bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum‐free suspension cultivation of PER.C6® cells and recombinant adenovirus production under different pH conditions
Authors: Xie Liangzhi , Pilbrough Warren , Metallo Christian , Zhong Tanya , Pikus Lana , Leung John , Auniņš John G. , Zhou Weichang
Published: October 2002

PER.C6® cell growth, metabolism, and adenovirus production were studied in head‐to‐head comparisons in stirred bioreactors under different pH conditions. Cell growth rate was found to be similar in the pH range of 7.1–7.6, while a long lag phase and a slower growth rate were observed at pH 6.8. The specific consumption rates of glucose and glutamine decreased rapidly over time during batch cell growth, as did the specific lactate and ammonium production rates. Cell metabolism in both infected and uninfected cultures was very sensitive to culture pH, resulting in dramatic differences in glucose/glutamine consumption and lactate/ammonium production under different pH conditions. It appeared that glucose metabolism was suppressed at low pH but the efficiency of energy production from glucose was enhanced. Adenovirus infection resulted in profound changes in cell growth and metabolism. Cell growth was largely arrested under all pH conditions, while glucose consumption and lactate production were elevated post virus infection. Virus infection induced a reduction in glutamine consumption at low pH but an increase at high pH. The optimal pH for adenovirus production was found to be 7.3 under the experimental conditions used in the study. Deviations from this optimum resulted in significant reductions of virus productivity. The results indicate that culture pH is a very critical process parameter in PER.C6® cell culture and adenovirus production. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 80: 569–579, 2002.
Legal issues in maximum security institutions for people with mental illness: liberty, security, and administrative discretion
Authors: Petrila John , Douglas Kevin S.
Published: October 2002

This article explores four legal issues relevant to the provision of care in secure hospitals. These include the current status of right to treatment litigation; the potential impact of the Americans with Disabilities Act; new developments in laws governing restraint and seclusion; and the need for uniform institutional policies on risk assessment. These issues illustrate the potential conflicts between individual autonomy and institutional control that have been at the heart of mental health law for three decades. The article suggests that because of the diminishing oversight provided by the federal judiciary, institutional custodians have a particular obligation to ensure that individual rights are not overwhelmed by concerns with security. Copyright © 2002 John Wiley & Sons, Ltd.
Architectural design of a secure forensic state psychiatric hospital
Authors: Dvoskin Joel A. , Radomski Steven J. , Bennett Charles , Olin Jonathan A. , Hawkins Robert L. , Dotson Linda A. , Drewnicky Irene N.
Published: October 2002

This article describes the architectural design of a secure forensic state psychiatric hospital. The project combined input from staff at all levels of the client organization, outside consultants, and a team of experienced architects. The design team was able to create a design that maximized patient dignity and privacy on one hand, and the ability of staff to observe all patient activity on the other. The design centers around 24‐bed units, broken into smaller living wings of eight beds each. Each eight‐bed living wing has its own private bathrooms (two) and showers (two), as well as a small living area solely reserved for these eight patients and their guests. An indoor–outdoor dayroom allows patients to go outside whenever they choose, while allowing staff to continue observing them. The heart of the facility is a large treatment mall, designed to foster the acquisition of social, emotional, cognitive, and behavioral skills that will help patients to safely return to their communities. Copyright © 2002 John Wiley & Sons, Ltd.
Analysis of medical students' use of Web‐based resources for a gross anatomy and embryology course
Authors: Nieder Gary L. , Nagy Frank
Published: October 2002

An extensive Web site supporting our gross anatomy and embryology course, which includes various course management pages as well as online lectures, has been in use for the past 2 years. To determine how this Web site is being used by students, we examined server log files to track access to each of the Web pages on the site. Using this data, along with student responses on a course evaluation, we have been able to quantitatively characterize Web site use and gain some insight into students' perception of the site. This analysis showed that all of the resources available online, including course management information, exam reviews, online lectures, and dissection guides were heavily used and deemed useful by students. Despite universal computer ownership and Internet access from home, most use of the Web site was from on‐campus computer labs, especially for lectures with audio streams. This was probably due to the limited bandwidth of off‐campus connections. Data on the day of the week and time of the day of access showed peak activity at expected times, but also significant activity at all hours, as students took full advantage of ‘access on demand.’ This on‐demand nature of the Web was also evident in students' viewing of lectures in short sessions rather than in one sitting. Online lectures were used regularly by a majority of students both before and after corresponding class sessions, however, this was not the preferred venue for all students. Although the flexibility of Web‐based resources accommodates students' varying study habits, the alternative of traditional print material and live lectures should not be abandoned lightly. Clin. Anat. 15:409–418, 2002. © 2002 Wiley‐Liss, Inc.
Feasibility study of a fiber‐optic system for invasive blood pressure measurements
Authors: Reesink Koen D. , van der Nagel Theo , Bovelander Jan , Jansen Jos R.C. , van der Veen Frederik H. , Schreuder Jan J.
Published: October 2002

