bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of patients with advanced or bulky Hodgkin disease with a 12‐week doxorubicin, bleomycin, vinblastine, and dacarbazine‐like chemotherapy regimen followed by extended‐field, full‐dose radiotherapy
Authors: Djeridane Malika , Oudard Stéphane , Escoffre‐Barbe Martine , Lacotte‐Thierry Laurence , Desablens Bernard , Briére Jean , Dib Mamoun , Cassasus Philippe , Ghandour Christiane , Lamy Thierry , Lejeune Françoise , Simon Marc , Traullé Catherine , Vigier Magda , Maisonneuve Henri , Briére Josette , Colonna Pierre , Andrieu Jean‐Marie
Published: November 2002

BACKGROUND

This Phase II study was performed in patients with advanced or bulky Hodgkin disease (HD) to evaluate the results of a 7‐drug chemotherapy (CT) regimen that was administered over 12 weeks according to 2 randomized modalities followed by high‐dose lymph node irradiation.

METHODS

From 1990 to 1996, 162 patients with HD at clinical stages (CS) I–III with bulky disease (mediastinal mass ratio ≥ 0.45 and/or unilateral or bilateral pelvic plus lumboaortic disease; 86 patients) or CS IV (76 patients) were randomized to receive the same cumulated dose of a CT regimen consisting of epirubicin (240 mg/m2), bleomycin (60 mg/m2), vinblastine (20 mg/m2), vincristine (4 mg/m2), cyclophosphamide (4000 mg/m2), etoposide (900 mg/m2), and methotrexate (180 mg/m2) plus methylprednisolone (1500 mg/m2) over 12 weeks either every 4 weeks (Arm Y, 79 patients) or every 3 weeks (Arm Z, 83 patients). Patients with disease in complete remission (CR) or partial remission after CT received extended‐field lymph node irradiation (involved areas, 40 grays [Gy]; noninvolved areas, 30 Gy).

RESULTS

Forty‐two percent of patients achieved a post‐CT CR, and 86% of patients achieved a CR after the completion of irradiation (there was no difference between Arm Y and Arm Z). Thirty‐five patients developed recurrent disease; most of those patients were in post‐CT partial remission. The 10‐year freedom from first progression rate was 63.9% (there was no difference between Arm Y and Arm Z). Thirty‐eight patients died: 24 patients from HD, 3 patients from CT‐related early sepsis, 1 patient from radiation‐induced pneumonitis, 6 patients from a second malignancy, and 4 patients from causes unrelated to treatment. The overall 10‐year survival rate was 76.7%. Survival was slightly higher among patients in Arm Y (83.3%) compared with patients in Arm Z (70.2%; P = 0.12).

CONCLUSIONS

No differences were found when the same amount of CT was delivered in three courses or in four courses. In 1997, because most recurrences of the H90‐A/B trial occurred in patients who achieved a post‐CT partial remission, the authors decided to reinforce the intensity of the initial CT and designed a new randomized study comparing two modalities of more intensive CT plus consolidative radiotherapy (H97‐LM trial). Cancer 2002;95:2169–79. © 2002 American Cancer Society.

DOI 10.1002/cncr.10932
Breast, cervical, and colorectal carcinoma screening in a demographically defined region of the southern U.S.
Authors: Coughlin Steven S. , Thompson Trevor D. , Seeff Laura , Richards Thomas , Stallings Fred
Published: November 2002

BACKGROUND

The “Southern Black Belt,” a term used for > 100 years to describe a subregion of the southern U.S., includes counties with high concentrations of African Americans and high levels of poverty and unemployment, and relatively high rates of preventable cancers.

METHODS

The authors analyzed data from a state‐based telephone survey of adults age ≥ 18 years to compare the cancer screening patterns of African‐American and white men and women in nonmetropolitan counties of this region, and to compare those rates with those of persons in other southern counties and elsewhere in the U.S. The primary study groups were comprised of 2165–5888 women and 1198 men in this region interviewed through the Behavioral Risk Factor Surveillance System. The respondents lived in predominantly rural counties in 11 southern states with sizeable African‐American populations (≥ 24.5% of county residents). The main outcome measures were recent use of the Papanicolau (Pap) test, mammography, test for fecal occult blood in the stool (FOBT), and flexible sigmoidoscopy or colonoscopy.

