bluuebunny/crossref_metadata_2025 huggingface dataset:
Highly diastereoselective addition of silyldihalomethyllithiums to chiral alkyl esters
Authors: Shinokubo Hiroshi , Kondo Junichi , Inoue Atsushi , Oshima Koichiro
Published: December 2002

Treatment of benzoate, formate, or trifluoroacetate esters with silyldibromomethyllithiums provides alkyl silyl mixed acetals via the 1,3‐rearrangement of a silyl group from carbon to oxygen. A high level of asymmetric induction onto the acetal carbon is observed when chiral alkyl esters are employed. The stereochemical assignment of the silyl acetal 13j was accomplished on the basis of X‐ray crystallographic analysis. A one‐pot synthesis of a three‐component coupling product R1C(OR2)(OSiMe2‐t‐Bu)CX2E′ (X = Cl, Br) by sequential additions of an ester (R1CO2R2) and the second electrophile was achieved. Chirality 15:31–37, 2003. © 2002 Wiley‐Liss, Inc.
Interpretation of enantioresolution in nordeoxycholic acid channels based on the four‐location model
Authors: Kato Kazuaki , Aoki Yuriko , Sugahara Michihiro , Tohnai Norimitsu , Sada Kazuki , Miyata Mikiji
Published: December 2002

Nordeoxycholic acid (NDCA) forms three kinds of host frameworks, M1, M2, and M3, with channels where aliphatic alcohols (1–7) are accommodated. 13C‐NMR studies clarified that racemic alcohols 1‐ or 2–6 are enclosed in the M1‐ or M2‐type channel with lower than 15% enantiomeric excess, respectively, while 3‐methyl‐2‐pentanol (7) is done in the M3‐type with 47% ee. These inclusion phenomena can be explained due to the Difference Fourier maps of electron densities of their enantiomers in the channels. In addition, analysis of the manner of packing indicates that four locations in the channels should be fixed for the enantioresolution of the alcohols. These results support the four‐location model, which has been proposed by Mesecar et al.20 with respect to enantioresolution on protein surfaces. Chirality 15:53–59, 2003. © 2002 Wiley‐Liss, Inc.
Stereospecific substitution at α‐carbon to trifluoromethyl group: Application to optically active fluorinated amino acid syntheses
Authors: Katagiri Toshimasa , Uneyama Kenji
Published: December 2002

This account summarizes how we performed the intramolecular nucleophilic substitutions of the hydroxy groups at α‐position to trifluoromethyl group. The origin of the steric hindrance of the trifluoromethyl group was found to be the electrostatic repulsive force between the nucleophile and the negatively charged fluorine atoms. Chirality 15:4–9, 2003. © 2002 Wiley‐Liss, Inc.
Practical asymmetric Mukaiyama‐Michael reaction of benzalacetone derivatives catalyzed by allo‐threonine‐derived oxazaborolidinone
Authors: Wang Xiaowei , Harada Toshiro , Iwai Hiroyoshi , Oku Akira
Published: December 2002

In the presence of 2,6‐diisopropylphenol and t‐BuOMe (1 equiv. each), asymmetric Mukaiyama‐Michael reaction of a variety of benzalacetone derivatives 2 with silyl ketene acetal 3 is efficiently catalyzed by O‐(2‐naphthoyl)‐N‐tosyl‐(L)‐allo‐threonine‐derived B‐phenyloxazaborolidinone 1 (10 mol%) to give the corresponding adducts 5 in 60–90% ee. Chirality 15:28–30, 2003. © 2002 Wiley‐Liss, Inc.
Molecular design of DABNTf as a highly efficient resolving reagent for racemic Pd complex with Tropos biphenylphosphine (BIPHEP) ligand: Circular dichroism (CD) spectra of enantiopure BIPHEP‐Pd complex
Authors: Mikami Koichi , Yusa Yukinori , Aikawa Kohsuke , Hatano Manabu
Published: December 2002

The racemic Pd complexes with chirally flexible (tropos) biphenylphosphine (BIPHEP) ligands can be resolved but transformed into the enantio‐ and diastereo‐pure complex. The enantiopure metal complex of BIPHEP ligand is thus obtained through enantiomer‐selective complexation of a racemic BIPHEP‐Pd complex with enantiopure 1,1′‐binaphthyl‐2,2′‐di(triflyl)amide, DABNTf. The differential CD spectra of the enantiopure BIPHEP‐Pd complex is also reported. Chirality 15:105–107, 2003. © 2002 Wiley‐Liss, Inc.
Catalytic enantioselective allylation of ketones with novel chiral bis‐titanium(IV) catalyst
Authors: Kii Satoshi , Maruoka Keiji
Published: December 2002

Our recently designed chiral bis‐titanium(IV) catalyst can be successfully utilized for the catalytic enantioselective allylation of ketones with tetraallyltin. The high asymmetric induction is achievable in the case of aromatic ketones. Chirality 15:68–70, 2003. © 2002 Wiley‐Liss, Inc.
Synthesis of new chiral bis(isoxazoline) ligands containing spiro[5.5]undecane skeleton
Authors: Arai Midori A. , Kuraishi Minori , Arai Takayoshi , Sasai Hiroaki
Published: December 2002

New chiral bis(isoxazoline) ligands bearing a spiro[5.5]undecane skeleton were designed and synthesized in five steps from diethyl malonate (3). These ligands showed a coordinating ability to Cu(II) as chiral ligands. A complex of (+)‐(M*,S*,R*)‐[5.5]‐SPRIX 2b and Cu(OTf)2 catalyzed the conjugate addition of diethyl‐zinc to 2‐cyclohexenone (8) to give (S)‐3‐ethyl‐cyclohexanone (9) in 93% yield with 54% ee. Chirality 15:101–104, 2003. © 2002 Wiley‐Liss, Inc.
Enantioselective electrochemical oxidation of enol acetates using a chiral supporting electrolyte
Authors: Maekawa Hirofumi , Itoh Kotaro , Goda Satoshi , Nishiguchi Ikuzo
Published: December 2002