A comparative study was conducted to evaluate the feasibility of a fiber‐optic sensor in invasive blood pressure measurements. Static and wide‐bandwidth stimuli were offered to the fiber‐optic, Millar, Baxter, and Sentron devices to measure static transfer function and transient response. Animal experiments focused on offset drift, dynamic accuracy, and electromagnetic sensitivity. Compared to the Millar, Sentron, and Baxter devices, the fiber‐optic sensor had a near‐identical static transfer function. Gain and offset errors were < 3.4% and < 0.25%, respectively. Hysteresis nonlinearity was < 0.1%. The dynamic accuracy of the fiber‐optic system matched that of the Millar and Sentron systems. Time delay was < 1 msec. Maximum rate of change was > 30,000 mm Hg/sec and bandwidth was 0–150 Hz minimum. Offset drift was 0.6 ± 0.03 mm Hg. Application of diathermy highlighted the fiber‐optic sensor's excellent electromagnetic disturbance rejection. The fiber‐optic system appears to be a reliable, high‐fidelity pressure monitor in demanding clinical environments. Cathet Cardiovasc Intervent 2002;57:272–276. © 2002 Wiley‐Liss, Inc.
Extraction of previously deployed stent by an entrapped cutting balloon due to the blade fracture
Authors: Kawamura Akio , Asakura Yasushi , Ishikawa Shiro , Asakura Keiko , Okabe Teruo , Yamane Akiko , Fujikura Kana , Suzuki Yusuke , Ogawa Satoshi
Published: October 2002

During treatment for in‐stent restenosis, entrapment of cutting balloon occurred because of the blade fracture. Removal of the balloon caused stent extraction, inducing acute occlusion of the coronary artery. Application of cutting balloon for in‐stent restenosis requires every caution against such type of complications. Cathet Cardiovasc Intervent 2002;57:239–243. © 2002 Wiley‐Liss, Inc.
Use of online‐dual‐column extraction in conjunction with chiral liquid chromatography tandem mass spectrometry for determination of terbutaline enantiomers in human plasma
Authors: Xia Yuan‐Qing , Liu David Q. , Bakhtiar Ray
Published: October 2002

An online sample extraction chiral bioanalytical method was developed and validated for the quantification of terbutaline, a β2‐selective adrenoceptor agonist, spiked into human plasma by using two extraction columns and a chiral stationary phase (CSP) in conjunction with liquid chromatography tandem mass spectrometry (LC‐MS/MS). In this method, two Oasis HLB extraction columns were used in parallel for plasma sample purification and a Chirobiotic T CSP was used for enantiomeric separation. Atmospheric pressure chemical ionization MS/MS was employed in multiple reaction monitoring mode for the detection and quantification. Subsequent to the addition of an internal standard solution, the plasma samples were directly injected onto the system for extraction and analysis. This method allowed the use of one of the extraction columns for purification while the other was being equilibrated. Hence, the time required for reconditioning the extraction columns did not contribute to the total analysis time per sample, which resulted in a shorter run time and higher throughput. A lower limit of quantification of 1.0 ng/mL was achieved using only 50 microliter of human plasma. The method was validated with a dynamic range of 1.0–200 ng/mL. The intra‐ and interday precision was no more than 11% CV and the assay accuracy was between 94–106%. Chirality 14:742–749, 2002. © 2002 Wiley‐Liss, Inc.
Racial differences in treatment and survival from early‐stage breast carcinoma
Authors: Joslyn Sue A.
Published: October 2002

BACKGROUND

African‐American women have a significantly worse prognosis from breast carcinoma compared with white women, even when the stage at diagnosis is equivalent. The purpose of this study was to analyze racial differences in the treatment (use of breast‐conserving surgery and radiation therapy) of women with early‐stage breast carcinoma and the resulting effects on survival rates.

METHODS

Subjects included 10,073 African‐American and 123,127 white women diagnosed with Stage I, IIA, or IIB breast carcinoma in the National Cancer Institute's Surveillance, Epidemiology, and End Results program between 1988 and 1998. Comparisons were made by race with treatment, age, hormone receptor status, and stage at the time of diagnosis. Survival analyses were conducted to compare risk of death for African‐American and white women while controlling for age, stage, and hormone receptor status.

RESULTS

Among women diagnosed with early‐stage breast carcinoma who receive breast‐conserving surgery, African‐American women were significantly less likely to receive follow‐up radiation therapy in every 10‐year age group except in the older than 85 age group. Whether treatment was equivalent or suboptimal, survival for African‐American women with early‐stage breast carcinoma was significantly worse. However, when treatment was equivalent, the effects of racial differences on survival were significantly less compared with survival associated with suboptimal treatment.

CONCLUSIONS

Significant racial differences exist in the treatment of women with early‐stage breast carcinoma. Public health efforts to eliminate suboptimal treatment would reduce, but not eliminate, racial disparity in survival. Cancer 2002;95:1759–66. © 2002 American Cancer Society.

DOI 10.1002/cncr.10827
Parathyroid hormone‐related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia
Authors: Hiraki Akio , Ueoka Hiroshi , Bessho Akihiro , Segawa Yoshihiko , Takigawa Nagio , Kiura Katsuyuki , Eguchi Kenji , Yoneda Toshiyuki , Tanimoto Mitsune , Harada Mine
Published: October 2002

BACKGROUND

Parathyroid hormone‐related protein (PTH‐rP) is a major cause of tumor‐induced hypercalcemia (TIH) and frequently is found to be elevated in serum of patients with TIH. In the current study, the authors examined the usefulness of PTH‐rP measurement at the time of first presentation in the follow‐up of lung carcinoma patients with TIH.

METHODS

The authors retrospectively studied 23 of 1149 lung carcinoma patients who were found to have TIH at the time of first presentation for the correlation between serum PTH‐rP and the development of bone metastases and survival compared with lung carcinoma patients without TIH who were matched by gender, age, Eastern Cooperative Oncology Group performance status, histological type of tumor, and stage of the disease.