RESULTS

Between 1998–2000, 66.3% (95% confidence interval [95% CI] ± 2.7%) of 1817 African‐American women in the region age ≥ 40 years had received a mammogram within the past 2 years, compared with 69.3% (95% CI ± 1.8%) of 3922 white women (P = 0.066). The proportion of African‐American and white women who had received a Pap test within the past 3 years was similar (85.7% [95% CI ± 1.9%] vs. 83.4% [95% CI ± 1.5%]; P = 0.068]. In 1997 and 1999, 29.3% of African‐American women in these counties reported ever receiving an FOBT, compared with 36.9% in non‐Black Belt counties and 42.5% in the remainder of the U.S. Among white women, 37.7% in Black Belt counties, 44.0% in non‐Black Belt counties, and 45.3% in the remainder of the U.S. ever received an FOBT. Overall, similar patterns were noted among both men and women with regard to ever‐use of FOBT, flexible sigmoidoscopy, or colonoscopy. Screening rates appeared to vary less by race than by region.

CONCLUSIONS

The results of the current study underscore the need for continued efforts to ensure that adults in the nonmetropolitan South receive educational messages, outreach, and provider recommendations concerning the importance of routine cancer screening. Cancer 2002;95:2211–22. Published 2002 by the American Cancer Society.

DOI 10.1002/cncr.10933
Hepatic intraductal oncocytic papillary carcinoma
Authors: Martin Robert C. G. , Klimstra David S. , Schwartz Lawrence , Yilmaz Asli , Blumgart Leslie H. , Jarnagin William
Published: November 2002

BACKGROUND

There has been an increasing incidence and mortality from peripheral cholangiocarcinoma (PC) in the United States over the past 24 years. PC has been classified into two principal types, a mass‐forming type and a periductal‐infiltrating type, with a significant difference in the clinical behavior between the two. A third type, demonstrating a noninvasive intraductal growth of PC, was described as papillary PC. Rarely, papillary hepatic tumors composed of oncocytic cells have been described. Intraductal oncocytic papillary carcinomas (IOPCs) of the liver present as large, mucin‐filled, cystic lesions lined by noninvasive or focally microinvasive oncocytic tumors.

METHODS

From June 1999 to August 2001, three patients with hepatic IOPCs were identified in the files of the Hepatobiliary Service, Department of Surgery, and the Department of Pathology at Memorial Sloan‐Kettering Cancer Center. They form the basis of this study. We report the clinicopathologic presentation, as well as the outcome, with a review of the literature.

RESULTS

All three cases presented with well defined intrahepatic cystic masses ranging in size from 7.2 to 21.1 cm. The most prominent cells of the lining epithelium were columnar with oncocytic features showing abundant eosinophilic granular cytoplasm and centrally located nucleoli. All three patients underwent resection with one demonstrating local bile duct recurrence that was managed with stenting. Review of the literature has identified 39 patients with papillary PC and 2 patients with IOPC. The biology of these reported cases has been variable with overall survival better than that of nonpapillary PC patients, with recurrence in 15% of the reported cases.

CONCLUSION

Papillary PC is a rare type of cholangiocarcinoma that includes an interesting variant: IOPC. These tumors are predominantly found in men, who present with large (> 5 cm) mucinous cystic lesions of the bile duct. A noninvasive histology is seen, and long‐term survival may be achieved with complete resection. Invasive variants of IOPC have been reported in the literature and have a worse overall prognosis. Cancer 2002;95:2180–7. © 2002 American Cancer Society.

DOI 10.1002/cncr.10934
Neuropilin 1 and neuropilin 2 co‐expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma
Authors: Kawakami Tsutomu , Tokunaga Tetsuji , Hatanaka Hiroyuki , Kijima Hiroshi , Yamazaki Hitoshi , Abe Yoshiyuki , Osamura Yoshiyuki , Inoue Hiroshi , Ueyama Yoshito , Nakamura Masato
Published: November 2002

BACKGROUND

Cell‐retained isoforms of vascular endothelial growth factor A (VEGF‐A) have been reported to play an essential role in tumor progression through stromal neovascularization in malignant solid tumors. While more than 95% of nonsmall cell lung carcinoma (NSCLC) expresses cell‐retained VEGF‐A isoform, the clinicopathologic implications of neuropilin (NRP), considered the specific receptor for limited types of VEGF‐A isoform, are not well understood.

