bluuebunny/crossref_metadata_2025 huggingface dataset:
Product Variety Optimization Simultaneously Designing Module Combination and Module Attributes
Authors: Fujita Kikuo , Yoshida Hiroko
Published: May 2004

This paper proposes a product variety optimization method for both module combination and module attributes of multiple products. As manufacturing competition has become restricted with high profitability and external constraints, simultaneous design of multiple products, called product variety design etc., becomes an important strategy. The systems-based optimal design paradigm is essential for rationalizing such practices, since design for product variety is more complicated than for a single product. In such a direction, we configure an optimization method for simultaneously designing both module combination and module attributes across multiple products. The optimization method hybridizes a genetic algorithm, a mixed-integer programming method with a branch-and-bound technique, and a constrained nonlinear programming method, i.e., a successive quadratic programming method. In its optimization process, the first optimizes the combinatorial pattern of module commonality and similarity among different products, the second optimizes the directions of similarity-based variety, and the third optimizes the continuous module attributes under the others. Finally it is applied to the simultaneous design problem of multiple airplanes to demonstrate its validity and effectiveness.
A Novel Genetic Label for Detection of Specific Probiotic Lactic Acid Bacteria
Authors: Fernandez L. , Marin M. L. , Langa S. , Martin R. , Reviriego C. , Fernandez A. , Olivares M. , Xaus J. , Rodriguez J. M.
Published: May 2004

A novel method for genetic labelling of specific lactic acid bacteria strains was developed. The approach implied the transformation of the hosts with a plasmid containing a heterologous DNA fragment. The sequence of a DNA fragment that has been used to label a variety of genetically modified (GM) soya was used to design a forward primer and three reverse primers yielding PCR products recognisable by their sizes. Stability of the recombinant plasmid in the transformed strains was studied by PCR, and the results varied significantly depending on the strain. To test the usefulness of the DNA label to study in vivo properties of probiotic bacteria, such as viability after transit through the digestive tract, mice were orally inoculated with a genetically-labelled Enterococcus faecium strain. Later, their faeces were aseptically collected and the genetically-labelled strain was detected among the colonies that grew on MRS agar.
Note. Effect of Storage Temperature on the Shelf Life of Hass Avocado (Persea Americana)
Authors: Perez K. , Mercado J. , Soto-Valdez H.
Published: May 2004

The effect of storage temperature on the shelf life, weight loss, respiration rate and ethylene production of Hass avocado (Persea americana Mill) was studied. Two batches of green mature avocado fruits, classified as ‘‘super extra’’ were stored at 10 and 20 C (first batch) and at 7 and 25 C (second batch). The avocado shelf lives were 22, 8, 32 and 6 days at 10, 20, 7 and 25 C, respectively. Based on the data of the first assay Q10 was calculated as 2.75, with this value the predicted shelf life at 7 and 25 C were 29.8 and 4.8 days, respectively. That meant shelf life was underestimated 7 and 20% at 7 and 25 C, respectively. Weight loss was linear at both the storage temperatures, it was 4.3% in fruits at 20 C for 8 days and 3.0% at 10 C for 22 days. The maximum CO2 production at 20 C was reached during the second day of storage, while at 10 C it was reached at the 17th day (176.17 15.98 and 74.73 7.32 mL/kg h, respectively). The maximum ethylene production at 20 C was reached the second day of storage, and at 10 C the 6th day (239.06 54.55 and 28.00 8.12 mL/kg h, respectively).
Effect of Some Hydrocolloids on the Rheological Properties of Rye Starch
Authors: Juszczak L. , Witczak M. , Fortuna T. , Banachowicz A.
Published: May 2004

The effect of three non-starch hydrocolloids (guar, carob and arabic gums) on some rheological properties of rye starch pastes/gels at a constant 6.5% concentration of polysaccharides was determined throughout: (i) pasting characteristics, (ii) flow curves and apparent viscosity–shear time curves at 50 C and (iii) mechanical spectra at 25 C. The presence of gums in the system modified the rheological properties of rye starch pastes/gels and these alterations depended on the type and concentration of the gum. The systems with guar and carob gums exhibited higher apparent viscosities during pasting and higher shear stresses during flow than the paste of native starch. The viscosity of the system with carob was bigger than the one with guar gum. The presence of arabic gum decreased the apparent viscosity of the system both during pasting and during flow. Replacing part of starch with a gum modified the viscoelastic properties of gels, the changes depended on the kind and concentration of the gum.
Kinetics of Physico-Chemical and Microbiological Changes During Storage of Commercial Frankfurters
Authors: Santiago L. G. , Aringoli E. E. , Sabbag N. G. , Bonaldo A. G. , Gonzalez R. J.
Published: May 2004