RESULTS

Twenty‐three lung carcinoma patients with TIH demonstrated significantly increased serum levels of PTH‐rP (mean ± standard error [SE], 84.1 ± 16.5 pmol/L) compared with control patients without TIH (mean ± SE, 36.2 ± 2.0 pmol/L) at the time of first presentation, (P < 0.001). In these hypercalcemic patients, patients whose serum PTH‐rP was > 150 pmol/L (n = 16) were found to have a significantly increased rate of bone metastases (71.4% vs. 12.5%; P = 0.01) and decreased survival (median survival of 1.4 months vs. 5.4 months; P < 0.015) compared with patients whose serum PTH‐rP was < 150 pmol/L (n = 7).

CONCULUSIONS

The data from the current study suggest that serum PTH‐rP as determined at the time of first presentation is a useful indicator of not only hypercalcemia but also bone metastasis and eventual survival in patients with lung carcinoma. Cancer 2002;95:1706–13. © 2002 American Cancer Society.

DOI 10.1002/cncr.10828
Characteristics and outcome of patients with Philadelphia chromosome negative,bcr/ablnegative chronic myelogenous leukemia
Authors: Onida Francesco , Ball Greg , Kantarjian Hagop M. , Smith Terry L. , Glassman Armand , Albitar Maher , Scappini Barbara , Rios Mary Beth , Keating Michael J. , Beran Miloslav
Published: October 2002

BACKGROUND

Up to 5% of patients with chronic myelogenous leukemia (CML) do not have the Philadelphia (Ph) translocation t(9;22)(q34;q11) or abcr/ablmolecular rearrangement. Although the diagnostic criteria of this entity are still under debate, there is general agreement that patients with Ph negative,bcr/ablnegative CML have a severe clinical course that is not affected significantly by current treatment options.

METHODS

A population of 76 patients withbcr/ablnegative CML who had received minimal or no previous therapy was characterized carefully with the intent of investigating clinical and hematologic variables and their association with survival by univariate, correlation, and multivariate analyses. A group of 73 patients with Ph negative CML who were not tested for thebcr/ablrearrangement (bcr/ablunknown) was analyzed separately and used for extension of the analysis.

RESULTS

In thebcr/ablnegative patient population, the median overall survival was 24 months. At the time of the analysis, 38 patients (50%) had died, and blastic transformation preceded death in 31%. Chromosomal abnormalities were found in 30% of the 76 patients, with trisomy 8 the most common abnormality. Complex chromosomal abnormalities were rare, and monosomy 7 was not observed. Survival was not affected significantly by treatment. Multivariate analysis identified older age (> 65 years), anemia (hemoglobin < 10 g/dL), and severe leukocytosis (white blood cells > 50 × 109/L) as variables with independent prognostic significance for poor survival. A prognostic scoring system stratified patients into a low‐risk group (53%) and a high‐risk group (47%), with median survivals of 38 months and 9 months, respectively.

CONCLUSIONS

Bcr/ablnegative CML is a distinct clinical entity associated with very poor prognosis. Two risk categories are identifiable using a simple scoring system based on age, hemoglobin level, and leukocyte number. Cancer 2002;95:1673–84. © 2002 American Cancer Society.

DOI 10.1002/cncr.10832
Childhood cancer survival in Europe and the United States
Authors: Gatta Gemma , Capocaccia Riccardo , Coleman Michel P. , Ries Lynn A. Gloeckler , Berrino Franco
Published: October 2002

BACKGROUND

Survival rates for most major adult cancers are higher in the United States compared with the survival rates in Europe. The objective of this study was to determine whether transatlantic differences in survival also are present in childhood cancers.

METHODS

The authors analyzed 16,148 European patients and 3476 patients in the United States who were diagnosed with malignant disease at age < 15 years during 1985–1989. The patients were obtained from 34 EUROCARE cancer registries in 17 countries and from 9 SEER registries in the United States. The authors considered the major 14 diagnostic categories of the International Classification of Childhood Cancers. To increase the power of comparisons, they also considered all childhood cancers together. Observed survival was calculated by actuarial methods.

RESULTS

For all cancers combined, northern Europe had the highest 5‐year survival rate at 75% (95% confidence interval [95%CI], 72–78%), and Eastern Europe had the lowest survival rate at 55% (95%CI, 52–58%). The survival rate in the United States was roughly comparable to the survival rates in Italy and other Western European countries at 70%. Northern Europe also had highest survival rate for patients with lymphoid leukemias (83%; 95%CI, 78–88%); whereas Germany, Italy, and the other Western European countries had survival rates similar to the average survival rate for patients in the United States (77%; 95%CI, 74–80%). The survival rate was 7–9% lower in Europe compared with the survival rate in United States for patients with neuroblastoma and Wilms tumors and 8% higher for patients with retinoblastoma (all significant). Small, nonsignificant differences were found for patients with osteosarcoma, ependymoma, and medulloblastoma (with a higher survival rate in the United States) and for patients with acute nonlymphocytic leukemia (with a higher survival rate in Europe). Very similar survival rates among the two populations were found for the other cancers.

CONCLUSIONS

Unlike the survival of adults with cancer, the survival of children with cancer in Europe (except Eastern Europe) is very similar to that in the United States. Childhood cancers are generally more responsive to therapy than adult cancers, but these results also may reflect wide accessibility of these treatments for most patients. These results are relevant to the interpretation of differences in adult cancer survival. Cancer 2002;95:1767–72. © 2002 American Cancer Society.

