bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring manufacturing process yields, purity and stability of structural variants of PEGylated staphylokinase mutant SY161 by quantitative reverse‐phase chromatography
Authors: Johnson Catharine , Royal Mabel , Moreadith Randall , Bedu‐Addo Frank , Advant Siddharth , Wan Min , Conn Greg
Published: July 2003

Staphylokinase variant SY161 is a recombinant mutant of the Staphylococcus aureus polypeptide staphylokinase (Sak), and is currently in human clinical trials as a thrombolytic agent. The 15 kDa single chain SY161 protein is expressed as a soluble cytoplasmic product in E. coli with a single cysteine inserted near the N‐terminus. The protein as extracted from E. coli is a mixture of both monomeric and intermolecularly disulfide crosslinked species. To improve protein purification yields SY161 is sulfitolyzed during the early stages of production, preventing disulfide formation. The protein is later modified during manufacturing to incorporate a single 5 kDa polyethylene glycol group on the single sulfhydryl sidechain. We have developed and qualified a reverse‐phase chromatographic method to quantitate SY161 during product manufacturing. We discuss the use of the assay during manufacturing development to monitor fermentation yields, the SY161 PEGylation reaction, and as an in‐process manufacturing control assay. The assay has been applied as a product purity and identity release assay and is suitable for use in assessing product structural integrity during stability testing. The assay has a linear range of quantitation for SY161 from at least 0.15 to 16 µg, and is­in addition capable of detecting and quantitating protein de‐PEGylation events and host cell‐derived protein contaminants. Copyright © 2003 John Wiley & Sons, Ltd.
An optimized method for determination of intracellular glutathione in mouse macrophage cultures by fluorimetric high‐performance liquid chromatography
Authors: Komatsu Hiroyoshi , Obata Fumiya
Published: July 2003

We have optimized a method for the determination of intracellular glutathione by high‐performance liquid chromatography, using fluorimetric detection. To minimize artifacts and provide an accurate determination of intracellular glutathione, cell extracts were prepared using extraction conditions specifically designed to inhibit autoxidation and enzymatic degradation of glutathione. The sensitivity of the method was enhanced by adjusting the dansyl chloride derivatization reaction with regard to parameters such as pH, reaction time and dansyl chloride concentration. Both oxidized and reduced forms of glutathione were quantified using the refined method in extracts of oxidatively stressed J774A.1 mouse macrophage cells and reflected an expected shift in cellular redox status. Copyright © 2003 John Wiley & Sons, Ltd.
Bioanalytical considerations for compounds containing free sulfhydryl groups
Authors: Srinivas Nuggehally R. , Mamidi Rao N. V. S.
Published: July 2003

Thiol‐containing compounds pose bioanalytical challenge in several dimensions due to extreme reactivity of the sulfhydryl group. The development of robust bioanalytical methodology for thiol groups should address the aspects of adequate stabilization in the biological matrix and selectivity considerations. In this context, availability of plethora of thiol reagents provides ample opportunity to achieve the above goals. However, several considerations need to be factored into the decision‐making of a suitable scheme for the thiol drugs under investigation. This review provides some critical insights to many such considerations that may be vital for development and validation of methods for thiol‐containing drugs. Copyright © 2003 John Wiley & Sons, Ltd.
Changes in the surgical management of patients with breast carcinoma based on preoperative magnetic resonance imaging
Authors: Bedrosian Isabelle , Mick Rosemarie , Orel Susan G. , Schnall Mitchell , Reynolds Carol , Spitz Francis R. , Callans Linda S. , Buzby Gordon P. , Rosato Ernest F. , Fraker Douglas L. , Czerniecki Brian J.
Published: July 2003

BACKGROUND

Breast magnetic resonance imaging (MRI) is a developing technique for the evaluation of patients with primary breast carcinoma. The authors assessed the impact of preoperative breast MRI on surgical management.

METHODS

The current study was a retrospective review of 267 patients with primary breast tumors who had MRI studies prior to undergoing definitive surgery.

RESULTS

Two hundred sixty‐seven patients with invasive breast carcinoma who had preoperative breast MRI studies and had complete clinical, radiologic, and pathologic data available were identified and formed the basis of this analysis. The overall sensitivity of MRI for detecting primary, intact breast tumors was 95%. Planned surgical management was altered in 69 of 267 patients (26%); and, in 49 of those patients (71%), there was pathologic verification of malignancy in the surgical specimen that confirmed the need for wider or separate excision or mastectomy. Forty‐four of 267 patients (16.5%) had conversion of planned breast conservation to mastectomy. In a univariate analysis, change in management was associated significantly with histology; management was altered in 11 of 24 lobular tumors (46%) compared with 58 of 243 ductal tumors (24%; P = 0.02).

CONCLUSIONS

Breast MRI was very sensitive for the detection of primary, intact, invasive breast carcinoma and improved local staging in almost 20% of patients. Preoperative breast MRI studies may be particularly useful in surgical planning for and management of patients with lobular carcinoma. Cancer 2003;98:468–73. © 2003 American Cancer Society.

DOI 10.1002/cncr.11490
Race independently predicts prostate specific antigen testing frequency following a prostate carcinoma diagnosis
Authors: Zeliadt Steven B. , Penson David F. , Albertsen Peter C. , Concato John , Etzioni Ruth D.
Published: July 2003

BACKGROUND

The goals of the current study were to describe patterns of prostate specific antigen (PSA) surveillance for prostate carcinoma progression in a community‐based cohort of patients and to identify independent clinical and sociodemographic factors that predict the frequency of surveillance.