Anodic oxidation of 1‐acetoxy‐3,4‐dihydronaphthalene (1) and α‐acetoxy‐β‐alkylstyrenes (3) at –78°C in a mixed solvent of acetonitrile (CH3CN), tetrahydrofuran (THF), and acetic acid (AcOH) containing (S)‐tetraethylammonium camphorsulfonate as a chiral supporting electrolyte brought about enantioselective formation of the corresponding 2‐acetoxy‐1‐tetralones (2) and (R)‐2‐acetoxy‐1‐phenyl‐1‐alkanone (4) with maximum enantiomeric excess (ee) of 44% and 21%, respectively. Introduction of a 7‐methoxy group into 1 and increase in bulkiness of a β‐alkyl group in 3 resulted in improvement of enantioselectivity of the reactions. Chirality 15:95–100, 2003. © 2002 Wiley‐Liss, Inc.
Remote chirality transfer in nucleophilic catalysis with N‐(4‐pyridinyl)‐L‐proline derivatives
Authors: Kawabata Takeo , Stragies Roland , Fukaya Takayuki , Fuji Kaoru
Published: December 2002

Chiral nucleophilic catalysts 5–15 were prepared starting from L‐proline. Catalysts 9 and 14 promoted acylative kinetic resolution of racemic amino alcohol derivative 16 with selectivity factors of 8.1 and 11, respectively, at ambient temperature. Since chiral elements are not present in the catalytically active pyridine ring in these catalysts, chirality transfer from the remote stereogenic center to the reactive site (N‐acylpyridinium) is suggested to be responsible for the differentiation between enantiomers. Chirality 15:71–76, 2003. © 2002 Wiley‐Liss, Inc.
Asymmetric catalysis with self‐organized chiral lanthanum complexes: Practical and highly enantioselective epoxidation of α,β‐unsaturated ketones
Authors: Daikai Kazuhiro , Hayano Tetsuji , Kino Rie , Furuno Hiroshi , Kagawa Takumi , Inanaga Junji
Published: December 2002

A highly efficient and practical method for obtaining α,β‐epoxy ketones with high optical purities was developed. The chiral lanthanum complex self‐organized in situ from lanthanum triisopropoxide, (R)‐BINOL, triarylphosphine oxide, and alkyl hydroperoxide (1:1:1:1) was found to catalyze the epoxidation of α,β‐unsaturated ketones with tert‐butyl hydroperoxide or cumene hydroperoxide at room temperature to give the corresponding epoxy ketones in high enantioselectivities (up to >99% enantiomeric excess (ee)). A remarkably high asymmetric amplification, a positive nonlinear effect, was observed in the epoxidation of chalcone, which strongly suggests the formation of a dinuclear peroxide‐involved μ‐complex as the active catalyst. Chirality 15:83–88, 2003. © 2002 Wiley‐Liss, Inc.
Kinetically controlled optical resolution of racemic norbornene aldehyde derivatives
Authors: Fujioka Hiromichi , Kotoku Naoyuki , Fujita Tetsuya , Inoguchi Ryoko , Murai Kenichi , Nagatomi Yasushi , Sawama Yoshinari , Kita Yasuyuki
Published: December 2002

A new method for obtaining optically pure 5‐norbornene 2‐endo‐aldehyde derivatives was developed. The reaction of a diastereomeric mixture of the ene acetals 2 and 2′, derived from racemic norbornene aldehydes (±)‐1 and chiral nonracemic (S,S)‐hydrobenzoin 7, with NBS (0.5–0.6 eq.) in the presence of H2O proceeded in a kinetically controlled manner to give the optically pure hydroxy aldehydes 3 along with the intact ene acetals 2′. Both compounds 3 and 2′ were converted into the optically pure norbornene aldehydes 1 and ent‐1, respectively. This method opens the way to produce various types of 5‐norbornene 2‐endo‐aldehydes with 3‐exo‐ or 3‐endo‐substituents in optically pure forms. Chirality 15:60–67, 2003. © 2002 Wiley‐Liss, Inc.
Preparation of chiral stationary phase for HPLC based on immobilization of cellulose 3,5‐dimethylphenylcarbamate derivatives on silica gel
Authors: Kubota Takateru , Yamamoto Chiyo , Okamoto Yoshio
Published: December 2002

The immobilization of cellulose 3,5‐dimethylphenylcarbamate derivatives having a polymerizable vinyl group, i.e., 4‐vinylphenylcarbamate or 2‐methacyloyloxyethylcarbamate, on silica gel was examined under various conditions. The immobilization was basically conducted through the radical copolymerization of the derivatives with a vinyl monomer. Several factors, such as the vinyl monomer content and the type and amount of the vinyl group of cellulose derivatives, were varied. The introduction of a vinyl group onto the silica surface resulted in a more efficient immobilization of the cellulose phenylcarbamate derivatives on the silica gel. As the content of the vinyl group on the cellulose derivatives was reduced, the immobilization became more difficult, although the obtained phase exhibited higher chiral recognition abilities. These immobilized CSPs could be stably used with the eluent containing 10% chloroform, which cannot be used for the phase prepared by coating the derivatives on silica gel. Some racemates were better resolved on the immobilized CSP by using chloroform as a component of the eluent. Chirality 15:77–82, 2003. © 2002 Wiley‐Liss, Inc.
Stereospecific synthesis of aldoses based on the epoxide‐opening reaction with double inversion of the configuration
Authors: Hirai Atsushi , Tonooka Terumichi , Tanino Keiji , Miyashita Masaaki
Published: December 2002

A new synthetic methodology for aldoses and aldonitols was developed in which two stereospecific epoxide‐opening reactions with double inversion of the configuration, i.e., the ring‐opening reaction of epoxy sulfides with phenylboronic acid and the stereospecific interconversion of trans‐ and cis‐epoxy sulfides, were designed as the key steps. The synthetic potential of the new methodology was exemplified by the highly stereoselective synthesis of two pentose‐derived sugars, arabitol and adonitol (ribitol). Chirality 15:108–109, 2003. © 2002 Wiley‐Liss, Inc.
Sequelae of axillary lymph node dissection in older women with stage 1 and 2 breast carcinoma
Authors: Mandelblatt Jeanne S. , Edge Stephen B. , Meropol Neal J. , Senie Ruby , Tsangaris Theodore , Grey Luther , Peterson Burt , Hwang Yi‐Ting , Weeks Jane C.
Published: December 2002

BACKGROUND

There are few data on the long‐term sequelae of axillary dissection among older breast carcinoma patients. We describe the impact of axillary dissection in a cohort of older women.