DOI 10.1002/cncr.10833
Prospective analysis of circulating endostatin levels in patients with renal cell carcinoma
Authors: Feldman Andrew L. , Alexander H. Richard , Yang James C. , Linehan W. Marston , Eyler Robin A. , Miller Marshall S. , Steinberg Seth M. , Libutti Steven K.
Published: October 2002

BACKGROUND

The aim of the current study was to assess circulating levels of endogenous endostatin in patients with renal carinoma and to determine the relationship of these levels to circulating levels of vascular endothelial growth factor (VEGF) and prognosis.

METHODS

The authors prospectively studied 66 patients (48 male, 18 female; mean age, 50 years) undergoing nephrectomy for renal carcinoma on clinical trials at the National Cancer Institute. Metastases were present in 51 of 66 patients (77%) at the time of nephrectomy. Preoperative and followup serum endostatin and VEGF levels were determined using competitive enzyme immunoassays and compared to a group of 32 age‐ and gender‐matched healthy controls. Associations between circulating endostatin levels and clinicopathologic variables, including survival, were determined.

RESULTS

Preoperative endostatin levels were higher in renal carcinoma patients than in healthy controls (P = 0.05). There was a weak to moderate correlation between pretreatment serum endostatin levels and serum VEGF levels (r = 0.47; P = 0.001), and levels of both proteins increased significantly following nephrectomy (P < 0.0001 and P < 0.0001, respectively; n = 41). In addition, patients whose endostatin levels increased more than twofold after nephrectomy had significantly poorer prognoses than patients without such an increase (P = 0.018). This association was more pronounced when patients without metastases were excluded (P = 0.0037).

CONCLUSIONS

Circulating endostatin levels are elevated in patients with renal carcinoma and correlate with circulating VEGF levels. Endostatin levels increase after nephrectomy, and patients with the greatest increases experience shortened survival times. These findings suggest an association between tumor aggressiveness and the production of endogenous endostatin in patients with renal carcinoma. Cancer 2002;95:1637–43. Published 2002 by the American Cancer Society.

DOI 10.1002/cncr.10845
Improved outcomes in patients with osteogenic sarcoma of the head and neck
Authors: Patel Snehal G. , Meyers Paul , Huvos Andrew G. , Wolden Suzanne , Singh Bhuvanesh , Shaha Ashok R. , Boyle Jay O. , Pfister David , Shah Jatin P. , Kraus Dennis H.
Published: October 2002

BACKGROUND

The current study reviews the authors' recent institutional experience in the treatment of osteosarcoma of the head and neck (OSHN).

METHODS

The clinical records of 44 patients who were treated between 1981 and 1998 for OSHN were reviewed retrospectively. Archived histologic material was reviewed and data were analyzed to identify factors predictive of disease control and survival. Outcomes were compared with a previously reported historic cohort treated at the study institution.

RESULTS

Patients ranged in age from 6 to 64 years (median, 31 years). The mandible was the primary site in 18 patients (41%), the maxilla in 20 patients (45%), and the skull in 6 patients (14%). Surgery was employed in all 44 patients, neoadjuvant chemotherapy was administered in 30 patients (68%), and postoperative radiation therapy was given to 7 patients (16%). The surgical excision margins were positive in 13 patients (30%). High‐grade lesions were reported in 50% patients and low‐grade lesions were noted in 18% of patients (grade was not assessable in 32%). Histologic response was “unfavorable” in 22 of 30 patients (73%) who were treated with neoadjuvant chemotherapy. The 3‐year overall, disease‐specific, and recurrence‐free survival rates were approximately 81%, 81%, and 73%, respectively (median follow‐up of 41 months). Positive surgical margins were found to be the only significant predictor of worse disease‐specific survival. Compared with the historical cohort, the current experience demonstrated an obvious improvement in the 5‐year local control (35% vs. 78%), distant metastases (37% vs. 13%), and overall survival (23% vs. 70%).

CONCLUSIONS

Negative surgical margins were found to be the only significant predictor of overall and disease‐specific survival. The results of the current study represent a considerable improvement over the authors' previously published experience and compare favorably with the results reported in the literature. Cancer 2002;95:1495–503. © 2002 American Cancer Society.

DOI 10.1002/cncr.10849
The continuing increase in the incidence of primary central nervous system non‐Hodgkin lymphoma
Authors: Olson Janet E. , Janney Carol A. , Rao Ravi D. , Cerhan James R. , Kurtin Paul J. , Schiff David , Kaplan Richard S. , O'Neill Brian Patrick
Published: October 2002

BACKGROUND

Primary central nervous system lymphoma (PCNSL) is an extranodal form of non‐Hodgkin lymphoma arising in the craniospinal axis. The incidence of PCNSL appears to be increasing.

METHODS

PCNSL incidence data from 1973–1997 were obtained from the nine Surveillance, Epidemiology and End Results (SEER) registries. To limit the influence of the human immunodeficiency virus on incidence rates, data of never–married males and females and persons of unknown marital status were excluded. As a surrogate for new technology, SEER data were reviewed by dates of diagnosis (surrogate for imaging) and compared with glioma incidence (surrogate for stereotactic neurosurgery and improved diagnostic neuropathology). Age‐adjusted incidence rates were estimated and compared for the period prior to computed tomography (CT) (1973–1984) and the magnetic resonance imaging (MRI) period (1985–1997). The estimated annual percent change was calculated based on linear regression analyses using SEER*STAT.

RESULTS

The incidence of PCNSL appears to be increasing in all SEER registries examined. All age groups demonstrated an increase over time. This increase was observed both in the CT era as well as in the MRI era. PCNSL age‐adjusted incidence (0.15 to 0.48, a 3‐fold increase) outpaced that of systemic lymphoma (14.1 to 18.5, a 33% increase) for the same registries over the same time periods. The rate of increase has begun to slow since 1985; the estimated annual percent change for PCNSL was three‐fold higher during the period 1973–1985 compared with 1986–1997.