METHODS

Patients diagnosed with localized prostate carcinoma from October 1, 1991 to December 31, 1992 in New Haven and Hartford, Connecticut, were identified. Data were collected through standardized outpatient medical record review. Multivariate statistical methods were used to determine the factors that independently predicted the frequency of surveillance.

RESULTS

Six hundred fifty‐eight men with localized prostate carcinoma were included in the cohort. Forty‐five percent of all patients were tested at least once annually, and 69% were tested at least once every 2 years. Multivariate models indicated that African American men were half as likely as Caucasian men to receive annual testing (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.24–0.97). Men diagnosed at age 70 years or older were 38% less likely to have annual testing than men diagnosed between the ages of 65 and 69 (OR, 0.62; 95% CI, 0.41–0.94). A higher Gleason score and PSA at presentation also were associated independently with higher rates of annual PSA surveillance.

CONCLUSIONS

Postdiagnosis PSA surveillance is common, although not universal. African American men were at significantly greater risk for receiving less frequent testing compared with Caucasian men. This disparity in access to care may explain, in part, previously observed racial differences in survival in prostate carcinoma. Further research is needed to identify the reasons for the racial disparity in PSA surveillance and to design interventions to lessen these differences. Cancer 2003;98:496–503. © 2003 American Cancer Society.

DOI 10.1002/cncr.11492
Prognosis of localized diffuse large B‐cell lymphoma in younger patients
Authors: Møller Michael B. , Christensen Bjarne E. , Pedersen Niels T.
Published: July 2003

BACKGROUND

The International Prognostic Index (IPI) is widely used as a predictive model in diffuse large B‐cell lymphoma (DLBCL) patients of all ages and stages. To determine the optimal IPI‐based prognostic system at the time of diagnosis in younger patients with limited‐stage DLBCL, the authors evaluated the age‐adjusted IPI and the recently proposed stage‐adjusted IPI, and constructed an IPI‐based model adjusted for both age and stage.

METHODS

From the population‐based LYFO registry of the Danish Lymphoma Group, 233 patients not older than 60 years with Stage I‐II DLBCL treated with anthracycline‐based chemotherapy with or without involved‐field irradiation were identified. The primary endpoint of analysis was overall survival.

RESULTS

At the end of the observation period, 151 patients were alive with a median follow‐up time of 8.3 years. All the variables in the age‐adjusted and the stage‐adjusted IPI had major prognostic significance (P≤ 0.0001). Log‐rank analyses of survival showed highly significant differences between the subgroups in each model (P< 0.0001); however, the stage‐adjusted IPI was more powerful (chi‐square test = 44.99) than the age‐adjusted IPI (chi‐square test = 36.27). By using the median age of the cohort (50 years) as a cutoff point, age was found to be a strong prognostic factor (P= 0.0036). An age‐/stage‐adjusted IPI was constructed, the predictive power of which was equal to the stage‐adjusted IPI (chi‐square test = 44.16) but with different distribution of patients between the risk groups, making the proposed model better suited to identify poor‐risk patients.

CONCLUSIONS

The data from the current study suggest that the proposed age‐/stage‐adjusted IPI is the superior IPI‐based model in predicting outcome in younger patients with localized DLBCL. Cancer 2003;98:516–21. © 2003 American Cancer Society.

DOI 10.1002/cncr.11497
Spinal cord malignant astrocytomas
Authors: Santi Mariarita , Mena Hernando , Wong Kondi , Koeller Kelly , Olsen Cara , Rushing Elisabeth J.
Published: July 2003

BACKGROUND

Malignant astrocytomas of the spinal cord are uncommon neoplasms with a dismal prognosis. To the authors' knowledge, little information has been published to date regarding the prognostic impact of clinicopathologic factors.

METHODS

The authors studied 36 cases to investigate the prognostic effect of the World Health Organization (WHO) tumor grade, tumor localization, cell proliferative activity, p53 expression, and therapy.

RESULTS

Sixteen patients (44%) underwent biopsy alone, 11 (31%) underwent subtotal resection, and 7 (19%) underwent macroscopic total excision. For two patients, there were no data available regarding surgical treatment. Among the 36 patients (mean age, 32.4 years), there were 23 males (63%) and 13 (36%) females. Their initial biopsies showed 21 (63%) glioblastoma multiforme (GBM) cases (WHO Grade 4), 13 (36%) anaplastic astrocytomas (AA) (WHO Grade 3), and 2 (6%) astrocytomas (A) (WHO Grade 2). After initial surgery, 10 (29%) patients were treated with radiation therapy alone and 7 (19%) received radiation therapy with chemotherapy. Patterns of disease recurrence included extraneural metastases (two cases), brain metastases (five cases), local extension (one case), and diffuse spread along the neuraxis (six cases). Two A (100%) and six AA (46%) cases progressed to GBM. The overall median survival time was 33 months (range, 24–42 months) for A, 10 months (range, 1–84 months) for AA, and 10 months (range, 1–43 months) for GBM.

CONCLUSIONS

Patients older than 40 years have a shorter survival period compared with younger patients. There is a high risk of central nervous system dissemination in patients with this disease. Cancer 2003;98:554–61. © 2003 American Cancer Society.

DOI 10.1002/cncr.11514
High syndecan‐1 expression in breast carcinoma is related to an aggressive phenotype and to poorer prognosis
Authors: Barbareschi Mattia , Maisonneuve Patrick , Aldovini Daniela , Cangi Maria Giulia , Pecciarini Lorenza , Angelo Mauri Francesco , Veronese Silvio , Caffo Orazio , Lucenti Antonio , Palma Paolo Dalla , Galligioni Enzo , Doglioni Claudio
Published: July 2003

BACKGROUND

Syndecan‐1 is a transmembrane heparan sulphate proteoglycan that is involved in cell–cell adhesion, organization of cell–matrix adhesion, and regulation of growth factor signaling.