Numerous changes occur in frankfurters during processing and storage. Reaction kinetics depends on various factors such as composition, temperature and packaging. Physico-chemical, microbiological and textural changes were analysed in two commercial formulations of frankfurters during their storage at 5, 10 and 15 C. This information allowed to calculate kinetics parameters and to predict shelf life at the usual storage temperature range. The formulation with higher content of meat protein was more resistant and elastic and had lower purge loss. The variability within each lot was higher than the effect of storage time and temperature on texture parameters, so these parameters would not be sensitive enough to detect changes and predict frankfurters shelf life. At 5 C, pH, acidity and purge loss remained constant with storage time while at 10 and 15 C good linear correlations (r> 0.958) were found. Microbiological growth fitted a logarithmic equation (r> 0.978). Physico-chemical changes followed a zero-order reaction while microbiological growth followed a first-order one. All reaction rate constants increased with temperature. Changes in pH, acidity and purge loss were higher for the formulation with higher starch and lower meat protein content. Shelf life at the normal storage temperatures could be predicted only from microbiological kinetic changes. Two brands of Frankfurter with different contents of protein (13.33 and 11.89 respectively) were used.
Influence of Tomato Paste Processing on the Linear Viscoelasticity of Tomato Ketchup
Authors: Valencia C. , Sanchez M. C. , Ciruelos A. , Gallegos C.
Published: May 2004

Tomato paste is used as an ingredient for the manufacture of tomato ketchup. This paper deals with the influence that some tomato paste processing variables (finisher screen opening and breaking temperature) and tomato variety exert on the linear viscoelastic properties of tomato ketchup. Two tomato varieties (H-282 and H-282F) were used. H-282 is a commercial variety whilst H-282F is a variety with a lower content in polygalacturonase (PG). Dynamic viscoelastic tests and particle size distribution measurements were carried out. Viscoelastic properties of tomato ketchup were mainly related to their mean volume diameter, tomato paste water-insoluble solids content (that depended on the tomato paste processing) and tomato variety.
Lipid Peroxidation Inhibitory Effects of Hizikia Fusiformis Methanolic Extract on Fish Oil and Linoleic Acid
Authors: Siriwardhana Nalin , Lee K. -W. , Kim S. -H. , Ha J. -H. , Park G. -T. , Jeon Y. -J.
Published: May 2004

The lipid peroxidation inhibitory effects of Hizikia fusiformis methanolic extract (HME) on fish oil and linoleic acid were studied by means of peroxide value (PV), thiobarbituric acid-reactive substances (TBARS), conjugated diene hydroperoxides (CDH) and weight gaining assays. Heat and UV light stability were determined by DPPH assay. HME significantly (p<0.05) reduced the lipid peroxidation in a dosedependent manner. Increasing the level of HME from 0.01 to 0.1% caused a higher antioxidative effect than the one produced by butylated hydroxytoluene (BHT) (BHT reported the best effect compared to -tocopherol and butylated hydroxyanisole). HME reduced the formation of primary oxidation products as showed by the lower CDH values compared to its control counterpart. HME reduced also the addition of oxygen to form lipid peroxyl radicals that indicated a low weight gaining in HME-treated oils. Moreover, it could reduce the formation of lipid peroxide. Furthermore, it diminished the total lipid peroxidation resulting in low TBARS values. The heat and UV light study showed that H. fusiformis contained heat- and UV-light resistant antioxidants. These results indicated that the H. fusiformis antioxidants could be useful in preventing oxidative damages of food oils.
Note. Chlorotrimethylsilane – A Reagent for the Direct Analysis of Fats and Oils in Solid and Paste Samples
Authors: Eras J. , Dolcet A. , Ferran J. , Canela R.
Published: May 2004

Fatty acid pentyl esters (FAPEs) from eight solid and paste samples of various substances – olives, sunflower seeds, semiroasted hazelnuts, infant milk powder, mayonnaise sauce, sausage, muesli and cheese – were directly prepared using chlorotrimethylsilane (CTMS) and pentanol. The pentyl esters were analysed by GLC and the relative percentages were compared with those obtained applying the CTMS method to the oil extracted from the samples. Although significant differences in individual fatty acid compositions were observed in some cases, those differences were randomly distributed. Moreover, applying the minimum least square regression method the two sets of results might be considered statistically equivalent. Thus, calculated slope and intercept did not differ significantly from 1 and 0.
A Technique for Online Biaxial Birefringence Measurements and Its Application
Authors: Ajji A.
Published: May 2004

In this study, we discuss the applications of a birefringence technique for online or off-line quantitative measurement of biaxial orientation in transparent films, sheets, bottles, etc. Absolute values of biaxial birefringence are measured in two directions using a technique based on an incident multiwavelength double beam and photodiode array assemblies, combined with in-house developed software. Both machine and transverse direction birefringences (relative to the normal direction) were measured simultaneously. Film and sheet of different thicknesses can be tested and birefringence values from 0.0005 to 0.25 can be measured. The results reported here are on the use of this technique for online birefringence measurements in two different cases: orientation and relaxation of birefringence during and after deformation of polyethylene terephthalate sheet; and online biaxial orientation of polystyrene sheet monitoring in an industrial process plant.
Effect of Crystalline Structure on Tear Resistance of LDPE and LLDPE-Blown Films
Authors: Zhang X. M. , Elkoun S. , Ajji A. , Huneault M. A.
Published: May 2004

Low-density polyethylene (LDPE) and linear low-density polyethylene (LLDPE)-blown films differ significantly in the ratio between machine and transverse direction tear resistances. In this paper, the relationship between crystalline morphology and the differences in film tear anisotropy is investigated. The crystalline morphology and its orientation are probed using microscopy and infrared spectroscopy. Significant differences in crystalline morphology are observed: LDPE develops a row-nucleated structure, while a spherulite-like superstructure is observed for LLDPE. These structural differences are shown to translate into different ratios of machine and transverse direction tear strengths.
Influence of Sample Preparation and Instrument Settings on Hot Tack Measurements of Thin Sealant Films
Authors: Berger Kenneth R. , Knoelke Matthew , Welt Bruce
Published: May 2004