CONCLUSION

The incidence rate of PCNSL continues to rise. The increase is evident in all age groups and in both genders. Data from the current study suggest that improved diagnostic tools, such as CT or MRI, cannot explain this increase. Cancer 2002;95:1504–10. © 2002 American Cancer Society.

DOI 10.1002/cncr.10851
Small‐volume image‐guided radiotherapy using hypofractionated, coplanar, and noncoplanar multiple fields for patients with inoperable Stage I nonsmall cell lung carcinomas
Authors: Fukumoto Shin‐ichi , Shirato Hiroki , Shimzu Shinichi , Ogura Shigeaki , Onimaru Rikiya , Kitamura Kei , Yamazaki Koichi , Miyasaka Kazuo , Nishimura Masaharu , Dosaka‐Akita Hirotoshi
Published: October 2002

BACKGROUND

Occasionally, medically compromised and/or elderly patients with nonsmall cell lung carcinomas (NSCLCs) cannot be treated surgically. We investigated small‐volume hypofractionated image‐guided radiotherapy (IGRT) without the need for breath control in patients with inoperable Stage I NSCLCs.

METHODS

Between September 1996 and September 1999, 22 patients with Stage I NSCLCs, including 19 males and 3 females, were treated with IGRT. Among these patients, there were 13 Stage IA and 9 Stage IB tumors. The tumors ranged in size from 14.2 to 58.5 mm, with a median size of 26.7 mm. Of the 22 patients, 19 were unfit for surgical treatment due to poor pulmonary function, complications, and/or advanced age and 3 refused surgery. Computed tomographic scans (CT) of the primary tumor were taken during three respiratory phases and they were analyzed to determine the planning target volume, which included only the primary tumor with allowances for respiratory movement. The radiation doses administered at the edge of the moving tumor during normal breathing were 80% of the prescribed dose, either 48 or 60 Gy given in eight fractions over 2 weeks. Clinical evaluation, chest CT scan, and pulmonary function tests were performed before irradiation and at regular intervals for the post‐IGRT follow‐up. The median follow‐up period was 24 months (range, 2–44 months; mean, 21.8 months) (at least 24 months for survivors).

RESULTS

Of 17 tumors assessed at the initial follow‐up 2–6 months after treatment (5 complete responses, 11 partial responses, and 1 progressive disease), 16 (94%) were controlled locally. One local recurrence was observed during the follow‐up. The lung carcinoma‐specific survival rate at 1 year was 94% and the 1‐year actuarial recurrence‐free survival rate was 71%. The lung carcinoma‐specific survival rate at 2 years was 73% and the 2‐year actuarial recurrence‐free survival rate was 67%. The treatment was well tolerated and no major side effects were observed. Localized radiation pneumonitis was observed in all patients who were examined by CT scan, but the patients were asymptomatic. Parameters of pulmonary function, including vital capacity, total lung capacity, and diffusion capacity for carbon monoxide, decreased very little or not at all, indicating that IGRT rarely deteriorated pulmonary functions.

CONCLUSIONS

Small‐volume hypofractionated IGRT without breath control is a feasible and beneficial method for the curative treatment of patients with Stage I NSCLCs. It has the potential of a high local tumor control rate and low morbidity. Cancer 2002;95:1546–53. © 2002 American Cancer Society.

DOI 10.1002/cncr.10853
Trastuzumab‐associated cardiotoxicity
Authors: Keefe Deborah L.
Published: October 2002

Trastuzumab is a monoclonal antibody used for the treatment of metastatic breast carcinoma in women whose tumors overexpress the HER2 protein. Cardiotoxicity has been reported to occur with trastuzumab when administered alone and in combination with antineoplastic agents, particularly anthracyclines. The risk of cardiotoxicity with trastuzumab has been reported to be 4% with monotherapy and 27% when administered in combination with an anthracycline and cyclophosphamide, but to the author's knowledge severe outcomes, such as death or permanent disability, are uncommon. The majority of reported cardiac effects are mild to moderate, nonspecific, and medically manageable. Signs and symptoms are similar to those observed in patients who develop anthracycline‐induced cardiomyopathy and include tachycardia, palpitations, and exertional dyspnea, which may progress to congestive heart failure. The pathogenesis and histologic changes responsible for trastuzumab‐associated cardiotoxicity currently are under investigation. Unlike anthracycline‐induced toxicity, trastuzumab‐associated toxicity usually responds to standard treatment or the discontinuation of trastuzumab, and there is no evidence that the toxicity is dose related. Current methods for the early detection of cardiotoxicity in trastuzumab‐treated patients are similar to those used in anthracycline‐treated patients. Cardiac function is established at baseline and monitored regularly during treatment by physical examination and measurement of left ventricular ejection fraction. The majority of patients improve with proper treatment, and some are able to continue to receive trastuzumab. Cancer 2002;95:1592–600. © 2002 American Cancer Society.

DOI 10.1002/cncr.10854
Strategies for improving melanoma education and screening for men age ≥ 50 years
Authors: Geller Alan C. , Sober Arthur J. , Zhang Zi , Brooks Daniel R. , Miller Donald R. , Halpern Allan , Gilchrest Barbara A.
Published: October 2002

BACKGROUND

Recently, the Institute of Medicine (2000) and the Third United States Preventive Services Task Force (2001) called for studies to help clinicians identify patients, especially elderly patients, who are at high risk for melanoma. In the current study, the authors sought to identify factors associated with a high yield in skin cancer screening and to explore strategies for improving mass screenings for melanoma.