METHODS

Specimens from 254 consecutive breast carcinoma (BC) cases (110 N0, 144 N1/2) with long‐term follow‐up (median, 95 months) were immunostained for syndecan‐1, estrogen receptor (ER), progesterone receptor (PgR), and p53; in 154 cases, c‐erbB‐2 status was known. Syndecan‐1 mRNA and protein expression also were evaluated in 20 breast tissue samples (10 normal and tumor pairs).

RESULTS

Syndecan‐1 was expressed at high levels in 106 (42%) BCs; syndecan‐1 up‐regulation was confirmed by reverse transcriptase–polymerase chain reaction (RT‐PCR) studies. High syndecan‐1 expression was associated with high histologic grade, large tumor size, high mitotic count, c‐erbB‐2 overexpression, and ER and PgR negative status. At univariate survival analysis syndecan overexpression was related to poor prognosis (P < 0.01 for both overall survival (OS) and disease‐free survival). Bivariate survival analysis showed an additive adverse effect for syndecan‐1 and c‐erbB‐2 overexpression. At multivariate analysis, syndecan‐1 overexpression was independently associated with poor OS (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.08–2.69). High syndecan‐1 expression also was of independent prognostic value for OS in the group of 102 ER‐negative patients (HR, 2.42; 95% CI, 1.21–4.82). Stratifying patients on the basis of the type of adjuvant therapy given, high syndecan‐1 expression was associated with a higher risk of death only in patients treated with the cyclophosphamide‐methotrexate‐fluorouracil regimen (HR, 1.9; P = 0.09); at multivariate analysis for OS, this association proved to be of independent statistical significance (P = 0.03; HR, 2.15).

CONCLUSIONS

Syndecan‐1 is expressed at high levels in a significant percentage of breast carcinomas and is related to an aggressive phenotype and poor clinical behavior. Cancer 2003;98:474–83. © 2003 American Cancer Society.

DOI 10.1002/cncr.11515
Racial differences in mammographic breast density
Authors: del Carmen Marcela G. , Hughes Kevin S. , Halpern Elkan , Rafferty Elizabeth , Kopans Daniel , Parisky Yuri R. , Sardi Armando , Esserman Lisa , Rust Steven , Michaelson James
Published: July 2003

BACKGROUND

African American women have a lower incidence but a higher mortality from breast carcinoma than Caucasians. A proposed explanation for this discrepancy is the decreased efficacy of screening among African American women. Increased breast density in African American women may result in decreased sensitivity of mammography. The purpose of this article is to determine whether there is a difference in mammographic breast density between African American and Caucasian women.

METHODS

A series of 769 women were recruited from 5 sites. Mammograms were reviewed centrally by seven reviewers using Breast Imaging Reporting and Data System categories converted to numeric values. The mean mammographic densities for Caucasian, African American, and Latina patients were compared using a two‐way analysis of covariance. The mean values for each race were estimated adjusting for the reader as well as for each patient's age and body mass index (BMI).

RESULTS

African American women had the lowest mean breast density. The reported density in this group was 2.43, compared with 2.69 among Caucasians and 2.65 among Latina patients. After adjusting for age and BMI as well as the reader, there was still an independent racial effect on breast density (P = 0.0050).

CONCLUSIONS

Mammographic breast density was lower in African American women than in Caucasians and Latinas. This discrepancy may be an intrinsic racial difference due to undetermined causes. Factors, such as the growth rate of tumors and the incidence of calcifications, must be studied to confirm that other forces do not have a negative impact on the efficacy of screening mammograms in African American women. Cancer 2003;98:590–6. © 2003 American Cancer Society.

DOI 10.1002/cncr.11517
Chronic myelogenous leukemia: A review and update of therapeutic strategies
Authors: Garcia‐Manero Guillermo , Faderl Stefan , O'Brien Susan , Cortes Jorge , Talpaz Moshe , Kantarjian Hagop M.
Published: July 2003

DOI 10.1002/cncr.11520
Clinical implications of the tumor necrosis factor family in benign and malignant hematologic disorders
Authors: Younes Anas , Aggarwall Bharat B.
Published: July 2003

Tumor necrosis factor (TNF), originally identified as a factor produced in the serum of endotoxin‐injected animals, is a cytokine that mediates tumor necrosis. To date, 20 different members of the TNF superfamily and 21 different receptors have been identified. All ligands of the TNF superfamily have been found to activate transcription factor NF‐κB and c‐Jun kinase. Members of this family have diverse biologic effects, including induction of apoptosis, promotion of cell survival, and regulation of the immune system. The current review focuses on four members that play important roles in regulating hematopoietic cells and are involved in the pathogenesis of several hematologic malignancies. The potential therapeutic use of these members also is discussed. Cancer 2003;98:458–67. © 2003 American Cancer Society.

DOI 10.1002/cncr.11524
Disparity in pathologic and clinical lymph node staging in oral tongue carcinoma
Authors: Greenberg Jayson S. , El Naggar Adel K. , Mo Vivian , Roberts Dianna , Myers Jeffrey N.
Published: July 2003

BACKGROUND

Regional lymph node metastasis is the most reliable predictor of treatment outcomes for patients with squamous cell carcinoma of the oral tongue (SCCOT). A recent American Joint Committee on Cancer staging update of malignant melanoma has incorporated pathologic lymph node staging. The authors hypothesized that pathologic lymph node staging (pN) would be a more reliable predictor of treatment outcomes than clinical lymph node staging (cN).