METHODS

A longitudinal cohort of 571 patients with Stage 1 and 2 breast carcinoma, 67 years and older, diagnosed between 1995 and 1997 from 29 hospitals in five regions, and followed for 2 years. Data were collected from patients and medical charts. The primary outcome was posttreatment quality of life. Generalized estimation equation longitudinal modeling was used to evaluate the outcome, controlling for baseline function, comorbidity, age, clinical status, and other factors.

RESULTS

Sixty percent of women reported arm problems at some time in the 2 years after surgery. The cumulative risk of having arm problems 2 years posttreatment was three times higher (95% confidence interval 1.94–4.67) for women who underwent axillary surgery compared with women without axillary surgery, controlling for covariates. The effects of having axillary dissection and arthritis were multiplicative 2 years postsurgery. Arm problems were, in turn, the primary determinate of lower physical and mental functioning (P = 0.0001 and 0.04, respectively), controlling for other factors. Undergoing axillary dissection did not lessen fears about recurrence.

CONCLUSIONS

Arm problems after axillary dissection have a consistent negative impact on quality of life, suggesting that the risks may outweigh the potential benefits in this population. Cancer 2002;95:2445–54. © 2002 American Cancer Society.

DOI 10.1002/cncr.10983
Relation of regimens of combined hormone replacement therapy to lobular, ductal, and other histologic types of breast carcinoma
Authors: Daling Janet R. , Malone Kathleen E. , Doody David R. , Voigt Lynda F. , Bernstein Leslie , Coates Ralph J. , Marchbanks Polly A. , Norman Sandra A. , Weiss Linda K. , Ursin Giske , Berlin Jesse A. , Burkman Ronald T. , Deapen Dennis , Folger Suzanne G. , McDonald Jill A. , Simon Michael S. , Strom Brian L. , Wingo Phyllis A. , Spirtas Robert
Published: December 2002

BACKGROUND

The incidence of invasive lobular carcinoma has been increasing among postmenopausal women in some parts of the United States. Part of this may be due to changes in classification over time. However, the use of combined (estrogen and progestin) hormone replacement therapy (CHRT) also has increased during the last decade and may account in part for the increase in invasive lobular breast carcinoma.

METHODS

A large, multicenter case–control study of Caucasian and African‐American women who were diagnosed at age < 65 years with their first invasive breast tumor from July 1, 1994 through April 30, 1998 was conducted. In‐person interviews were conducted with 1749 postmenopausal patients, and their responses were compared with the responses of 1953 postmenopausal control women identified through random‐digit dialing who met the study criteria of being postmenopausal at the time of diagnosis. Polytomous logistic regression was used to calculate the odds ratio (OR) as an estimate of the relative risk and to compute the 95% confidence interval (95%CI) associated with the use of various regimens of hormone replacement therapy (HRT) among women diagnosed with ductal breast carcinoma, lobular (or mixed lobular and ductal) breast carcinoma, and a grouping of other histologic types of breast carcinoma.

RESULTS

Ever use of unopposed estrogen therapy (ERT) was not associated with an increase in the risk of any histologic type of breast carcinoma. The risk of invasive lobular breast carcinoma and the risk of breast carcinoma of the grouping of other histologies increased among women currently using CHRT (OR, 2.2; 95%CI, 1.4–3.3; and OR, 1.9; 95%CI, 1.0–3.4, respectively). The risk increase was greater for the mixed lobular‐ductal type than for the pure lobular type of breast carcinoma, although the difference was not statistically significant. There was some indication that ≥ 5 years of continuous CHRT (≥ 25 days per month of progestin) was associated with a higher risk of lobular breast carcinoma (OR, 2.5; 95%CI, 1.4–4.3) compared with sequential CHRT (< 25 days per month of progestin; OR, 1.5; 95%CI, 0.8–2.6). Current use of continuous CHRT was only moderately associated with risk of ductal breast carcinoma.

CONCLUSIONS

Postmenopausal women who take CHRT appear to be at an increased risk of lobular breast carcinoma. Data from this study suggest that neither ERT use nor CHRT substantially increase the risk of ductal breast carcinoma among women age < 65 years. Cancer 2002;95:2455–64. Published 2002 by the American Cancer Society.

DOI 10.1002/cncr.10984
Advanced age and adjuvant tamoxifen prescription in early‐stage breast carcinoma patients
Authors: Blackman Sarah B. , Lash Timothy L. , Fink Aliza K. , Ganz Patricia A. , Silliman Rebecca A.
Published: December 2002

BACKGROUND

Adjuvant tamoxifen is recommended for all women with estrogen receptor‐positive breast carcinoma without regard for age. We investigated age‐dependent variations in adjuvant tamoxifen prescription patterns in a cohort of women 80 years of age and older.

METHODS

We studied 92 women diagnosed at four U.S. sites with primary, early‐stage breast carcinoma. Each woman consented to a medical record review and participated in two telephone interviews. We compared the proportion of tamoxifen prescriptions received by women 85–92 years of age with those received by women 80–84 years of age. Relative risks (RR) and 95% confidence intervals (95% CI) were generated using generalized estimating equations. Confounding by demographic, disease, and treatment characteristics was assessed.

