (hazard ratio = 1.07; 95% CI, 0.92 to 1.24; P = .41), and median overall survival time was 13 months for the EP group and 14 months for the EC group (hazard ratio = 1.02; 95% CI, 0.87 to 1.19; P = .8). EP patients, compared with EC patients, had more grade 3 and 4 mucositis (6% v 2%, respectively; P = .0006) and grade 3 and 4 neurotoxicity (5% v 1%, respectively; P < .0001).

Conclusion

In terms of progression-free survival and overall survival, there was no evidence of a difference between EP and EC. The data demonstrate no additional advantage to using EP instead of EC as first-line chemotherapy for MBC in taxane-naïve patients.
Tumor Necrosis Factor and Lymphotoxin Alfa Genetic Polymorphisms and Outcome in Pediatric Patients With Non-Hodgkin’s Lymphoma: Results From Berlin-Frankfurt-Münster Trial NHL-BFM 95
Authors: Seidemann Kathrin , Zimmermann Martin , Book Marion , Meyer Ulrike , Burkhardt Birgit , Welte Karl , Reiter Alfred , Stanulla Martin
Published: November 2005

Purpose

To analyze the association of genetic variation within the tumor necrosis factor (TNF −308 [G→A]) and lymphotoxin alfa (LT-a +252 [A→G]) genes with outcome in non-Hodgkin's lymphoma of childhood and adolescence.

Patients and Methods

Genotyping of the TNF −308 (G→A) and LT-a +252 (A→G) polymorphisms in patients (n = 488) enrolled onto the German-Austrian-Swiss multicenter trial NHL-BFM 95 from April 1996 to January 2000 was performed by polymerase chain reaction with subsequent restriction fragment length polymorphism analysis on DNA from tumor-free specimen.

Results

In patients with Burkitt's lymphoma (BL) and B-cell acute lymphoblastic leukemia (B-ALL; n = 219, 211 eligible patients), patients carrying at least two variant alleles (high-producer haplotypes) had an increased risk of events: probability of event-free survival (pEFS) at 3 years was 81% (SE = 5%), compared with 91% (SE = 2%) in low-producer haplotypes (P = .018). In BL/B-ALL with high tumor load (lactate dehydrogenase [LDH] ≥ 500 U/L; n = 104), pEFS was 69% (SE = 8%) in high-producer versus 85% (SE = 4%) in low-producer haplotypes (P = .05). In multivariate analysis including risk factors for events (LDH ≥ 500 U/L, CNS involvement, methotrexate infusion regimen), TNF −308/LT-α +252 haplotype kept prognostic relevance: patients with high-producer haplotypes had a 2.34-fold increase in risk of events (P = .048). The TNF −308 (G→A) and LT-α +252 (A→G) polymorphisms were not associated with pEFS in lymphoblastic lymphoma (n = 101), anaplastic large-cell lymphoma (n = 67), or diffuse large B-cell lymphoma (n = 65), nor with therapy-related toxicity.

Conclusion

The TNF −308 (G→A) and LT-a +252 (A→G) polymorphisms were negative prognostic factors in pediatric BL/B-ALL. Among patients with serum LDH ≥ 500 U/L, haplotype analysis further determined patients at risk for events.
Phase III Trial of Gemcitabine Plus Carboplatin Versus Single-Agent Gemcitabine in the Treatment of Locally Advanced or Metastatic Non–Small-Cell Lung Cancer: The Swedish Lung Cancer Study Group
Authors: Sederholm Christer , Hillerdal Gunnar , Lamberg Kristina , Kölbeck Karl , Dufmats Monika , Westberg Ronny , Gawande Sulochana R.
Published: November 2005

Purpose

This phase III study compared overall survival in patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) when treated with single-agent gemcitabine versus gemcitabine/carboplatin. Secondary objectives were to compare response, time to progression, toxicity, and quality of life.

Patients and Methods

Chemotherapy-naive patients received either gemcitabine alone (1,250 mg/m2on days 1 and 8; gemcitabine arm) or with carboplatin (area under the curve 5 on day 1; GC arm) every 21 days.