METHODS

The authors retrospectively reviewed 266 patients who received primary surgical treatment for SCCOT, including a neck dissection, from January 1980 to December 1995. Overall and disease‐specific survival and disease‐free interval were compared with respect to clinical and pathologic lymph node stages.

RESULTS

Statistically significant survival differences were identified for both clinical (cN0–cN2) and pathologic lymph node stages (pN0–pN2). However, survival and disease‐free interval differences for pathologic lymph node staging reached higher statistical significance (P < 0.0001) than for clinical lymph node staging (P < 0.002). This disparity can be explained by stage migration (i.e., patients with cN0–1 disease have a more advanced lymph node stage at the time of pathologic review compared with patients without cN0–1 disease). The authors found a 34% rate of occult lymph node disease in the cN0 group (19% of occult lymph nodes had extracapsular spread [ECS]). Similarly, 43% of cN1 patients had a higher stage than pN2b disease and 50% had ECS.

CONCLUSIONS

Pathologic lymph node staging, based on a staging or therapeutic neck dissection, should be considered for patients treated for SCCOT to identify high‐risk patients who may benefit from additional adjuvant therapy. Prospective studies are essential to validate these findings before pathologic lymph node staging is included in standard staging criteria. Cancer 2003;98:508–15. © 2003 American Cancer Society.

DOI 10.1002/cncr.11526
Blockage of the lacrimal drainage apparatus as a side effect of docetaxel therapy
Authors: Esmaeli Bita , Hidaji Lillie , Adinin Rosnie B. , Faustina Misha , Coats Carol , Arbuckle Rebecca , Rivera Edgardo , Valero Vicente , Tu Shi‐Ming , Amir Ahmadi M.
Published: July 2003

BACKGROUND

The current study was conducted to report the severity and management of canalicular and nasolacrimal duct stenosis as a side effect of docetaxel therapy and to report the outcomes of surgical intervention for this condition.

METHODS

The records of 148 patients with epiphora associated with docetaxel therapy who were evaluated at the Ophthalmology Service at The University of Texas M. D. Anderson Cancer Center were reviewed. The frequency of docetaxel administration, the dose intensity, the cumulative dose of docetaxel, and any concomitant chemotherapeutic agents were recorded. Each patient underwent an ophthalmologic examination and in‐office probing and irrigation. The patients either were treated with topical steroids or offered a surgical procedure for canalicular stenosis– (silicone intubation, dacryocystorhinostomy [DCR] with the placement of silicone tubes, or DCR with the placement of Pyrex glass tubes), depending on the severity of the canalicular stenosis.

RESULTS

Docetaxel was given weekly in 71 patients, every 2 weeks in 5 patients, and every 3 weeks in 72 patients. Thirty patients (59 eyes) who received weekly docetaxel underwent surgery to correct epiphora. Twenty‐three patients (39 eyes) were treated with temporary silicone tube placement, 9 patients (13 eyes) were treated with DCR with temporary silicone tube placement, and 4 patients (7 eyes) were treated with DCR with permanent Pyrex glass tube placement. Twenty‐nine of the 30 patients who underwent surgery reported improvement or total resolution of epiphora after the procedure. Ten additional patients (20 eyes) who received weekly docetaxel had complete closure of their canaliculi but elected not to undergo surgery. Of special note were two patients who received weekly docetaxel in the neoadjuvant setting and developed complete closure of the canaliculi. Of the patients who received docetaxel every 2 or 3 weeks, only 3 required a surgical intervention to correct epiphora; none required Pyrex glass tube placement.

CONCLUSIONS

Canalicular and nasolacrimal duct obstruction is a common side effect of weekly docetaxel therapy and can occur even when this drug is used in the neoadjuvant setting. The results of the current study indicate that early temporary silicone intubation in symptomatic patients receiving weekly docetaxel can prevent further closure of the lacrimal drainage apparatus and obviate more involved surgical interventions and permanent Pyrex glass tube placement. Cancer 2003;98:504–7. © 2003 American Cancer Society.

DOI 10.1002/cncr.11527
The clinical and pathogenetic significance of estrogen receptor‐β expression in chronic liver diseases and liver carcinoma
Authors: Iavarone Massimo , Lampertico Pietro , Seletti Chiara , Francesca Donato Maria , Ronchi Guido , Del Ninno Ersilio , Colombo Massimo
Published: July 2003

BACKGROUND

Estrogen receptor‐α (ERα) is variably expressed in hepatocellular carcinoma (HCC) and is believed to be correlated with prognosis and survival. Recently, another estrogen receptor (ERβ) has been identified, but its relevance in liver diseases is unknown.

METHODS

The expression of ERβ in the liver of 42 patients with HCC (10 with paired extratumoral tissues) and 26 with chronic liver disease without HCC was studied by a reverse transcriptase‐polymerase chain reaction method, and correlated with the expression of ERα and severity of the liver disease.

RESULTS

Both ERβ and wild‐type ERα were found to be expressed more often in patients with chronic liver disease compared with those with HCC (69% vs. 45% [P = 0.046] and 46% vs. 10% [P = 0.0008], respectively). ERs were similarly expressed in HCC and in the paired extratumoral tissue. Wild‐type receptors, either alone or together with the deleted mutants ERδ5, were more often coexpressed in chronic liver disease (58%) than in HCC (29%); in 13 tumors (31%), either ERδ5 or no receptors at all were detected (P = 0.006). Hepatitis B virus (HBV)‐related tumors either did not appear to express ERs or expressed ERδ5 more often than hepatitis C virus (HCV)‐related tumors (67% vs. 15%; P = 0.007). The same was true for multinodular compared with single nodular tumors (50% vs. 19%; P = 0.04).