METHODS

The authors analyzed the data base of the 242,374 skin cancer screenings conducted on more than 206,000 Americans who attended the American Academy of Dermatology National Skin Cancer Screening Programs during the period 1992–1994.

RESULTS

Ninety‐six percent of 3476 screenees with a presumptive diagnosis of melanoma or possible melanoma were contacted, and follow‐up records were obtained for 73% of screenees. Of these, 363 screenees had histologically proven melanoma. Middle‐aged and older men (age ≥ 50 years) comprised only 25% of screenees but comprised 44% of those with a confirmed diagnosis of melanoma. The overall yield of melanoma (the number of confirmed diagnoses per the number of screenees) was 1.5 per 1000 screenings (363 diagnoses of 242,374 screenees) compared with a yield of 2.6 per 1000 screenings among men age ≥ 50 years. The yield was improved further for men age ≥ 50 years who reported either a changing mole (4.6 per 1000 screenings) or skin types I and II (3.8 per 1000 screenings). The predictive value of a screening diagnosis of melanoma was more than twice as high for men age ≥ 50 years with either a changing mole or skin types I and II compared with all other participants.

CONCLUSIONS

The yield of mass screening for melanoma would be improved by outreach to middle‐aged and older men, with particular focus on men with changing moles or with skin types I and II. Primary care physicians should be attuned to the risk factors among all of their patients but should be alerted in particular to the heightened risk of melanoma for men age ≥ 50 years. Formal assessment of the impact of targeted screening on mortality warrants further study. Cancer 2002;95:1554–61. © 2002 American Cancer Society.

DOI 10.1002/cncr.10855
Apoptosis and apoptosis‐related factors Bcl‐2, Bax, tumor necrosis factor‐α, and NF‐κB in human endometrial hyperplasia and carcinoma
Authors: Vaskivuo Tommi E. , Stenbäck Frej , Tapanainen Juha S.
Published: October 2002

BACKGROUND

Apoptosis controls cell homeostasis in the endometrium during normal menstrual cycles, and morphologic studies have suggested its association with the development of endometrial carcinoma. Apoptosis is regulated by several genes, especially those of the Bcl‐2 gene family, but their significance in endometrial pathologies is not well understood.

METHODS

To study the role and regulation of apoptosis in endometrial hyperplasia and carcinoma, human endometrial specimens were analyzed using in situ 3′‐end labeling of apoptotic cells and in situ hybridization and immunohistochemistry of apoptosis‐related factors.

RESULTS

Apoptosis was scarce in normal proliferating endometrium as well as in simplex, complex, and atypical hyperplasia and was low in Grade I adenocarcinoma. In Grade II adenocarcinoma a significant increase in the rate of apoptosis was observed. Apoptosis decreased in Grade III adenocarcinoma, but it was still higher than in normal or hyperplastic endometrium. Bcl‐2 and Bax were expressed in normal and hyperplastic endometrium, and the Bcl‐2/Bax ratio was lower in endometrial carcinoma. Tumor necrosis factor‐α was expressed in normal endometrium and simplex and complex hyperplasia, but it was down‐regulated in atypical hyperplasia and endometrial carcinoma. The transcription factor NF‐κB was present in proliferating endometrium and in endometrial hyperplasia, but its expression was lower in carcinoma.

CONCLUSIONS

In endometrial proliferation and hyperplasia a low rate of apoptosis is present. In Grade I carcinoma the rate of apoptosis is decreased, but the rate is subsequently increased in advanced carcinoma. The decrease in the rate of apoptosis in Grade III adenocarcinoma may reflect loss of control of cell homeostasis, decreased differentiation, and increased malignancy. Cancer 2002;95:1463–71. © 2002 American Cancer Society.

DOI 10.1002/cncr.10876
Thin primary cutaneous melanomas
Authors: Schwartz Jennifer L. , Wang Timothy S. , Hamilton Ted A. , Lowe Lori , Sondak Vernon K. , Johnson Timothy M.
Published: October 2002

BACKGROUND

Public awareness and education may lead to the detection of thinner melanomas, which may result in a decrease in morbidity and mortality rates. Which detection patterns, lesion, and patient characteristics are associated with early detection?

METHODS

Using the University of Michigan prospective melanoma database, the detection patterns, lesion characteristics, and patient characteristics of 1515 consecutive patients with in situ or invasive cutaneous melanomas were reviewed. Tumor thickness (measured in millimeters) was evaluated in relationship to detection patterns (patient, physician, spouse), lesion characteristics (change in color, size, shape/elevation, ulceration, bleeding, tenderness, itching), and patient characteristics (gender, skin type, number of atypical and clinically benign nevi, history of sunburn, personal and family history of melanoma).

RESULTS

Patient characteristics associated with early detection included female gender, at least one atypical nevus, greater than 20 clinically benign nevi, and/or a personal history of melanoma. Skin types I, II, and III, a history of sunburn, and/or a family history of melanoma were also associated with thinner lesions, but these associations were not statistically significant. Lesion characteristics associated with earlier detection included a change in color, size, shape/elevation, and/or itching. Physician‐detected melanomas were significantly thinner than patient or spouse‐detected lesions.