Sample preparation can greatly influence the results of laboratory testing of packaging sealant materials. Factors such as test strip width, edge uniformity, sealing die temperature, and die pressure were considered as variables to be considered in the measurement of hot tack. A design of experiment approach was used to explore the rank importance of these factors and any interactive effects that may occur. A commercially used structure – ethylene vinyl acetate (EVA) sealant on a high density polyethylene (HDPE) film – was used for these tests. Experimental results indicated that sample width, die temperature, and die pressure were the most influential factors. Edge effects, namely a regular sine wave pattern and a random irregular edge had little influence on hot tack results and there were no significant interactive effects noted.
Phase II Study of Capecitabine in Patients With Fluorouracil-Resistant Metastatic Colorectal Carcinoma
Authors: Hoff Paulo M. , Pazdur Richard , Lassere Yvonne , Carter Susan , Samid Dvorit , Polito Diane , Abbruzzese James L.
Published: May 2004

Purpose

Capecitabine is an oral fluoropyrimidine converted to fluourouracil (FU) preferentially in tumor tissue. It has proven clinical activity against colorectal cancer when used as first-line therapy. The objectives of this study were to assess the safety and efficacy of capecitabine in patients with metastatic colorectal carcinoma who progressed despite previous FU therapy.

Patients and Methods

According to the group sequential analysis design of this study, accrual would stop if no responses were observed in the first 20 patients treated. If one or more objective responses were confirmed, the trial would be expanded. Patients received capecitabine 1,250 mg/m2 twice a day for 14 days, every 3 weeks. Tumor lesions were assessed every 6 weeks, and patients were followed for survival every 3 months after completing treatment.

Results

Twenty-three patients were enrolled onto the study; 22 fulfilled all the eligibility criteria. No objective responses were observed among the 22 eligible patients; 11 patients (50%) had stable disease for a median duration of 141 days (range, 88–289 days). The Kaplan-Meier estimate of median time to disease progression was 64 days (95% CI, 41 to 134 days). The median survival time estimate was 389 days (95% CI, 267 to 637 days). The most frequent treatment-related adverse events were hand-foot syndrome, diarrhea, and nausea or vomiting. There were no grade 4 toxicities and no treatment-related deaths.

Conclusion

Single-agent capecitabine in patients with metastatic colorectal carcinoma refractory to FU showed no objective responses and clinical benefit that was, at best, modest. The use of capecitabine in combination with other treatments in this patient population is under investigation.
Phase II Trial of Pleural Photodynamic Therapy and Surgery for Patients With Non–Small-Cell Lung Cancer With Pleural Spread
Authors: Friedberg Joseph S. , Mick Rosemarie , Stevenson James P. , Zhu Timothy , Busch Theresa M. , Shin Daniel , Smith Debbie , Culligan Melissa , Dimofte Andreea , Glatstein Eli , Hahn Stephen M.
Published: May 2004

Purpose

Non—small-cell lung cancer (NSCLC) with pleural spread is incurable, with median survival rates ranging from 6 to 9 months. Surgery alone fails to locally control this disease or extend survival beyond the accepted treatment, palliative chemotherapy.

Methods

We conducted a phase II trial to evaluate the effects on local control and survival of combining surgery with intraoperative photodynamic therapy (PDT), a light-based cancer treatment, in patients with NSCLC with pleural spread. Patients received porfimer sodium (2 mg/kg), 24 hours before surgery, at which time all gross tumor was resected and followed by illumination of the hemithorax with 630 nm light to a measured dose of 30 J/cm2. Photosensitizer levels in tumor and surrounding normal tissue were measured.

Results

Twenty-two patients with NSCLC were enrolled; 17 underwent complete debulking and PDT, three underwent partial debulking/PDT, and two patients were unresectable. Local control of pleural disease at 6 months was achieved in 11 of 15 (73.3%; 95% CI, 44.9% to 92.2%) assessable patients. Median overall survival for all 22 patients was 21.7 months (95% CI, 17.7 to 25.8 months). Measured levels of porfimer sodium in tumor were greater than those measured in normal tissues, with ratios ranging from 1.19 to 22.42.

Conclusion

Our results indicate surgery and PDT can be performed safely with very good local control. The median survival of 21.7 months, calculated from the time of surgery and PDT is encouraging. Further evaluation of this therapy is warranted.
Phase II Randomized Study of Vaccine Treatment of Advanced Prostate Cancer (E7897): A Trial of the Eastern Cooperative Oncology Group
Authors: Kaufman Howard L. , Wang Wei , Manola Judith , DiPaola Robert S. , Ko Yoo-Joung , Sweeney Christopher , Whiteside Theresa L. , Schlom Jeffrey , Wilding George , Weiner Louis M.
Published: May 2004

Purpose

A phase II clinical trial was conducted to evaluate the feasibility and tolerability of a prime/boost vaccine strategy using vaccinia virus and fowlpox virus expressing human prostate-specific antigen (PSA) in patients with biochemical progression after local therapy for prostate cancer. The induction of PSA-specific immunity was also evaluated.