CONCLUSIONS

Both receptors were expressed in chronic liver disease and neoplastic livers demonstrating different patterns in relation to the etiology and clinical presentation of the tumor. These differences might underscore different pathogenetic mechanisms in HBV‐related and HCV‐related HCC and a different evolutionary course for the tumor. Cancer 2003;98:529–34. © 2003 American Cancer Society.

DOI 10.1002/cncr.11528
Characteristics and prognosis of patients after resection of nonsmall cell lung carcinoma measuring 2 cm or less in greatest dimension
Authors: Okada Morihito , Sakamoto Toshihiko , Nishio Wataru , Uchino Kazuya , Tsubota Noriaki
Published: July 2003

BACKGROUND

There remains ongoing controversy with regard to the optimal management strategy and the prognostic significance of small‐sized nonsmall cell lung carcinoma. Therefore, in the current study, the authors analyzed the clinical characteristics of patients who underwent complete resection of these lung tumors, the follow‐up data, and the significant prognostic factors.

METHODS

Of 1726 consecutive patients surgically treated for proven primary lung carcinoma, 265 patients underwent complete removal of a nonsmall cell lung carcinoma in which the greatest dimension of the resected specimen was ≤ 2 cm.

RESULTS

The cancer‐specific 5‐year and 10‐year survival rates were 86% and 83%, respectively. Univariate analyses revealed that advanced pathologic stage, a tumor size of 16–20 mm, lymphatic vessel invasion, vascular vessel invasion, a high serum level of carcinoembryonic antigen (CEA), and extended resection were significantly unfavorable prognostic factors. Among these factors, multivariate analyses demonstrated that pathologic stage (P < 0.0001), vascular vessel invasion (P = 0.0040), and CEA level (P = 0.0291) were significant, independent determinants of survival. None of the patients with pathologic Stage I disease, no vascular vessel invasion, and a low serum CEA level died of their disease after undergoing complete resection.

CONCLUSIONS

The preoperative level of serum CEA and vascular vessel invasion by tumor cells were found to be independent prognostic factors that were as significant as the well established determinant of pathologic stage for patients with a nonsmall cell lung carcinoma measuring ≤ 2 cm in greatest dimension. These data may contribute to the explanation of the lower‐than‐expected survival of patients after complete surgical resection of such a small‐sized tumor. Cancer 2003;98:535–41. © 2003 American Cancer Society.

DOI 10.1002/cncr.11530
Identification of germline 185delAG BRCA1 mutations in non‐Jewish Americans of Spanish ancestry from the San Luis Valley, Colorado
Authors: Mullineaux Lisa G. , Castellano Teresa M. , Shaw Jeffrey , Axell Lisen , Wood Marie E. , Diab Sami , Klein Catherine , Sitarik Mark , Deffenbaugh Amie M. , Graw Sharon L.
Published: July 2003

BACKGROUND

Germline mutations in the BRCA1 and BRCA2 genes are associated with an inherited predisposition to breast and ovarian carcinoma, and specific mutations in these genes are found at increased frequency in certain populations. The authors observed a repeated occurrence of the 185delAG mutation (BRCA1; also known as 187delAG) in a non‐Jewish population that originated from the San Luis Valley in Colorado.

METHODS

This was a retrospective analysis of mutations that occur in non‐Jewish Americans of Spanish ancestry from Colorado who were tested clinically for BRCA1 and BRCA2 genetic mutations using DNA sequencing.

RESULTS

Between August 1994 and December 2001, 19 Spanish/Latin American individuals from different families underwent genetic counseling and clinical genetic testing using direct DNA sequencing for mutations of the BRCA1 and BRCA2 genes. The results showed that 10 of 19 individuals had mutations or variants of BRCA1 or BRCA2, and 6 of 10 individuals (60%) carried the 185delAG mutation in BRCA1. All six families originated from the San Luis Valley in Colorado, indicated that they were of Spanish/Latin American ethnicity, and denied Jewish ancestry.

CONCLUSIONS

The 185delAG mutation is common in families of non‐Jewish ancestry originating from the San Luis Valley in Colorado with hereditary breast/ovarian carcinoma, possibly due to a founder effect. Further investigation may lead to simplified genetic testing and may allow clinicians to serve this population better. The repeated occurrence of the 185delAG mutation in this specific population may have clinical and public health implications. Cancer 2003;98:597–602. © 2003 American Cancer Society.

DOI 10.1002/cncr.11533
Racial differences in survival after diagnosis with primary malignant brain tumor
Authors: Barnholtz‐Sloan Jill S. , Sloan Andrew E. , Schwartz Ann G.
Published: July 2003

BACKGROUND

Previous studies have shown that the overall incidence of primary malignant brain tumor is greatest in Caucasians, although survival is better in African Americans. The objective of this study was to examine racial differences in survival after diagnosis with primary malignant brain tumor in a population‐based sample of patients while adjusting for prognostic variables that differ by race.

METHODS

The authors analyzed 21,493 patients (20,493 Caucasians and 1000 African Americans) who were diagnosed with primary malignant brain tumors from 1973 to 1997 (with follow‐up through 1999) from the population‐based Surveillance, Epidemiology, and End Results (SEER) Program. Chi‐square tests were used to determine statistical significance of prognostic variables and race (using two‐sided P values). Kaplan–Meier and Cox proportional hazards models were used to assess survival differences by race.

RESULTS

The univariable model for race showed no survival difference by race. The multivariable model demonstrated that African American patients were at a 13% increased risk of death from any cause compared with Caucasian patients. The racial difference was explained further by an interaction between race and surgery type in which there was an increased risk of death for African American patients who underwent subtotal resections or surgery not otherwise specified compared with Caucasian patients who underwent the same procedures.