RESULTS

Before adjustment, patients 85–92 years of age were 28% less likely to receive a tamoxifen prescription compared with patients 80–84 years of age (RR = 0.72, 95% CI 0.57–0.91). In this sample, patients not prescribed tamoxifen had substantially more comorbidity. After adjusting the crude finding for comorbidity, the RR was 0.74 (95% CI 0.58–0.93). In addition, the oldest patients and those not prescribed tamoxifen were significantly less likely to be married or have living children. After adjusting the crude finding for these two factors, the RR was 0.75 (95% CI 0.59–0.95). There was no confounding by the other demographic, disease, or treatment covariates assessed.

CONCLUSION

Given the increasing longevity of the oldest old, undertreatment with adjuvant tamoxifen may put older breast carcinoma patients at an increased risk of disease recurrence and breast carcinoma mortality. Cancer 2002;95:2465–72. © 2002 American Cancer Society.

DOI 10.1002/cncr.10985
A survival–stratification model of human colorectal carcinomas with β‐catenin and p27kip1
Authors: Cheah Peh Yean , Choo Poh Heok , Yao Jocelyn , Eu Kong Weng , Seow‐Choen Francis
Published: December 2002

BACKGROUND

The stabilization and nuclear translocation of β‐catenin are early events in the majority of sporadic colorectal carcinomas (CRC). β‐catenin up‐regulates c‐Myc and cyclin D1, which antagonize the association of the cyclin‐dependent kinase (Cdk) inhibitor, p27kip1, with Cdk2, thus allowing cell cycle progression through G1 to S‐phase. Lack of p27 is a significant predictor of poor survival in a series of 136 CRC specimens. A combination of molecules in the same pathway may be a better prognostic factor.

METHODS

The expression of β‐catenin, c‐Myc, and cyclin D1 in relation to patients' survival and clinicopathologic parameters in the same series was evaluated by immunohistochemistry.

RESULTS

Intense nuclear overexpression of β‐catenin, but not a lack of cell membrane or cytoplasmic expression, is a significant predictor of poor survival by both univariate (P = 0.0029) and multivariate analyses (P = 0.004, risk ratio =3.8), suggesting that β‐catenin is retained in the nucleus to function as an oncogene. None of the patients with high nuclear β‐catenin and low p27 expression survived 5 years or more whereas 65% of patients with all other combinations of the two markers survived (P < 0.0001). This combination is also a significant and independent prognostic factor (P = 0.001; risk ratio = 9.7). Overexpression of c‐Myc is associated with higher mortality rates, but the expression of cyclin D1 has no prognostic significance.

CONCLUSIONS

The combined expression of β‐catenin and p27 can stratify patients into markedly different survival groups, possibly via their antagonistic effects on metastasis promotion. Cancer 2002;95:2479–86. © 2002 American Cancer Society.

DOI 10.1002/cncr.10986
Decreased expression of DFF45/ICAD is correlated with a poor prognosis in patients with esophageal carcinoma
Authors: Konishi Shigeru , Ishiguro Hideyuki , Shibata Yasuyuki , Kudo Junzo , Terashita Yukio , Sugiura Hironori , Koyama Hiroshi , Kimura Masahiro , Sato Atsushi , Shinoda Noriyuki , Kuwabara Yoshiyuki , Fujii Yoshitaka
Published: December 2002

BACKGROUND

DNA fragmentation factor 45 (DFF45)/inhibotor of caspase activated DNAse (ICAD) forms a complex with DFF40/CAD and inhibits its DNA cleaving function during apoptosis. DFF45 also functions as a chaperone for native DFF40 and is necessary for its function. It has been indicated that defects in the apoptotic pathway may exist in neoplastic cells.

METHODS

The authors investigated mRNA expression of DFF45 in a series of 46 esophageal squamous cell carcinoma (ESCC) specimens using polymerase chain reaction amplification. The results were correlated with the patients' clinicopathologic characteristics.

RESULTS

DFF45 mRNA expression was significantly lower in tumors with higher pathologic stage, higher tumor status (T status), lymph node metastasis, or more extensive lymphatic invasion. Patients who had low DFF45 mRNA expression (indicated by the ratio of DFF45 mRNA expression in tumor to DFF45 mRNA expression in normal esophageal mucosa [tumor:normal] < 1) had a significantly shorter survival after undergoing surgery compared with patients who had high DFF45 mRNA expression (tumor:normal > 1, P = 0.0006; log‐rank test, P = 0.0003; median follow‐up, 14.6 months).

CONCLUSIONS

Patients with ESCC with decreased DFF45 mRNA expression levels had a poor prognosis compared with patients who had high DFF45 mRNA expression levels. Cancer 2002;95:2473–8. © 2002 American Cancer Society.

DOI 10.1002/cncr.10987
Telomerase reverse transcriptase subunit immunoreactivity
Authors: Iczkowski Kenneth A. , Pantazis Cooley G. , McGregor Douglas H. , Wu Yaping , Tawfik Ossama W.
Published: December 2002

BACKGROUND

Telomerase, a ribonucleoprotein complex that maintains telomeric DNA, has been detected in 67–93% of prostate carcinomas by telomeric repeat‐amplification protocol assay (involving polymerase chain reaction). One study used in situ hybridization in nine patients; however, to date, no immunohistochemical results have been published.

METHODS

From two hospitals, the authors compiled data on 62 patients who underwent prostatectomy from January 1996 to May 2001. Representative tissue sections were immunostained with a polyclonal antibody to telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase. Staining was evaluated by two observers and was correlated with grade, stage, and biochemical failure. There were 28 sections from low‐grade to intermediate‐grade tumors (Gleason score, 3–6), 14 sections with a Gleason score of 3 + 4 = 7, 9 sections with a Gleason score of 4 + 3 = 7, and 11 sections from high‐grade tumors (Gleason score, 8–10).