Patients and Methods

A randomized clinical trial was conducted by the Eastern Cooperative Oncology group and 64 eligible patients were randomly assigned to receive four vaccinations with fowlpox-PSA (rF-PSA), three rF-PSA vaccines followed by one vaccinia-PSA (rV-PSA) vaccine, or one rV-PSA vaccine followed by three rF-PSA vaccines. The major end point was PSA response at 6 months, and immune monitoring included measurements of anti-PSA and anti-vaccinia antibody titers and PSA-specific T-cell responses.

Results

The prime/boost schedule was well tolerated with few adverse events. Of the eligible patients, 45.3% of men remained free of PSA progression at 19.1 months and 78.1% demonstrated clinical progression-free survival. There was a trend favoring the treatment group that received a priming dose of rV-PSA. Although no significant increases in anti-PSA antibody titers were detected, 46% of patients demonstrated an increase in PSA-reactive T-cells.

Conclusion

Therapy with poxviruses expressing PSA and delivered in a prime/boost regimen was feasible and associated with minimal toxicity in the cooperative group setting. A significant proportion of men remained free of PSA and clinical progression after 19 months follow-up, and nearly half demonstrated an increase in PSA-specific T-cell responses. Phase III studies are needed to define the role of vaccination in men with prostate cancer or those who are at risk for the disease.
Posttherapy [18F] Fluorodeoxyglucose Positron Emission Tomography in Carcinoma of the Cervix: Response and Outcome
Authors: Grigsby Perry W. , Siegel Barry A. , Dehdashti Farrokh , Rader Janet , Zoberi Imran
Published: May 2004

Purpose

The aim of this study was to evaluate response to therapy using posttherapy molecular imaging with [18F] fluorodeoxyglucose (FDG), and to compare the response with patient outcome.

Patients and Methods

This was a retrospective medical record review of 152 patients with carcinoma of the cervix. All patients underwent a pre- and posttreatment whole-body positron emission tomography (PET) imaging scan with FDG. Patients were treated with external irradiation and intracavitary brachytherapy, and most received concurrent weekly cisplatin. Posttherapy whole-body FDG-PET was performed 1 to 12 months (mean, 3 months) after completion of treatment.

Results

The posttherapy PET did not show any abnormal FDG uptake in 114 patients, and their 5-year cause-specific survival estimate was 80%. There was persistent (in the irradiated region) abnormal FDG uptake in the cervix or lymph nodes in 20 patients. Their 5-year cause-specific survival estimate was 32%. New anatomic sites (in unirradiated regions) of abnormal FDG uptake were present in 18 patients, and none were alive at 5 years. A Cox proportional hazards model of survival outcome indicated that any abnormal posttherapy FDG uptake (persistent or new) was the most significant prognostic factor for developing metastatic disease and death from cervical cancer when compared with pretreatment- and treatment-related prognostic factors (P < .0001).

Conclusion

Posttherapy abnormal FDG uptake (persistent or new) as detected by whole-body PET measures tumor response and might be predictive of tumor recurrence and death from cervical cancer. Prospective validation of these results is warranted.
Adjuvant Chemotherapy With Paclitaxel and Carboplatin in Patients With Advanced Carcinoma of the Upper Urinary Tract: A Study by the Hellenic Cooperative Oncology Group
Authors: Bamias A. , Deliveliotis Ch. , Fountzilas G. , Gika D. , Anagnostopoulos A. , Zorzou M.P. , Kastritis E. , Constantinides C. , Kosmidis P. , Dimopoulos M.A.
Published: May 2004

Purpose

Radical surgery represents the treatment of choice for carcinoma of the upper urinary tract. Nevertheless, approximately 50% of patients with stage T ≥ 3 or lymph node involvement die from their disease, mainly as a result of the development of distant metastases. Therefore, there is a need for effective adjuvant systemic treatment. We prospectively studied a cohort of patients who underwent surgery for high-risk carcinoma of the upper urinary tract to assess the feasibility of the combination of paclitaxel and carboplatin as adjuvant treatment.

Patients and Methods

Thirty-six patients with tumor stage ≥ 3 or lymph node involvement were treated with four cycles of paclitaxel at 175 mg/m2 and carboplatin (area under the curve 5, Calvert Formula) every 3 weeks following surgery.

Results

Median follow-up was 40.6 months. Chemotherapy was well tolerated with 32 patients (89%) receiving full carboplatin and paclitaxel doses without delays. The most frequent grade 3/4 toxicity was neutropenia (39%), which was complicated with fever in only one case (3%). Nonhematologic grade 3 or 4 toxicities were reported in only one case. Five-year survival was 52% (95% CI, 35% to 69%), while 5-year disease-free survival was 40.2% (95% CI, 15.8% to 64.6%). Local failure rate was 30%, as opposed to 17% of patients who developed distant metastases. No patients with grade 2 tumors relapsed during follow-up, as opposed to 60% of patients with grade 3 tumors.

Conclusion

Adjuvant chemotherapy with paclitaxel and carboplatin is feasible and may reduce the risk of distant metastases in high-risk upper urinary tract carcinoma.
Pentoxifylline in the Treatment of Radiation-Induced Fibrosis
Authors: Okunieff Paul , Augustine Elizabeth , Hicks Jeanne E. , Cornelison Terri L. , Altemus Rosemary M. , Naydich Boris G. , Ding Ivan , Huser Amy K. , Abraham Edward H. , Smith Judith J. , Coleman Norman , Gerber Lynn H.
Published: May 2004

Purpose

Fibrotic sequelae remain the most important dose-limiting toxicity of radiation therapy to soft tissue. Functionally, this is reflected in loss of range of motion and muscle strength and the development of limb edema and pain. Tumor necrosis factor alpha and fibroblast growth factor 2 (FGF2), which are abnormally elevated in irradiated tissues, may mediate radiation fibrovascular injury.