CONCLUSIONS

There was a significant difference in the risk of death due to any cause for Caucasian patients and African American patients who were diagnosed with first primary brain tumors. Cancer 2003;98:603–9. © 2003 American Cancer Society.

DOI 10.1002/cncr.11534
Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma
Authors: Danson Sarah , Middleton Mark R. , O'Byrne Kenneth J. , Clemons Mark , Ranson Malcolm , Hassan Jurjees , Anderson Heather , Burt Paul A. , Fairve‐Finn Corrine , Stout Ronald , Dowd Isabel , Ashcroft Linda , Beresford Cheryl , Thatcher Nicholas
Published: July 2003

BACKGROUND

The authors compared gemcitabine and carboplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) or mitomycin, vinblastine, and cisplatin (MVP) in patients with advanced nonsmall cell lung carcinoma (NSCLC). The primary objective was survival. Secondary objectives were time to disease progression, response rates, evaluation of toxicity, disease‐related symptoms, World Health Organization performance status (PS), and quality of life (QoL).

METHODS

Three hundred seventy‐two chemotherapy‐naïve patients with International Staging System Stage III/IV NSCLC who were ineligible for curative radiotherapy or surgery were randomized to receive either 4 cycles of gemcitabine (1000 mg/m2 on Days 1, 8, and 15) plus carboplatin (area under the serum concentration‐time curve, 5; given on Day 1) every 4 weeks (the GC arm) or MIC/MVP every 3 weeks (the MIC/MVP arm).

RESULTS

There was no significant difference in median survival (248 days in the MIC/MVP arm vs. 236 days in the GC arm) or time to progression (225 days in the MIC/MVP arm vs. 218 days in the GC arm) between the 2 treatment arms. The 2‐year survival rate was 11.8% in the MIC/MVP arm and 6.9% in the GC arm. The 1‐year survival rate was 32.5% in the MIC/MVP arm and 33.2% in the GC arm. In the MIC/MVP arm, 33% of patients responded (4 complete responses [CRs] and 57 partial responses [PRs]) whereas in the GC arm, 30% of patients responded (3 CRs and 54 PRs). Nonhematologic toxicity was comparable for patients with Grade 3–4 symptoms, except there was more alopecia among patients in the MIC/MVP arm. GC appeared to produce more hematologic toxicity and necessitated more transfusions. There was no difference in performance status, disease‐related symptoms, or QoL between patients in the two treatment arms. Fewer inpatient stays for complications were required with GC.

CONCLUSIONS

The results of the current study failed to demonstrate any difference in efficacy between the newer regimen of GC and the older regimens of MIC and MVP. Cancer 2003;98:542–53. © 2003 American Cancer Society.

DOI 10.1002/cncr.11535
Nevoid basal cell carcinoma syndrome: Relation with desmoplastic medulloblastoma in infancy
Authors: Amlashi Seyed F. A. , Riffaud Laurent , Brassier Gilles , Morandi Xavier
Published: July 2003

BACKGROUND

Patients with nevoid basal cell carcinoma syndrome (NBCCS) are believed to be predisposed to develop early‐onset neoplasms including medulloblastomas (MB). The desmoplastic subtype of MB is associated most commonly with NBCCS. The goals of this study were to demonstrate the relation between desmoplastic MB and NBCCS and to evaluate the concomitant diagnosis of NBCCS and MB.

METHODS

The medical records of 76 consecutive children who received surgical treatment for MB between 1970 and 2000 were studied. A review of the literature was performed based on the National Library of Medicine database and bibliographies of selected articles were scanned.

RESULTS

The authors reported three patients with NBCCS who received surgical treatment for an MB during infancy. The literature review identified 33 patients with NBCCS who were treated for MB at a mean age of 28 months. The desmoplastic subtype was the only histopathologic subtype of MB reported in the NBCCS population. Although patients with NBCCS are predisposed to develop multiple basal cell carcinomas and intracranial tumors in the field of irradiation, the prognosis for syndromic MBs was much better compared with the prognosis for sporadic MBs.

CONCLUSIONS

Patients with NBCCS have an increased risk for other malignancies, especially radiation‐induced neoplasms. Early diagnosis of this syndrome is important for the selection of appropriate adjuvant treatment and family genetic counseling. The authors did not advocate the use of radiotherapy as an adjuvant treatment in desmoplastic MB diagnosed in children younger than 5 years of age. They suggested that the desmoplastic subtype of MB in children younger than 2 years of age is a major diagnostic criterion for the diagnosis of NBCCS. Cancer 2003;98:618–24. © 2003 American Cancer Society.

DOI 10.1002/cncr.11537
Nicotine dependence treatment for patients with cancer
Authors: Cox Lisa Sanderson , Africano Nicole L. , Tercyak Kenneth P. , Taylor Kathryn L.
Published: July 2003

BACKGROUND

Cancer patients who use tobacco demonstrate characteristics of strong nicotine dependence and are at increased risk for future tobacco‐related morbidity and mortality. Continued smoking may contribute to poorer cancer treatment outcome and additional illness. In contrast, stopping smoking may improve quality of life and facilitate cancer treatment. Unfortunately, limited attention has been given to addressing tobacco use and treating nicotine dependence in cancer patients.

METHODS

The authors reviewed the current literature on smoking cessation and nicotine dependence treatment in patients with cancer.

RESULTS

Nicotine dependence treatment in patients with cancer facilitates smoking cessation. Evidence that cancer patients are motivated and able to stop smoking support tobacco use treatment intervention. Research is needed to evaluate effective intervention to aid tobacco abstinence and evaluate related health benefits for this patient population.