RESULTS

From low‐grade to high‐grade tumors, the four groups described above disclosed nuclear reactivity in 64%, 100%, 100%, and 100% of sections, respectively. Mean percentages of 5%, 15%, 40%, and 51% of nuclei were reactive in the respective groups (P < 0.0001) with intratumoral heterogeneity. The percent of reactive tumor nuclei was not correlated with pathologic stage (P = 0.32) or margin status (P = 0.35). The basal cell layer in sections of high‐grade prostatic intraepithelial neoplasia (HGPIN) and benign/atrophic acini was reactive; secretory cells were reactive in 13 of 34 HGPIN foci (38%) in 1–20% of nuclei and were never reactive in benign acini. Lymphocytes and skeletal muscle were reactive. Weak, nonspecific, cytoplasmic staining was noted in benign and tumor acini.

CONCLUSIONS

Like cytokeratin 34βE12, nuclear anti‐TERT reactivity is a basal cell marker in nonneoplastic prostatic acini. Anti‐TERT reactivity is acquired by secretory cells in tumorigenesis, but consistent reactivity is restricted to high‐grade carcinoma (Gleason primary pattern ≥4). This histologic evidence suggests that higher grade tumors have maximally activated telomerase and may be most responsive to antitelomerase therapy. Cancer 2002;95:2487–93. © 2002 American Cancer Society.

DOI 10.1002/cncr.10988
Urinary levels of urokinase‐type plasminogen activator and its receptor in the detection of bladder carcinoma
Authors: Casella Roberto , Shariat Shahrokh F. , Monoski Mara A. , Lerner Seth P.
Published: December 2002

BACKGROUND

The authors found previously that plasma levels of urokinase‐type plasminogen activator (uPA) and its receptor (uPAR) were elevated in patients with bladder carcinoma and were associated with features of biologically aggressive disease. In the current study, they tested the hypothesis that elevated urinary levels of uPA and uPAR would predict the presence of bladder malignancy by comparing the performance of uPA and uPAR with the performance of bladder wash‐out cytology in the noninvasive diagnosis of bladder tumors.

METHODS

An enzyme‐linked immunosorbent assay was used to compare levels of uPA and uPAR in urine that was collected before cystoscopy from 122 patients with bladder carcinoma and from 107 participants in a control group. Seventy‐two patients had clinical Tis or Ta transitional cell carcinoma, and 50 patients had invasive disease (≥ T1); 85 patients had clinical Grade 1–2 tumors, and 37 patients had Grade 3 tumors. For cytology, only high grade was considered positive.

RESULTS

Urinary levels of uPA and uPAR were higher in patients with bladder carcinoma compared with levels in the control group (P < 0.001 and P = 0.016, respectively). However, only uPA levels were elevated in patients with abnormal urinary cytology (P = 0.006). After controlling for cytology (odds ratio [OR], 10.182; 95% confidence interval [95%CI], 4.451–23.291; P < 0.001), uPAR (P for trend = 0.168), and age (P = 0.091), those in the highest quartile for uPA had an increased risk of bladder carcinoma compared with those in the lowest quartile (OR, 3.022; 95%CI, 1.295–7.054; P for trend = 0.031).

CONCLUSIONS

The current findings suggest that urinary levels of uPA, but not uPAR, are related to the risk of bladder carcinoma. The study confirmed the central role of urinary cytology in the noninvasive diagnosis of bladder carcinoma. Cancer 2002;95:2494–9. © 2002 American Cancer Society.

DOI 10.1002/cncr.10989
Elevated focal adhesion kinase expression facilitates oral tumor cell invasion
Authors: Schneider Galen B. , Kurago Zoya , Zaharias Rebecca , Gruman Lynn M. , Schaller Michael D. , Hendrix Mary J. C.
Published: December 2002

BACKGROUND

Understanding the molecular mechanisms of metastasis is critical with respect to oral tumorigenesis. The focal adhesion kinase (FAK) is an intracellular tyrosine kinase associated with the regulation of cell growth, migration, and survival. The purpose of the current study was to determine whether elevated FAK expression in oral malignancies was associated with increased invasiveness and oral carcinoma.

METHODS

Immunohistochemical analysis was used to assess levels of FAK expression in archived oral carcinoma tissue samples. Invasion assays after transfections were used to assess the effect of increased FAK expression on invasive potential of oral tumor cells.

RESULTS

The human oral carcinoma cell line SCC25 was significantly more invasive (P < 0.05) and expressed higher levels of FAK compared with the less invasive human oral carcinoma cell line SCC15. FAK expression was 3.0‐fold higher in the SCC15 cell line and 5.0‐fold higher in the SCC25 cell line compared with normal epithelial cells. In the highly invasive SCC25 cell line, FAK expression was 1.5‐fold higher compared with the less invasive SCC15 cell line. FAK immunostaining in oral tumors was significantly more intense compared with the immunostaining in surrounding normal epithelium or chronic mucositis. Overexpression of FAK in low‐invading SCC15 cells resulted in a 4.5‐fold increase in the rate of invasion compared with untransfected or neotransfected control SCC15 cell lines and a nearly 1.5‐fold greater rate compared with the highly invasive untransfected SCC25 cell line.

CONCLUSIONS

The current results suggest that enhanced expression of FAK in oral carcinoma cells may lead to a selective growth advantage and increased invasive potential of the primary oral tumor. Cancer 2002;95:2508–15. © 2002 American Cancer Society.

DOI 10.1002/cncr.10992
Which dimensions of health‐related quality of life are altered in patients attending the different gynecologic oncology health care settings?
Authors: Capelli Giovanni , De Vincenzo Rosa I. , Addamo Alice , Bartolozzi Francesco , Braggio Nicola , Scambia Giovanni
Published: December 2002

BACKGROUND

We evaluated the feasibility of measuring health‐related quality of life (HRQOL) in a gynecologic oncology clinic by using an instrument that is nonspecific for cancer patients. Our aim was to study whether the HRQOL perception of cancer patients differed from general population norms for the same age and gender and if it varied across cancer type, cancer status, age, health care setting, and reason for the encounter.