Patients and Methods

In an open label drug trial, we studied the effects of pentoxifylline (400 mg orally tid for 8 weeks) on 30 patients who displayed late, radiation-induced fibrosis at 1 to 29 years posttreatment (40 to 84 Gy). The primary outcome measurement was change in physical impairments thought to be secondary to radiation, including active and passive range of motion (AROM and PROM), muscle strength, limb edema, and pain. Plasma levels of cytokines (tumor necrosis factor alpha and FGF2) also were measured. Twenty-seven patients completed baseline and 8-week assessments, and 24 patients completed baseline, 8-week, and 16-week assessments.

Results

After 8 weeks of pentoxifylline intervention, 20 of 23 patients with impaired AROM and 19 of 22 with impaired PROM improved; 11 of 19 patients with muscle weakness showed improved motor strength; five of seven patients with edema had decreased limb girth; and nine of 20 patients had decreased pain. Pretreatment FGF2 levels dropped from an average of 44.9 pg/mL to 24.0 pg/mL after 8 weeks of treatment.

Conclusion

Patients receiving pentoxifylline demonstrated improved AROM, PROM, and muscle strength and decreased limb edema and pain. Reversal of these delayed radiation effects was associated with a decrease in circulating FGF2.
The Changing Face of Low-Risk Prostate Cancer: Trends in Clinical Presentation and Primary Management
Authors: Cooperberg Matthew R. , Lubeck Deborah P. , Meng Maxwell V. , Mehta Shilpa S. , Carroll Peter R.
Published: May 2004

Purpose

Early intervention for prostate cancer is associated with excellent long-term survival, but many affected men, especially those with low-risk disease characteristics, might not experience adverse impact to survival or quality of life were treatment deferred. We sought to characterize temporal trends in clinical presentation and primary disease management among patients with low-risk prostate cancer.

Methods

Data were abstracted from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a disease registry of 8,685 men with various stages of prostate cancer. Included were 2,078 men who were diagnosed between 1989 and 2001 and had a serum prostate specific antigen ≤ 10 ng/mL, Gleason sum ≤ 6, and clinical T stage ≤ 2a. Trends in risk distribution, tumor characteristics, and primary treatment were evaluated.

Results

The proportion of patients with low-risk tumor characteristics rose from 29.8% in 1989 to 1992, to 45.3% in 1999 to 2001 (P < .0001). There have been sharp increases in the use of brachytherapy and androgen deprivation monotherapy, from 3.1% and 3.1%, to 12.0% and 21.7%, respectively. Utilization rates for prostatectomy, external-beam radiotherapy, and observation have fallen accordingly, from 63.8%, 16.1%, and 13.8%, to 51.6%, 6.8%, and 7.9% (P < .0001 for all except prostatectomy [P = .0019]). Age and socioeconomic status were significantly associated with treatment selection, but overall, the treatment trends were echoed on subgroup analysis of patients 75 years or older.

Conclusion

Low-risk features characterize a growing proportion of prostate cancer patients, and there have been significant shifts in the management of low-risk disease. Overtreatment may be a growing problem, especially among older patients.
Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer
Authors: Johnson David H. , Fehrenbacher Louis , Novotny William F. , Herbst Roy S. , Nemunaitis John J. , Jablons David M. , Langer Corey J. , DeVore Russell F. , Gaudreault Jacques , Damico Lisa A. , Holmgren Eric , Kabbinavar Fairooz
Published: May 2004

Purpose

To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer.

Patients and Methods

In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks.

Results

Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels.

Conclusion

Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.
Temozolomide for the Treatment of Brain Metastases Associated With Metastatic Melanoma: A Phase II Study
Authors: Agarwala Sanjiv S. , Kirkwood John M. , Gore Martin , Dreno Brigitte , Thatcher Nicholas , Czarnetski Beate , Atkins Michael , Buzaid Antonio , Skarlos Dimosthenis , Rankin Elaine M.
Published: May 2004

Purpose

Temozolomide is a well-tolerated oral alkylating agent with activity in the CNS. A multicenter, open-label, phase II study was conducted to assess the safety and efficacy of temozolomide in patients with brain metastases from metastatic melanoma (MM) who did not require immediate radiotherapy.

Patients and Methods

Eligible patients had histologically confirmed MM to the brain, and no prior radiotherapy or radiosurgery for brain metastases. Previously untreated patients received temozolomide at 200 mg/m2/d × 5 days; previously treated patients received 150 mg/m2/d × 5 days every 28 days. Treatment continued for 1 year or until disease progression or unacceptable toxicity.