Results

Demographics and disease characteristics of 334 randomly assigned patients were comparable on both arms. An intent-to-treat analysis showed significantly better overall survival (log-rank P = .0205) and 2-year survival (15% v 5%; P = .009) favoring the GC arm. Per Cox multivariate analysis, only two covariates, treatment arm (GC v G) and baseline performance status (0 or 1 v 2), independently influenced survival. Per-protocol analyses showed significantly longer median time to progression (5.7 v 3.9 months; P = .0001) and significantly higher objective response rate (29.6 v 11.3%; P < .0001) in the GC arm. Grade 3 to 4 leucopenia and thrombocytopenia were significantly more pronounced in the GC arm (P for both variables < .001) but importantly without associated increases in fever, infection, bleeding, or hospitalizations. There was no discernible difference in global quality-of-life patterns between treatment arms.

Conclusion

In advanced NSCLC, gemcitabine/carboplatin therapy resulted in significant survival benefit compared with single-agent gemcitabine without undue increase in toxicity.
Pediatric Phase I Trials in Oncology: An Analysis of Study Conduct Efficiency
Authors: Lee Debra P. , Skolnik Jeffrey M. , Adamson Peter C.
Published: November 2005

Purpose

To determine the efficacy and safety of pediatric phase I oncology trials in the era of dose-intensive chemotherapy and to analyze how efficiently these trials are conducted.

Methods

Phase I pediatric oncology trials published from 1990 to 2004 and their corresponding adult phase I trials were reviewed. Dose escalation schemes using fixed 30% dose increments were studied to theoretically determine whether trials could be completed utilizing fewer patients and dose levels.

Results

Sixty-nine pediatric phase I oncology trials enrolling 1,973 patients were identified. The pediatric maximum-tolerated dose (MTD) was strongly correlated with the adult MTD (r = 0.97). For three-fourths of the trials, the pediatric and adult MTD differed by no more than 30%, and for more than 85% of the trials, the pediatric MTD was less than or equal to 1.6 times the adult MTD. The median number of dose levels studied was four (range, two to 13). The overall objective response rate was 9.6%, the likelihood of experiencing a dose-limiting toxicity was 24%, and toxic death rate was 0.5%.

Conclusion

Despite the strong correlation between the adult and pediatric MTDs, more than four dose levels were studied in 40% of trials. There appeared to be little value in exploring dose levels greater than 1.6 times the adult MTD. Limiting pediatric phase I trials to a maximum of four doses levels would significantly shorten the timeline for study conduct without compromising safety.
Surgical Risk Factors in Primary Surgery for Localized Neuroblastoma: The LNESG1 Study of the European International Society of Pediatric Oncology Neuroblastoma Group
Authors: Cecchetto Giovanni , Mosseri Veronique , De Bernardi Bruno , Helardot Pierre , Monclair Tom , Costa Elisa , Horcher Ernst , Neuenschwander Sylvia , Tomà Paolo , Rizzo Antonino , Michon Jean , Holmes Keith
Published: November 2005

Purpose

Although tumor resection is the mainstay of treatment for localized neuroblastoma, there are no established guidelines indicating which patients should be operated on immediately and which should undergo surgery after tumor reduction with chemotherapy. In an effort to develop such guidelines, the LNESG1 study defined surgical risk factors (SRFs) based on the imaging characteristics.

Patients and Methods

A total of 905 patients with suspected localized neuroblastoma were registered by 10 European countries between January 1995 and October 1999; 811 of 905 patients were eligible for this analysis.