METHODS

Participants in this study included 115 women between the ages of 21 and 83 years who were referred to a university hospital for ovarian, endometrial, and cervical carcinoma. They completed the SF‐36 questionnaire. Mean results for the entire sample, for different disease status (primary vs. progressive/recurrent disease), and reason for encounter (surgery, preoperative, postoperative, palliative chemotherapy, and follow‐up) were compared with age‐specific expected mean values for each SF‐36 scale, based on published Italian reference values for the healthy population.

RESULTS

Patients' attitude to the questionnaire was generally good. Mean values on the SF‐36 scales varied. Role (Physical and Emotional) scales showed the highest differences from the expected age‐specific values in all situations. Patients with primary disease showed little or no differences for the other six scales from the expected values, whereas a significant 10‐point mean decrease in every SF‐36 scale was recorded for patients with progressive/recurrent disease. A biologic interaction among cervical carcinoma, age, and disease status was found in multivariate models, showing worst scores for patients with progressive/recurrent cervical carcinoma on almost all scales.

CONCLUSIONS

Administration of generic HRQOL questionnaires in specialist health care delivery settings is feasible and well accepted and may help physicians and nurses to look beyond “what's wrong” in their patients. Cancer 2002;95:2500–7. © 2002 American Cancer Society.

DOI 10.1002/cncr.10993
Chemotherapy with gemcitabine‐containing regimens for locally recurrent or metastatic nasopharyngeal carcinoma
Authors: Ma Brigette B. Y. , Tannock Ian F. , Pond Gregory R. , Edmonds Matthew R. , Siu Lillian L.
Published: December 2002

BACKGROUND

Results from Phase II trials conducted in Asia have shown that gemcitabine alone (GEM) or with cisplatin (GC) is active among patients with metastatic or locally recurrent nasopharyngeal carcinoma (NPC).

METHODS

At the Princess Margaret Hospital (PMH), Toronto, 32 patients with NPC were treated with GEM (n = 18) or GC (n = 14) from January 2000 to October 2001. Patients either received 1000 mg/m2 GEM on Days 1, 8, and 15 every 28 days as a single agent, or with cisplatin (CG) given on day 2 at 70 mg/m2.

RESULTS

Most patients (91%) were of Southeast Asian ancestry and 29 (91%) had Type 2 (World Health Organization 1991 classification) nonkeratinizing histology. Sixteen of the GEM (89%) and five (36%) of the GC patients had received chemotherapy before entering the study. Median follow‐up was 32 weeks (range, 2–97 weeks) for both groups. In the GEM group, there were five (28%) partial responses (PR) and one (6%) complete response (CR), giving an overall response rate of 34% (95% confidence interval [CI], 13.59). In the GC group, there were two (14%) CRs and seven PRs (50%), giving an overall response of 64% (95% CI, 35–87). Hematologic toxicity was dose limiting but uncomplicated. Nonhematologic toxicity included one patient with reversible reactivation of hepatitis, one with Grade 3 cisplatin‐related sensory neuropathy, and three with cardiovascular events that were possibly related to chemotherapy. The median duration of response for the GEM and GC patients was 17 and 24 weeks and the 1‐year survival rate was 48% (95% CI, 18–78) and 69% (95% CI, 40–99), respectively. Median survival has not been reached.

CONCLUSIONS

Our study confirms that GEM is an active and tolerable drug for patients with NPC. Cancer 2002;95:2516–23. © 2002 American Cancer Society.

DOI 10.1002/cncr.10995
Loss of adhesion‐regulated proteinase production is correlated with invasive activity in oral squamous cell carcinoma
Authors: Ghosh Supurna , Munshi Hidayatullah. G. , Sen Ratna , Linz‐McGillem Laura A. , Goldman Robert D. , Lorch Jochen , Green Kathleen J. , Jones Jonathan C. R. , Stack M. Sharon
Published: December 2002

BACKGROUND

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. However, the cellular and biochemical factors that underlie locoregional and distant spread of the disease are poorly understood. Invasion of OSCC requires multiple cellular events including dissolution of cell‐cell junctions, basement membrane attachment, extracellular matrix proteolysis, and migration.

METHODS

We evaluated these properties in vitro using premalignant gingival keratinocytes (ppl26) and two OSCC lines (SCC15 and SCC68). Expression of adhesion molecules integrins and cadherins, cytoplasmic intermediate filaments (IF) vimentin and keratin as well as matrix degrading proteins were evaluated. Moreover, regulation of protease production by adhesion molecules was tested.

RESULTS

All cell lines contained comparable levels of the epithelial cell‐cell adhesion molecule, E‐cadherin. Differential expression of cytoplasmic IF was evident between premalignant pp126 cells and OSCC cell lines. Expression levels of the α3β1 integrin, utilized for attachment to laminin‐5 and other matrix proteins, was high in SCC68 cells, moderate in SCC15 cells, and low in ppl26 cells. α3β1 integrin clustering up‐regulates expression of urinary‐type plasminogen activator (uPA) in ppl26 cells via a mechanism involving ERK activation. Both ppl26 and SCC15 cells were responsive to α3β1 clustering, resulting in enhanced uPA expression. However, basal uPA levels were high in SCC68 cells and integrin clustering did not further stimulate uPA production. ERK was constitutively activated in SCC68 cells and treatment of cells with an inhibitor of ERK activation (PD98059) reduced uPA expression. Consistent with the enhanced proteolytic potential, SCC68 cells readily penetrated Matrigel and invasion was blocked by an anticatalytic uPA antibody.

CONCLUSIONS

These data suggest that loss of adhesion‐regulated proteinase production may lead to elevated pericellular proteinase activity and coincident alterations in cytoskeletal IF protein expression, thereby contributing to the invasive potential of OSCC. Cancer 2002;95:2524–33. © 2002 American Cancer Society.