Results

Of 151 patients enrolled, 117 had received no prior systemic chemotherapy, and 34 had received prior chemotherapy for MM. Among previously untreated patients, 25% had more than four brain lesions, eight (7%) achieved an objective response (one complete and seven partial), and 34 (29%) had stable disease in brain metastases. Median overall survival was 3.5 months. Among previously treated patients, 21% had more than four brain lesions, one had a partial response, and six (18%) had stable disease in brain metastases. Median overall survival was 2.2 months. Temozolomide was well tolerated, with four (3%) patients discontinuing because of adverse events. Grade 3/4 hematologic toxicities included thrombocytopenia (3%), neutropenia (2%), and leukopenia (1%). Headache (9%) and vomiting (8%) were the most common nonhematologic grade 3/4 adverse events.

Conclusion

Temozolomide was well tolerated and demonstrated activity in the treatment of brain metastases from MM. Further evaluation of temozolomide combination therapy is warranted.
Secondary Leukemias in Refractory Germ Cell Tumor Patients Undergoing Autologous Stem-Cell Transplantation Using High-Dose Etoposide
Authors: Houck William , Abonour Rafat , Vance Gail , Einhorn Lawrence H.
Published: May 2004

Purpose

To quantify the risk of secondary leukemias in relapsed testicular cancer patients undergoing autologous stem-cell transplantation with high-dose etoposide.

Patients and Methods

Single institution, retrospective study of germ cell tumor patients who underwent autologous transplantation using high-dose etoposide from 1987 to 2001.

Results

One hundred thirteen patients received high-dose etoposide and carboplatin followed by autologous stem-cell transplantations for germ cell tumors. Follow-up ranged from 12 to 166 months (median, 51 months). Three patients (2.6%; 95% CI, 0.55% to 7.50%) subsequently developed leukemia at an average of 16 months post–autologous transplantation (range, 11 to 21 months). All three had received tandem transplantations and had been heavily pretreated, including at least one prior cycle of etoposide. Following autologous transplantation, all three patients exhibited refractory cytopenias before developing overt leukemia. All leukemias were of myeloid lineage. One patient developed an M2 with a t(8,21) chromosomal translocation; another, an M5 with a t(11,19); and one patient exhibited an unclassified leukemia with cytogenetic abnormalities resulting in monosomy for 7p and partial monosomy of 7q. Treatment of the leukemias involved allogeneic bone marrow transplantation.

Conclusion

High-dose chemotherapy using high-dose etoposide as therapy for relapsed germ cell tumors was associated with a 2.6% risk of developing a secondary myeloid leukemia. This figure was not significantly different from the expected rate of secondary leukemias when patients receive additional cycles of standard-dose etoposide as salvage chemotherapy for germ cell tumors. Other factors, including the use of platinum agents, may also have a role in leukemogenesis in this patient population.
XELOX (Capecitabine Plus Oxaliplatin): Active First-Line Therapy for Patients With Metastatic Colorectal Cancer
Authors: Cassidy Jim , Tabernero Josep , Twelves Chris , Brunet René , Butts Charles , Conroy Thierry , Debraud Filippo , Figer Arie , Grossmann Johannes , Sawada Noriaki , Schöffski Patrick , Sobrero Alberto , Van Cutsem Eric , Díaz-Rubio Eduardo
Published: May 2004

Purpose

Capecitabine has demonstrated high efficacy as first-line treatment for metastatic colorectal cancer (MCRC). Oxaliplatin shows synergy with fluorouracil (FU), with little toxicity overlap. The XELOX regimen (capecitabine plus oxaliplatin), established in a previous dose-finding study, should improve on infused oxaliplatin with FU and leucovorin (FOLFOX) regimens. The present studies further characterize efficacy and safety of the XELOX regimen.

Patients and Methods

The antitumor activity of XELOX was investigated in a colon cancer xenograft model. Patients with MCRC received first-line XELOX in 3-week treatment cycles: intravenous oxaliplatin 130 mg/m2 (day 1) followed by oral capecitabine 1,000 mg/m2 twice daily (day 1, evening, to day 15, morning).

Results

A preclinical study confirmed that capecitabine has supra-additive activity with oxaliplatin. In the clinical study, 53 of 96 patients (55%) achieved an objective response, and 30 (31%) experienced disease stabilization for ≥ 3 months following treatment. After 24 months' minimum follow-up, median time to disease progression (TTP) and median overall survival were 7.7 and 19.5 months, respectively. XELOX safety was predictable and similar to the FOLFOX4 regimen, except that myelosuppression was uncommon with XELOX (grade 3 or 4 neutropenia, 7%). Most adverse events were mild to moderate, the most common being acute sensory neuropathy (85%). Sixty-day, all-cause mortality was 2%.

Conclusion

XELOX is a highly effective first-line treatment for MCRC. Response rates, TTP, and overall survival are similar to those observed with FU/leucovorin/oxaliplatin combinations. XELOX provides a more convenient regimen, likely to be preferred by both patients and healthcare providers. Capecitabine has the potential to replace FU/LV in combination with oxaliplatin for MCRC.
Antiretroviral Treatment Regimens and Immune Parameters in the Prevention of Systemic AIDS-Related Non-Hodgkin's Lymphoma
Authors: Stebbing Justin , Gazzard Brian , Mandalia Sundhiya , Teague Alastair , Waterston Ashita , Marvin Vanessa , Nelson Mark , Bower Mark
Published: May 2004

Purpose

Immunosuppression induced by HIV-1 increases the risk of developing non-Hodgkin's lymphoma (NHL). We measured the influence of immunologic factors and highly active antiretroviral therapy (HAART) on this risk. As there are no data demonstrating that specific antiretroviral regimens are effective at protecting from NHL, we compared different HAART regimens.