Results

Information on SRFs was obtained for 719 of 811 patients; 367 without and 352 with SRFs. Of these 719 patients, 201 patients (four without and 197 with SRFs) underwent biopsy only. An attempt at tumor excision was made in 518 patients: 363 of 367 patients without and 155 of 352 patients with SRFs (98.9% v 44.0%). Complete excision was achieved in 271 of 363 patients without and in 72 of 155 patients with SRF (74.6% v 46.4%), near-complete excision was achieved in 81 and 61 patients (22.3% v 39.3%), and incomplete excision was achieved in 11 and 22 patients (3.0% v 14.2%), respectively. There were two surgery-related deaths. Nonfatal surgery-related complications occurred in 45 of 518 patients (8.7%) and were less frequent in patients without SRFs (5.0% v 17.4%). Associated surgical procedures were also less frequent in patients without SRFs (1.6% v 9.7%).

Conclusion

The adoption of SRFs as predictors of adverse surgical outcome was validated because their presence was associated with lower complete resection rate and greater risk of surgery-related complications. Additional studies aiming to better define the surgical approach to localized neuroblastoma are warranted.
Elevated Circulating Insulin-Like Growth Factor Binding Protein-1 Is Sufficient to Cause Fetal Growth Restriction
Authors: Watson Carole S. , Bialek Peter , Anzo Makoto , Khosravi Javad , Yee Siu-Pok , Han Victor K. M.
Published: November 2005

IGF binding protein-1 (IGFBP-1) inhibits the mitogenic actions of the IGFs. Circulating IGFBP-1 is elevated in newborns and experimental animals with fetal growth restriction (FGR). To establish a causal relationship between high circulating IGFBP-1 and FGR, we have generated transgenic mice using the mouse α-fetoprotein gene promoter to target overexpression of human IGFBP-1 (hIGFBP-1) in the fetal liver. These transgenic mice (AFP-BP1) expressed hIGFBP-1 mainly in the fetal hepatocytes, starting at embryonic d 14.5 (E14.5), with lower levels in the gut. The expression peaked at 1 wk postnatally (plasma concentration, 474 ± 34 ng/ml). At birth, AFP-BP1 pups were 18% smaller [weighed 1.34 ± 0.02 g compared with 1.62 ± 0.04 g for wild type (WT); P < 0.05], and they did not demonstrate any postnatal catch-up growth. The placentas of the AFP-BP1 mice were larger than WT from E16.5 onwards (150 ± 12 for AFP-BP1 vs. 100 ± 5 mg for WT at E16.5; P < 0.05). Thus, this model of FGR is associated with a larger placenta, but without postnatal catch-up growth. Overall, these data clearly demonstrate that high concentrations of circulating IGFBP-1 are sufficient to cause FGR.
Dehydroepiandrosterone Sulfate Is Neuroprotective when Administered Either before or after Injury in a Focal Cortical Cold Lesion Model
Authors: Juhász-Vedres Gabriella , Rózsa Éva , Rákos Gabriella , Dobszay Márton B. , Kis Zsolt , Wölfling János , Toldi József , Párducz Árpád , Farkas Tamás
Published: November 2005

Dehydroepiandrosterone and its sulfate (DHEAS) are sex hormone precursors that exert marked neurotrophic and/or neuroprotective activity in the central nervous system. The present study evaluated the effects of DHEAS and 17β-estradiol (E2) in a focal cortical cold lesion model, in which DHEAS (50 mg/kg, sc) and E2 (35 mg/kg, sc) were administered either as pretreatment (two subsequent injections 1 d and 1 h before lesion induction) or posttreatment (immediately after lesion induction). The focal cortical cold lesion was induced in the primary motor cortex by means of a cooled copper cylinder placed directly onto the cortical surface. One hour later, the animals were killed, the brains cut into 0.4-mm-thick slices, and the sections stained with 1% triphenyltetrazolium chloride. The volume of the hemispheric lesion was calculated for each animal. The results demonstrated that the lesion area was significantly attenuated in both the DHEAS- and E2- pre- and posttreated groups and that in the presence of letrozole, a nonsteroidal aromatase inhibitor, no neuroprotection was observed, suggesting that the beneficial effect of DHEAS on the cold injury might depend on the conversion of DHEAS to E2 within the brain. It is concluded that even a single posttraumatic administration of DHEAS may be of substantial therapeutic benefit in the treatment of focal brain injury with vasogenic edema.