CONCLUSIONS

Educational campaigns should include increasing melanoma awareness in males and educating the public on the early signs and symptoms. Education should be directed at both high and low‐risk groups. Physicians should consider performing total skin examinations routinely on patients. Although they detect a relatively small percentage of all melanomas, physicians detect significantly thinner lesions. Cancer 2002;95:1562–8. © 2002 American Cancer Society.

DOI 10.1002/cncr.10880
Projections of the basilar pontine nuclei and nucleus reticularis tegmenti pontis to the cerebellar nuclei of the rat
Authors: Parenti Rosalba , Zappalà Agata , Serapide Maria Francesca , Pantò Maria Rosita , Cicirata Federico
Published: October 2002

This study showed the precise projection pattern of the basilar pontine nuclei (BPN) and the nucleus reticularis tegmenti pontis (NRTP) to the cerebellar nuclei (CN), as well as the different anatomic features of BPN and NRTP projections. The staining of BPN or NRTP with biotinylated dextran labeled projection fibers to complementary topographic areas in the CN. In fact, BPN principally project to a rostrocaudally oriented column of the nucleus lateralis (NL), which at the midcentral level shifts to the lateroventral part of the nucleus, as well as to the caudolateral part of the nucleus interpositus posterioris. The NRTP projects to a rostrocaudal column of the NL, which at the midcentral level shifts medially, as well as to the nucleus interpositalis and to the caudal part of the nucleus medialis. BPN axons in the CN usually branch into short collaterals of simple morphology that involve small terminal areas, whereas NRTP axons branch into longer collaterals of complex morphology involving terminal areas of different sizes. Each site of injection is at the origin of a set of terminal areas in the CN. The set of projections from different BPN or NRTP areas were partially, but never completely, overlapping. Thus, the set of terminal areas in the CN was specific for each area of both BPN and NRTP. Injection of tetramethyl‐rhodamine‐dextran‐amine into the CN stained cell bodies of BPN and NRTP with different repartition on the two sides. The study showed that CN are innervated by the contralateral BPN and not very much by the ipsilateral BPN, whereas they are innervated by NRTP bilaterally, even if with a contralateral prevalence. In conclusion, this study supports the hypothesis that both BPN and NRTP are concerned in the central program for skilled movements, even if they are probably involved in different functional roles. J. Comp. Neurol. 452:115–127, 2002. © 2002 Wiley‐Liss, Inc.
Cellular localization of bursicon using antisera against partial peptide sequences of this insect cuticle‐sclerotizing neurohormone
Authors: Honegger Hans‐Willi , Market Daniel , Pierce Larry A. , Dewey Elizabeth M. , Kostron Barbara , Wilson Melanie , Choi Dennis , Klukas Kathleen A. , Mesce Karen A.
Published: October 2002

Bursicon is the final neurohormone released at the end of the molting cycle. It triggers the sclerotization (tanning) of the insect cuticle. Until now, its existence has been verified only by bioassays. In an attempt to identify this important neurohormone, bursicon was purified from homogenates of 2,850 nerve cords of the cockroach Periplaneta americana by using high performance liquid chromatography technology and two‐dimensional gel electrophoresis. Bursicon bioactivity was found in four distinct protein spots at approximately 30 kDa between pH 5.3 and 5.9. The protein of one of these spots at pH 5.7 was subsequently microsequenced, and five partial amino acid sequences were retrieved. Evidence is presented that two of these sequences are derived from bursicon. Antibodies raised against the two sequences labeled bursicon‐containing neurons in the central nervous systems of P. americana. One of these antisera labeled bursicon‐containing neurons in the crickets Teleogryllus commodus and Gryllus bimaculatus, and the moth Manduca sexta. A cluster of four bilaterally paired neurons in the brain of Drososphila melanogaster was also labeled. In addition, this antiserum detected three spots corresponding to bursicon in Western blots of two‐dimensional gels. The 12‐amino acid sequence detected by this antiserum, thus, seems to be conserved even among species that are distantly related. J. Comp. Neurol. 452:163–177, 2002. © 2002 Wiley‐Liss, Inc.
Light and electron microscopic analysis of aquaporin 1‐like‐immunoreactive amacrine cells in the rat retina
Authors: Kim In‐Beom , Lee Eun‐Jin , Oh Su‐Ja , Park Cheol‐Beom , Pow David V. , Chun Myung‐Hoon
Published: October 2002

Aquaporin 1 (AQP1; also known as CHIP, a channel‐forming integral membrane protein of 28 kDa) is the first protein to be shown to function as a water channel and has been recently shown to be present in the rat retina. We previously showed (Kim et al. [1998] Neurosci Lett 244:52–54) that AQP1‐like immunoreactivity is present in a certain population of amacrine cells in the rat retina. This study was conducted to characterize these cells in more detail. With immunocytochemistry using specific antisera against AQP1, whole‐mount preparations and 50‐μm‐thick vibratome sections were examined by light and electron microscopy. These cells were a class of amacrine cells, which had symmetric bistratified dendritic trees ramified in stratum 2 and in the border of strata 3 and 4 of the inner plexiform layer (IPL). Their dendritic field diameters ranged from 90 to 230 μm. Double labeling with antisera against AQP1 and γ‐aminobutyric acid or glycine demonstrated that these AQP1‐like‐immunoreactive amacrine cells were immunoreactive for glycine. Their most frequent synaptic input was from other amacrine cell processes in both sublaminae a and b of the IPL, followed by a few cone bipolar cells. Their primary targets were other amacrine cells and ganglion cells in both sublaminae a and b of the IPL. In addition, synaptic output onto bipolar cells was rarely observed in sublamina b of the IPL. Thus, the AQP1 antibody labels a class of glycinergic amacrine cells with small to medium‐sized dendritic fields in the rat retina. J. Comp. Neurol. 452:178–191, 2002. © 2002 Wiley‐Liss, Inc.
Amygdalo‐cortical sprouting continues into early adulthood: Implications for the development of normal and abnormal function during adolescence
Authors: Cunningham Miles Gregory , Bhattacharyya Sujoy , Benes Francine Mary
Published: October 2002