CONCLUSIONS

Cancer patients are able to stop smoking and benefit from intervention. Treatment of nicotine dependence in cancer patients merits attention from researchers and healthcare providers. The health risks of continued smoking and clear benefits of tobacco abstinence provide an ethical imperative for treating nicotine dependence in cancer patients. Research is needed to evaluate effective intervention with the overall goal of promoting tobacco abstinence to benefit oncology treatment and patient health. Cancer 2003;98:632–44. © 2003 American Cancer Society.

DOI 10.1002/cncr.11538
Measuring chemotherapy‐induced nausea and emesis
Authors: Martin Charles G. , Rubenstein Edward B. , Elting Linda S. , Kim Young Jun , Osoba David
Published: July 2003

BACKGROUND

Chemotherapy‐induced nausea and emesis (CINE) is one of the most dreaded side effects of cancer therapy. To investigate the influence of these symptoms on a patient's quality of life (QOL), a validated tool measuring many domains is needed.

METHODS

A QOL questionnaire consisting of scales from the European Organization for Research and Treatment of Cancer QLQ‐C30, the Morrow Assessment of Nausea and Emesis, the Osoba Nausea and Emesis Module, and new items specific to nausea, emesis, and retching was constructed and administered daily for 7–9 days to outpatients receiving emetogenic chemotherapy.

RESULTS

Test‐retest and internal consistency reliabilities ranged from 0.44 to 0.84 and from 0.59 to 0.85, respectively. Item and scale correlations indicated good convergent and discriminant validity. Scales and items measuring similar factors (e.g., severity of emesis and severity of nausea) had strong correlations than did scales measuring dissimilar factors (e.g., cognitive functioning and physical functioning). The validity of known groups was demonstrated by significant differences (P < 0.01) in patients' QOL scores between days with no episodes of nausea, emesis, or retching, days with 1 or 2 episodes, and days with more than 3 episodes. Patients' QOL significantly decreased as the number of episodes per day increased (P < 0.001).

CONCLUSIONS

A CINE QOL questionnaire that successfully measures the short‐term impact of nausea, emesis, and retching on patients receiving emetogenic chemotherapy has been developed, largely as a battery of preexisting questionnaires. The psychometric properties of the new questionnaire show adequate reliability and validity to warrant its use in clinical trials and outcomes studies. CINE adversely affects many domains within a patient's QOL. Cancer 2003;98:645–55. © 2003 American Cancer Society.

DOI 10.1002/cncr.11540
Results of decitabine (5‐aza‐2′deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia
Authors: Kantarjian Hagop M. , O'Brien Susan , Cortes Jorge , Giles Francis J. , Faderl Stefan , Issa Jean‐Pierre , Garcia‐Manero Guillermo , Rios Mary Beth , Shan Jianqin , Andreeff Michael , Keating Michael , Talpaz Moshe
Published: July 2003

BACKGROUND

General and site‐specific DNA methylation is associated with tumor progression and resistance in several cancers, including chronic myelogenous leukemia (CML). Decitabine is a hypomethylating agent that has shown encouraging preliminary anti‐CML activity. This study evaluated the activity and toxicity of decitabine in different phases of CML.

METHODS

One hundred and thirty patients with CML were treated: 123 with Philadelphia chromosome (Ph)‐positive CML (64 blastic, 51 accelerated, 8 chronic) and 7 with Ph‐negative CML. Decitabine was given at 100 mg/m2 over 6 hours every 12 hours × 5 days (1000 mg/m2 per course) in the first 13 patients, 75 mg/m2 in the subsequent 33 patients, and 50 mg/m2 in the remaining 84 patients.

RESULTS

A total of 552 courses were given to the 130 patients. Only four patients (3%) died during the first course from myelosuppressive complications (three patients) or progressive disease (one patient). Of 64 patients in the CML blastic phase, 18 patients (28%) achieved objective responses. Of these 18 patients, 6 achieved complete hematologic responses (CHR), 2 achieved partial hematologic responses (PHR), 7 achieved hematologic improvements (HI), and 3 returned to the second chronic phase (second CP). Five patients (8%) had cytogenetic responses. Among 51 patients in the accelerated phase, 28 patients (55%) achieved objective responses (12 CHR, 10 PHR, 3 HI, and 3 second CP). Seven patients (14%) had cytogenetic responses. Among eight patients treated in the chronic phase, five (63%) had objective responses. Of seven patients treated for Ph‐negative CML, four (57%) had objective responses. There was no evidence of a dose‐response effect. The estimated 3‐year survival rate was less than 5% in the blastic phase and 27% in the accelerated phase. The only significant toxicity reported was severe myelosuppression, which was delayed, prolonged, and dose dependent. With decitabine 50–75 mg/m2, the median time to granulocyte recovery above 0.5 × 109/L was about 4 weeks. Myelosuppression‐associated complications included febrile episodes in 37% and documented infections in 34%.

CONCLUSIONS

Decitabine appears to have significant anti‐CML activity. Future studies should evaluate lower‐dose, longer‐exposure decitabine schedules alone in imatinib‐resistant CML, as well as combinations of decitabine and imatinib in different CML phases. Cancer 2003;98:522–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11543
Influence of body mass index on outcomes and treatment‐related toxicity in patients with colon carcinoma
Authors: Meyerhardt Jeffrey A. , Catalano Paul J. , Haller Daniel G. , Mayer Robert J. , Benson Al B. , Macdonald John S. , Fuchs Charles S.
Published: July 2003

BACKGROUND

Obesity is a risk factor for the development of colon carcinoma. The influence of body mass index (BMI) on long‐term outcomes and treatment‐related toxicity in patients with colon carcinoma has not been well characterized.