Patients and Methods

The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the development of NHL was examined in a prospectively recorded cohort of 9,621 HIV-infected individuals. Lymphocyte and natural killer subset data were also entered in univariate and multivariate analyses to establish and stratify the risk of NHL.

Results

From this cohort of 9,621 patients, 102 have been diagnosed with systemic AIDS-related NHL since 1996, when HAART became freely available here. By univariate analysis, increased age, higher nadir CD4 and CD8 T-cell counts, CD19 B-cell count, CD16/56 natural killer count and exposure to NNRTI or PI containing HAART conferred significant protection against NHL (P < .05). In a multivariate analysis, age, nadir CD4 and CD8 T-cell counts, and exposure to HAART were independent predictors of risk of NHL (P < .02). NNRTI-based HAART (adjusted rate ratio, 0.4; 95% CI, 0.3 to 0.5) was as protective as PI-based HAART, and these were significantly more protective than nucleoside analogues alone (rate ratio, 0.5; 95% CI, 0.4 to 0.7) or no antiretrovirals (P < .001).

Conclusion

Effective HAART-induced maintenance of CD4 and CD8 counts protects from systemic AIDS-related NHL.
Estimate of Lung Cancer Mortality From Low-Dose Spiral Computed Tomography Screening Trials: Implications for Current Mass Screening Recommendations
Authors: Patz Edward F. , Swensen Stephen J. , Herndon James E.
Published: May 2004

Purpose

Low-dose computed tomography (CT) has been suggested for lung cancer screening. Several observational trials have published their preliminary results, and some investigators suggest that this technique will save lives. There are no mortality statistics, however, and the current study used published data from these trials to estimate the disease-specific mortality in this high-risk population.

Patients and Methods

Two nonrandomized CT screening trials were selected from the literature for analysis. The number of trial participants, the number of lung cancers diagnosed per year, and stage distribution of the cancers was recorded. Previously published 5-year survival data were used to calculate the number of predicted lung cancer deaths and estimate the overall lung cancer mortality per 1,000 person-years among participants screened. These statistics were then compared to the previous Mayo Lung Project, which used chest radiographs and sputum cytology for screening high-risk individuals.

Results

This study estimates the lung cancer mortality is 4.1 deaths per 1,000 person-years in the Mayo Clinic CT screening trial, and is 5.5 deaths per 1,000 person-years in the Early Lung Cancer Action Program trial. These data are similar to the lung cancer mortality of 4.4 deaths per 1,000 person-years in the interventional arm, and 3.9 deaths per 1,000 person-years in the usual-care arm of the previous Mayo Lung Project.

Conclusion

These data suggest that CT screening could produce similar outcomes to prior chest radiographic trials in this high-risk group. Results from randomized trials are required, however, before the true utility of mass screening with CT for lung cancer can be determined.
Graft-Versus-Lymphoma Effect in Relapsed Peripheral T-Cell Non-Hodgkin's Lymphomas After Reduced-Intensity Conditioning Followed by Allogeneic Transplantation of Hematopoietic Cells
Authors: Corradini Paolo , Dodero Anna , Zallio Francesco , Caracciolo Daniele , Casini Marco , Bregni Marco , Narni Franco , Patriarca Francesca , Boccadoro Mario , Benedetti Fabio , Rambaldi A. , Gianni Alessandro M. , Tarella Corrado
Published: May 2004

Purpose

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of malignancies characterized by a poor prognosis. We performed a pilot study to investigate the role of reduced-intensity conditioning (RIC) followed by allogeneic stem-cell transplantation in relapsed or refractory PTCLs.

Patients and Methods

We have conducted a phase II trial on 17 patients receiving salvage chemotherapy followed by RIC and allogeneic transplantation of hematopoietic cells. The RIC regimen consisted of thiotepa, fludarabine, and cyclophosphamide. The acute graft-versus-host disease prophylaxis consisted of cyslosporine and short course methotrexate.

Results

Patients had a median age of 41 years (range, 23 to 60 years). Two patients were primary chemorefractory, and 15 had relapsed disease; eight patients (47%) had a disease relapse after an autologous transplantation. After a median follow-up of 28 months from the day of study entry (range, 3 to 57 months), 14 of 17 patients were alive (12 in complete remission, one in partial remission, and one with stable disease), two died as a result of progressive disease, and one died as a result of sepsis concomitant to acute graft-versus-host disease. The estimated 3-year overall and progression-free survival rates were 81% (95% CI, 62% to 100%) and 64% (95% CI, 39% to 89%), respectively. The estimated probability of nonrelapse mortality at 2 years was 6% (95% CI, 1% to 17%). Donor lymphocyte infusions induced a response in two patients progressing after allografting.