Adolescence is a critical stage for the development of emotional maturity and diverse forms of psychopathology. The posterior basolateral nucleus of the amygdala is known to mediate fear and anxiety and is important in assigning emotional valence to cognitive processes. The medial prefrontal cortex, a homologue of the human anterior cingulate cortex, mediates emotional, attentional, and motivational behaviors at the cortical level. We postulate that the development of connectivity between these two corticolimbic regions contributes to an enhanced integration of emotion and cognition during the postnatal period. In order to characterize the development of this relay, injections of the anterograde tracer biocytin were stereotaxically placed within the posterior basolateral nucleus of the amygdala of rats at successive postnatal time points (postnatal days 6–120). Labeled fibers in the medial prefrontal cortex were evaluated using a combination of brightfield, confocal, and electron microscopy. We found that the density of labeled fibers originating from the posterior basolateral nucleus shows a sharp curvilinear increase within layers II and V of the anterior cingulate cortex and the infralimbic subdivisions of medial prefrontal cortex during the late postweanling period. This increase was paralleled by a linear rise in the number of axospinous and axodendritic synapses present in the neuropil. Based on these results, we propose that late maturation of amygdalo‐cortical connectivity may provide an anatomical basis for the development and integration of normal and possibly abnormal emotional behavior during adolescence and early adulthood. J. Comp. Neurol. 453:116–130, 2002. © 2002 Wiley‐Liss, Inc.
Human GABAA receptors on dopaminergic neurons in the pars compacta of the substantia nigra
Authors: Petri Susanne , Krampfl Klaus , Dengler Reinhard , Bufler Johannes , Weindl Adolf , Arzberger Thomas
Published: October 2002

The γ‐aminobutyric acid A (GABAA) receptor subunit expression of the dopaminergic cells of the substantia nigra (SN) was investigated in the present study. Especially the dopaminergic cells, located in the pars compacta of SN (SNc), are of great neurologic interest, because the functional deficit and depletion of these cells are the correlate of Parkinson's disease. We used a combination of in situ hybridization histochemistry (ISH) and immunohistochemistry (IHC) on sections of human postmortem mesencephalon to investigate the expression of GABAA receptor subunit messenger RNAs (mRNAs) and of the receptor protein in dopaminergic SN cells. Immunohistochemical detection of tyrosine hydroxylase (TH), the pivotal enzyme of dopamine synthesis, was used to define the boundaries of SN pars reticulata (SNr) and pars compacta subregions. In SNr, all neurons were labeled by subunit‐specific oligonucleotide probes and the amount of GABAA receptor mRNA expression was quantified as α1 = β2 > γ2 > α3. In contrast, in SNc, only around 25% of neurons expressed mRNA transcripts of GABAA receptor subunits, quantified as α1 = β2 > γ2 > α3 > α4 = β3. In approximately the same percentage of neurons, which were labeled by α1‐subunit–specific probe, the α1‐subunit also was detected at the protein level by a specific monoclonal antibody. We, therefore, could demonstrate that a subset of dopaminergic neurons in human SNc receive inhibitory synaptic input by means of GABAA receptors mainly of the α1β2γ2 subtype. This might represent a negative feedback loop between the striatum and the SNc and be a target of pharmacologic interventions in neurodegenerative diseases such as Parkinson's disease. J. Comp. Neurol. 452:360–366, 2002. © 2002 Wiley‐Liss, Inc.
Induction of microsomal prostaglandin E synthase in the rat brain endothelium and parenchyma in adjuvant‐induced arthritis
Authors: Engblom David , Ek Monica , Andersson Ingela M. , Saha Sipra , Dahlström Marie , Jakobsson Per‐Johan , Ericsson‐Dahlstrand Anders , Blomqvist Anders
Published: October 2002

Although central nervous symptoms such as hyperalgesia, fatigue, malaise, and anorexia constitute major problems in the treatment of patients suffering from chronic inflammatory disease, little has been known about the signaling mechanisms by which the brain is activated during such conditions. Here, in an animal model of rheumatoid arthritis, we show that microsomal prostaglandin E‐synthase, the inducible terminal isomerase in the prostaglandin E2‐synthesizing pathway, is expressed in endothelial cells along the blood‐brain barrier and in the parenchyma of the paraventricular hypothalamic nucleus. The endothelial cells but not the paraventricular hypothalamic cells displayed a concomitant induction of cyclooxygenase‐2 and expressed interleukin‐1 type 1 receptors, which indicates that the induction is due to peripherally released cytokines. In contrast to cyclooxygenase‐2, microsomal prostaglandin E synthase had very sparse constitutive expression, suggesting that it could be a target for developing drugs that will carry fewer side effects than the presently available cyclooxygenase inhibitors. These findings, thus, suggest that immune‐to‐brain communication during chronic inflammatory conditions involves prostaglandin E2‐synthesis both along the blood‐brain barrier and in the parenchyma of the hypothalamic paraventricular nucleus and point to novel avenues for the treatment of the brain‐elicited disease symptoms during these conditions. J. Comp. Neurol. 452:205–214, 2002. © 2002 Wiley‐Liss, Inc.