DOI 10.1002/cncr.10997
An elevated serum beta‐2‐microglobulin level is an adverse prognostic factor for overall survival in patients with early‐stage Hodgkin disease
Authors: Chronowski Gregory M. , Wilder Richard B. , Tucker Susan L. , Ha Chul S. , Sarris Andreas H. , Hagemeister Fredrick B. , Barista Ibrahim , Hess Mark A. , Cabanillas Fernando , Cox James D.
Published: December 2002

BACKGROUND

The relative importance of prognostic factors in patients with early‐stage Hodgkin disease remains controversial. The purpose of this study was to evaluate prognostic factors among patients who received chemotherapy before radiotherapy.

METHODS

From 1987 to 1995, 217 consecutive patients ranging in age from 16 to 88 years (median, 28 years) with Ann Arbor Stage I (n = 55) or II (n = 162) Hodgkin disease underwent chemotherapy before radiotherapy at a single center. Most were treated on prospective studies. Patients received a median of three cycles of induction chemotherapy. Mitoxantrone, vincristine, vinblastine, and prednisone (NOVP), doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), cyclophosphamide, vinblastine, procarbazine, prednisone, doxorubicin, bleomycin, dacarbazine, and CCNU (CVPP/ABDIC), or other chemotherapeutic regimens were given to 160, 18, 15, 10, and 14 patients, respectively. The median radiotherapy dose was 40 Gy. Serum β‐2‐microglobulin (β‐2M) levels ranged from 1.0 to 4.1 mg/L (median, 1.7 mg/L; upper limit of normal, 2.0 mg/L). We studied univariate and multivariate associations between survival and the following clinical features: serum β‐2M level above 1.25 times the upper limit of normal (n = 12), male gender (n = 113), hypoalbuminemia (n = 11), and bulky mediastinal disease (n = 94).

RESULTS

Follow‐up of surviving patients ranged from 0.9 to 13.4 years (median, 6.6 years) and 92% were observed for 3.0 or more years. Nineteen patients have died. Only elevation of the serum β‐2M level was an independent adverse prognostic factor for overall survival (P = 0.0009).

CONCLUSIONS

The prognostic significance of a simple, widely available, and inexpensive blood test, β‐2M, has not been studied routinely in patients with Hodgkin disease and should be tested prospectively in large, cooperative group trials. Cancer 2002;95:2534–8. © 2002 American Cancer Society.

DOI 10.1002/cncr.10998
Long‐term cognitive outcome, brain computed tomography scan, and magnetic resonance imaging in children cured for acute lymphoblastic leukemia
Authors: Iuvone Laura , Mariotti Paolo , Colosimo Cesare , Guzzetta Francesco , Ruggiero Antonio , Riccardi Riccardo
Published: December 2002

BACKGROUND

Prevention of meningeal recurrence achieved by intrathecal methotrexate (MTX) and systemic chemotherapy is part of standard acute lymphoblastic leukemia (ALL) treatment. Cranial irradiation has been a routine part of past protocol treatment but is currently reserved only for select subsets of patients. Central nervous system (CNS) prophylaxis may cause brain abnormalities such as intracerebral calcifications, cerebral atrophy, and white matter alterations. In addition, long‐term neuropsychologic sequelae following CNS prophylaxis have been investigated marginally in children cured for ALL.

METHODS

To explore possible correlations between neuroimaging findings and neuropsychologic outcome, we used detailed cognitive tests to evaluate 21 children with ALL who received cranial irradiation (range, 18–24 Gy) plus intrathecal MTX as CNS prophylaxis. All children were followed prospectively once a year by cerebral computed tomographic scan and magnetic resonance imaging. All patients had continuous complete disease remission for at least 4 years and cognitive tests were performed after neuroradiologic examinations.

RESULTS

White matter abnormalities were associated with poor performance only in a task exploring visual motor integration in about 50% of patients. Intracerebral calcifications correlate with the number of intrathecal MTX doses and with low scores in total intellectual quotient, performance intellectual quotient, and significant impairment in attention and visual motor integration tests. Girls are more vulnerable to the effects of CNS prophylaxis, whereas age at treatment and radiotherapy dose are not relevant to neuropsychologic outcome.

CONCLUSIONS

Our results indicate the need for careful follow‐up of children's cognitive abilities because global intellectual measures often fail to detect specific disorders that may cause learning difficulties. Moreover, as the clinical implications of neuroimaging findings are often limited, periodic extensive evaluation by specific neurocognitive tests of mental abilities is recommended to detect early signs of cognitive impairment. Cancer 2002;95:2562–70. © 2002 American Cancer Society.

DOI 10.1002/cncr.10997
Serum insulin‐like growth factor I evaluation as a useful tool for predicting the risk of developing hepatocellular carcinoma in patients with hepatitis C virus‐related cirrhosis
Authors: Mazziotti Gherardo , Sorvillo Francesca , Morisco Filomena , Carbone Antonella , Rotondi Mario , Stornaiuolo Gianfranca , Precone Davide F. , Cioffi Michele , Gaeta Giovanni B. , Caporaso Nicola , Carella Carlo
Published: December 2002

BACKGROUND

Although experimental studies have demonstrated an important role of insulin‐like growth factor I (IGF‐I) in hepatocarcinogenesis, the clinical data about IGF‐I in patients with hepatocellular carcinoma (HCC) are scarce and controversial. To the authors' knowledge, this is the first prospective study investigating the longitudinal correlation between modifications in serum IGF‐I levels and the development of HCC in a cohort of patients with hepatitis C virus (HCV)‐related cirrhosis.

METHODS

One hundred fourteen consecutive patients with HCV‐related Child Grade A cirrhosis were followed prospectively at the Second University of Naples for 56.4 ± 12.0 months with ultrasound examinations of the liver and serum α‐fetoprotein determination every 6 months. At each clinical evaluation, the severity of disease was graded according to the established Child–Pugh scoring system. Serum IGF‐I levels were measured prospectively at the study entry and at least every 12 months throughout follow‐up.