METHODS

This cohort study was conducted within a large, randomized adjuvant chemotherapy trial of 3759 men and women with high‐risk, Stage II and Stage III colon carcinoma who were treated between 1988 and 1992 throughout the United States. With a median follow‐up of 9.4 years, the authors examined the influence of BMI on disease recurrence, overall survival, and treatment‐related toxicity.

RESULTS

Compared with women of normal weight (BMI, 21.0–24.9 kg/m2), obese women with colon carcinoma (BMI ≥ 30.0 kg/m2) experienced significantly worse overall mortality (hazard ratio [HR], 1.34; 95% confidence interval [95% CI], 1.07–1.67) and a nonsignificant increase in the risk of disease recurrence (HR, 1.24; 95% CI, 0.98–1.59). The influence of BMI among women was not related to any differences in chemotherapy dose‐intensity across categories of BMI. In contrast, BMI was not related significantly to long‐term outcomes among male patients in this cohort. Among all study participants, obese patients had significantly lower rates of Grade 3–4 leukopenia and lower rates of any Grade ≥ 3 toxicity compared with patients of normal weight.

CONCLUSIONS

Among women with Stage II–III colon carcinoma, obesity was associated with a significant increase in overall mortality as well as a borderline significant increase in disease recurrence. Nonetheless, obesity was not associated with any increase in chemotherapy‐related toxicity. Cancer 2003;98:484–95. © 2003 American Cancer Society.

DOI 10.1002/cncr.11544
The association of P‐glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma
Authors: Pakos Emilios E. , Ioannidis John P. A.
Published: July 2003

BACKGROUND

There is controversy regarding whether P‐glycoprotein (Pgp) may be a prognostic factor for the response to chemotherapy and clinical disease progression in patients with osteosarcoma.

METHODS

The authors conducted a meta‐analysis of 14 studies (n = 631 patients) that evaluated the correlation between Pgp and histologic response to chemotherapy and clinical disease progression (death, metastasis, or recurrence). Data were synthesized in receiver operating characteristic curves and with fixed‐effects and random‐effects likelihood ratios and risk ratios.

RESULTS

Pgp had no discriminating ability for identifying poor responders versus good responders to chemotherapy: The positive likelihood ratio was 1.15 (95% confidence interval [95% CI], 0.93–1.43), and the negative likelihood ratio was 0.88 (95% CI, 0.65–1.18; random‐effects calculations). There was some between‐study heterogeneity, but no study showed strong discriminating ability. Conversely, Pgp positivity increased the risk of disease progression 1.92‐fold (95% CI, 1.18–3.13; random‐effects calculations) with some between‐study heterogeneity that disappeared when only studies that employed immunohistochemistry were considered (risk ratio, 2.23; 95% CI, 1.37–3.64). The results were robust in various sensitivity analyses, although smaller studies tended to show stronger associations with the risk of disease progression compared with larger studies (P = 0.03).

CONCLUSIONS

The available evidence showed conclusively that Pgp was not associated with the histologic response of patients with osteosarcoma to combination chemotherapy regimens. Conversely, Pgp positivity, as determined by immunohistochemistry, was a strong correlate of more rapid disease progression, although there was heterogeneity across the performed studies that, to some extent, may have reflected bias, differential measurements of Pgp, or confounding with other risk factors. Cancer 2003;98:581–9. © 2003 American Cancer Society.

DOI 10.1002/cncr.11546
Phase I dose and sequencing study of pegylated liposomal doxorubicin and docetaxel in patients with advanced malignancies
Authors: Fracasso Paula M. , Rodriguez Luis C. , Herzog Thomas J. , Fears Carole L. , Goodner Sherry A. , Govindan Ramaswamy , Picus Joel , Rader Janet S. , Tan Benjamin R. , Arquette Matthew A.
Published: July 2003

BACKGROUND

Pegylated liposomal doxorubicin (PEG‐LD) and docetaxel have single‐agent activity in several malignancies. The authors conducted a Phase I trial to evaluate the maximum tolerated dose (MTD), toxicities, and effect of dose sequencing of this combination in patients with advanced malignancies.

METHODS

Twenty‐two patients were enrolled in this two‐arm, accelerated, dose escalation trial. Both drugs were administered on Days 1 and 15 of a 28 day cycle. In Arm A, dose escalation proceeded from a sequence and starting dose of 15 mg/m2 PEG‐LD and 30 mg/m2 docetaxel. In Arm B, dose escalation proceeded from a sequence and starting dose of 30 mg/m2 docetaxel and 15 mg/m2PEG‐LD. In both arms, the dose of each drug was increased alternately by 5 mg/m2 at each dose level.

RESULTS

The MTD for Arm A was 20 mg/m2 PEG‐LD and 40 mg/m2 docetaxel, both of which were administered on Days 1 and 15 of a 28‐day cycle. The MTD for Arm B was 35 mg/m2 docetaxel and 20 mg/m2 PEG‐LD, both of which were administered on Days 1 and 15 of a 28‐day cycle. Dose‐limiting toxicities were Grade 3 (according to the National Cancer Institute Common Toxicity Criteria) skin toxicity and thrombocytopenia. One partial response was observed and stable disease was documented for three patients.

CONCLUSIONS

The recommended sequence and dose is 20 mg/m2 PEG‐LD followed by 40 mg/m2 docetaxel on Days 1 and 15 of a 28‐day cycle in Phase II trials for patients with breast and ovarian carcinoma to establish the efficacy of this well tolerated regimen. Cancer 2003;98:610–7. © 2003 American Cancer Society.

DOI 10.1002/cncr.11547