Conclusion

RIC followed by allogeneic stem-cell transplantation is feasible, has a low treatment-related mortality, and seems to be a promising salvage treatment for relapsed PTCL. These findings suggest that the existence of a graft-versus-T-cell lymphoma effect.
Gene expression during early ascidian metamorphosis requires signalling by Hemps, an EGF-like protein
Authors: Woods Rick G. , Roper Kathrein E. , Gauthier Marie , Bebell Lisa M. , Sung Kristin , Degnan Bernard M. , Lavin Martin F.
Published: May 2004

Hemps, a novel epidermal growth factor (EGF)-like protein, is expressed during larval development and early metamorphosis in the ascidian Herdmania curvata and plays a direct role in triggering metamorphosis. In order to identify downstream genes in the Hemps pathway we used a gene expression profiling approach, in which we compared post-larvae undergoing normal metamorphosis with larval metamorphosis blocked with an anti-Hemps antibody. Molecular profiling revealed that there are dynamic changes in gene expression within the first 30 minutes of normal metamorphosis with a significant portion of the genome (approximately 49%) being activated or repressed. A more detailed analysis of the expression of 15 of these differentially expressed genes through embryogenesis, larval development and metamorphosis revealed that while there is a diversity of temporal expression patterns, a number of genes are transiently expressed during larval development and metamorphosis. These and other differentially expressed genes were localised to a range of specific cell and tissue types in Herdmania larvae and post-larvae. The expression of approximately 24%of the genes that were differentially expressed during early metamorphosis was affected in larvae treated with the anti-Hemps antibody. Knockdown of Hemps activity affected the expression of a range of genes within 30 minutes of induction, suggesting that the Hemps pathway directly regulates early response genes at metamorphosis. In most cases, it appears that the Hemps pathway contributes to the modulation of gene expression, rather than initial gene activation or repression. A total of 151 genes that displayed the greatest alterations in expression in response to anti-Hemps antibody were sequenced. These genes were implicated in a range of developmental and physiological roles, including innate immunity, signal transduction and in the regulation of gene transcription. These results suggest that there is significant gene activity during the very early stages of H. curvata metamorphosis and that the Hemps pathway plays a key role in regulating the expression of many of these genes.
The maize duplicate genesnarrow sheath1andnarrow sheath2encode a conserved homeobox gene function in a lateral domain of shoot apical meristems
Authors: Nardmann Judith , Ji Jiabing , Werr Wolfgang , Scanlon Michael J.
Published: May 2004

The narrow sheath (ns) phenotype of maize is a duplicate factor trait conferred by mutations at the unlinked loci ns1 and ns2. Recessive mutations at each locus together confer the phenotypic deletion of a lateral compartment in maize leaves and leaf homologs. Previous analyses revealed that the mediolateral axis of maize leaves is comprised of at least two distinct compartments, and suggest a model whereby NS function is required to recruit leaf founder cells from a lateral compartment of maize meristems. Genomic clones of two maize homeodomain-encoding genes were isolated by homology to the WUSCHEL-related gene PRESSED FLOWER(PRS). PRS is required for lateral sepal development in Arabidopsis, although no leaf phenotype is reported. Co-segregation of the ns phenotype with multiple mutant alleles of two maize PRShomologs confirms their allelism to ns1 and ns2. Analyses of NS protein accumulation verify that the ns-R mutations are null alleles. ns transcripts are detected in two lateral foci within maize meristems, and in the margins of lateral organ primordia. Whereas ns1and ns2 transcripts accumulate to equivalent levels in shoot meristems of vegetative seedlings, ns2 transcripts predominate in female inflorescences. Previously undiscovered phenotypes in the pressed flower mutant support a model whereby the morphology of eudicot leaves and monocot grass leaves has evolved via the differential elaboration of upper versus lower leaf zones. A model implicating an evolutionarily conserved NS/PRS function during recruitment of organ founder cells from a lateral domain of plant meristems is discussed.
Stem cells, plasticity and cancer - uncomfortable bed fellows
Authors: Trounson Alan
Published: May 2004

Stem cell research is a vibrant and rapidly moving field of science that investigates self-renewing cells in the adult and embryo. Two debates currently exist in the stem cell field concerning the transcriptional redirection of stem cell differentiation and fate, and the reorganization of cell commitment through nuclear reprogramming caused by cell fusion and nuclear transfer. The recent Keystone Symposium in Colorado on stem cells,organised by Fiona Watt and Leonard Zon, brought together both leading and upcoming researchers in the field to explore stem cell biology and these issues.
Targeted expression of a dominant-negative N-cadherin in vivo delays peak bone mass and increases adipogenesis
Authors: Castro Charlles H. M. , Shin Chan Soo , Stains Joseph P. , Cheng Su-Li , Sheikh Sharmin , Mbalaviele Gabriel , Szejnfeld Vera Lucia , Civitelli Roberto
Published: May 2004

We studied the function of osteoblast cadherins in vivo by transgenic expression of a truncated N-cadherin with dominant-negative action, driven by an osteoblast-specific promoter (OG2-NcadΔC). During the first 3 months of life, bone mineral density was reduced, whereas percent body fat was increased in transgenic animals compared with wild-type littermates, with associated decreased bone formation rate and osteoblast number, but normal osteoclast number. Osteoblast differentiation was delayed in calvaria cells isolated from transgenic mice. Likewise, the number of osteoblast precursors in bone marrow stromal cells from OG2-NcadΔC mice was decreased compared with wild-type cultures, whereas the number of adipogenic precursors was increased. In vitro, a transcriptionally active β-catenin mutant reversed the delay in osteoblast differentiation and the exuberant adipogenesis. Thus, in vivo disruption of cadherin function hinders osteoblast differentiation and favors, indirectly, bone marrow progenitor cell commitment to the alternative adipogenic lineage via interference with β-catenin signaling. This results in decreased bone formation, delayed acquisition of peak bone mass and increased body fat.