RESULTS

Twenty patients (19.2%) developed HCC during follow‐up. Eleven of these patients had persistent Child Grade A cirrhosis for the whole study, whereas the other 9 patients developed HCC after their cirrhosis progressed from Child Grade A to Grade B. In patients who remained free of HCC for the whole study, serum IGF‐I concentrations did not modify significantly during follow‐up. Conversely, in patients who developed HCC, IGF‐I levels decreased significantly during follow‐up (from 72.6 ± 29.9 μg/L to 33.8 ± 14.5 μg/L; P = 0.001). In these patients, the significant decrease occurred both in patients with persistent Child Grade A cirrhosis and in patients with cirrhosis that progressed from Child Grade A to Grade B. The reduction in IGF‐I level preceded the diagnosis of HCC by 9.3 ± 3.1 months.

CONCLUSIONS

This prospective study demonstrates that, in patients with HCV‐related cirrhosis, 1) the development of HCC is accompanied by a significant reduction of serum IGF‐I levels independent of the grade of impairment of liver function; and 2) modification of the IGF‐I level precedes the morphologic appearance of HCC, permitting a precocious diagnosis of the tumor. Cancer 2002;95:2539–45. © 2002 American Cancer Society.

DOI 10.1002/cncr.11002
Modified scar grade
Authors: Maeshima Akiko M. , Niki Toshiro , Maeshima Arafumi , Yamada Tesshi , Kondo Haruhiko , Matsuno Yoshihiro
Published: December 2002

BACKGROUND

Several studies have shown the prognostic value of desmoplasia for lung adenocarcinomas. The authors evaluated the density and extent of desmoplasia by modifying the scar grade, as well as the prognostic impact on patient survival.

METHODS

Modified scar grade was defined as follows: Grade 1, no desmoplasia; Grade 2, sparse desmoplastic reaction; Grade 3, dense desmoplastic reaction with diameter of 10 mm or less; Grade 4, dense desmoplastic reaction with diameter exceeding 10 mm. In addition, the prognostic impact of conventional histologic factors and modified scar grade was analyzed in 239 cases of small peripheral lung adenocarcinoma (maximum dimension, ≤ 30 mm) for which long‐term follow‐up data were available.

RESULTS

The 5 and 10‐year survival rates according to the modified scar grade were 100% and 100% for Grade 1 lung adenocarcinoma (n = 29); 91.7% and 83.7% for Grade 2 (n = 61); 67.6% and 52.7% for Grade 3 (n = 78); and 50.0% and 37.5% for Grade 4 (n = 71), respectively. A significant difference in patient survival was found between Grade 1 or 2 versus Grade 3 or 4 (P < 0.0001, by log rank test). Multivariate analysis showed that modified scar grade was an independent prognostic factor (P = 0.0176), as were pathologic stage (P = 0.0293), lymph node metastasis (P = 0.0191), lymphatic permeation (P = 0.0022), and pleural involvement (P = 0.0452). Modified scar grade also had a significant impact on survival in various subsets of patients, including those with pathologic Stage IA disease, patients with tumors of diameter 20 mm or less, or patients with mixed subtype tumors with a bronchioloalveolar component.

CONCLUSIONS

Modified scar grade is a useful prognostic factor in patients with small lung adenocarcinomas. Tumors with a sparse fibroblastic reaction (modified scar Grade 2) may represent early invasive cancers or invasive cancers with low malignant potential, which should be distinguished from frankly invasive cancers (modified scar Grade 3 or 4). Cancer 2002;95:2546–54. © 2002 American Cancer Society.

DOI 10.1002/cncr.11006
p53 codon 72 polymorphism (C/G) and the risk of human papillomavirus‐associated carcinomas in China
Authors: Li Tao , Lu Zhe‐Ming , Guo Mei , Wu Qin‐Jiao , Chen Ke‐Neng , Xing Hai‐Ping , Mei Qiang , Ke Yang
Published: December 2002

BACKGROUND

Human papillomavirus (HPV) plays an important role in the development of carcinomas at various body sites. It was found previously that the p53 codon 72 polymorphism (C/G) is a high‐risk factor for the development HPV‐associated cervical carcinoma. However, it still was considered controversial in several studies of cervical and esophageal carcinoma.

METHODS

In the current study, the authors used an allele specific polymerase chain reaction (PCR) method to analyze correlation between the p53 codon 72 (C/G) polymorphism and HPV‐associated, noncancerous esophageal epithelium as well as esophageal, ovarian, and breast carcinoma in the Chinese population. Esophageal balloon cytology examination samples were obtained from high‐incidence and low‐incidence populations for esophageal carcinoma in Anyang (Henan Province).

RESULTS

Thirty‐six of 48 esophageal balloon samples from the high‐incidence population were HPV positive, and 13 of 33 esophageal balloon samples from the low‐incidence population were HPV positive. Thirty‐nine of 62 esophageal carcinoma samples from Anyang Tumor Hospital were HPV positive. Twenty‐six of 39 ovarian carcinoma samples from the Second Affiliated Hospital of Inner Mongolia Medical College were HPV positive. Nineteen of 82 breast carcinoma samples from Beijing Cancer Hospital were HPV positive. It is noteworthy that the distribution of the p53 codon 72 Arg homozygous genotype in HPV positive samples of esophageal epithelium, ovarian carcinoma, and breast carcinoma was significantly higher compared with HPV negative tumor samples. (P < 0.05).

CONCLUSIONS

The current results suggest that the p53 codon 72 Arg homozygous genotype is one of the high‐risk genetic factors for HPV‐associated malignancies among the Chinese population. Cancer 2002;95:2571–6. © 2002 American Cancer Society.

DOI 10.1002/cncr.11008