METHODS

The authors examined NRP1 and NRP2 mRNA expression in 68 NSCLCs and 15 extraneoplastic tissues by a densitometry–assisted, semi‐quantitative reverse transcription‐polymerase chain reaction. The authors determined the distinct expression of NRPs using the expression level of NRPs relative by optical density to β2‐microglobulin. The authors also investigated VEGF‐A isoforms, their receptors, and the clinical implications. Vascularity of NSCLC was morphologically estimated on sections immunostained with anti‐CD34 antibody.

RESULTS

Eleven of 15 extraneoplastic specimens showed NRP1 expression (73.3%) and 8 showed NRP2 expression (53.3%). The expression level of NRP1 or NRP2 of neoplasmic tissue was higher than that of extraneoplastic tissues (P < 0.01, Mann‐Whitney U test). Fifty‐five and 44 NSCLCs expressed NRP1 and NRP2, respectively. Forty patients co‐expressing NRP1 and NRP2 showed significantly poorer prognosis and increased vessel counts as compared to those 28 cases without co‐expression (P < 0.05, log‐rank test; P < 0.05, Mann‐Whitney U test).

CONCLUSIONS

The co‐expression of NRP1 and NRP2 genes is significantly correlated with tumor progression through neovascularization in NSCLC. These results suggest that both NRP1 and NRP2 are key molecules for stromal vascularization by cell‐retained VEGF in NSCLC. Cancer 2002;95:2196–201. © 2002 American Cancer Society.

DOI 10.1002/cncr.10936
Effect of topical morphine for mucositis‐associated pain following concomitant chemoradiotherapy for head and neck carcinoma
Authors: Cerchietti Leandro C. A. , Navigante Alfredo H. , Bonomi Marcelo R. , Zaderajko Mariel A. , Menéndez Pablo R. , Pogany Catalina E. , Roth Berta M. C.
Published: November 2002

BACKGROUND

Oral mucositis is the dose‐limiting toxicity for patients receiving concurrent chemoradiotherapy regimens for tumors of the head and neck area. Currently, the management of established mucositis includes the use of topical anesthetics and systemic analgesics. Based on the clinical evidence of pain alleviation by topical morphine in patients with some inflammatory and painful conditions, a clinical study was undertaken to determine this effect on mucositis‐associated pain.

METHODS

Twenty‐six patients with head and neck malignancies treated with concomitant chemoradiotherapy for head and neck carcinoma who had severe painful mucositis (World Health Organization Grade 2 or higher) were enrolled. Patients were randomly assigned to morphine mouthwash (MO; 14 patients) or magic mouthwash (MG), a mixture of equal parts of lidocaine, diphenhydramine, and magnesium aluminum hydroxide (12 patients).

RESULTS

The duration of severe pain was 3.5 days less in the MO group compared with the MG group (P = 0.032). The intensity of oral pain was also significantly lower in the MO group compared with the MG group (P = 0.038). No patient in the MO group required third‐step opiates for alleviation of the mouth pain. There was a significant difference in duration of severe functional impairment (P = 0.017). Five patients in the MG group complained of local side effects and only one in the MO group (P = 0.007).

CONCLUSIONS

For patients with head and neck carcinomas receiving concomitant chemoradiotherapy, MO is a simple and effective treatment to decrease the severity and duration of pain and the duration of functional impairment. Cancer 2002;95:2230–6. © 2002 American Cancer Society.

DOI 10.1002/cncr.10938
Prognostic potential of the telomerase subunit human telomerase reverse transcriptase in tumor tissue and nontumorous mucosa from patients with colorectal carcinoma
Authors: Gertler Ralf , Rosenberg Robert , Stricker Dominik , Werner Martin , Lassmann Silke , Ulm Kurt , Nekarda Hjalmar , Siewert Joerg‐Ruediger
Published: November 2002

BACKGROUND

The stabilization of telomere lengths by telomerase activation is an important step in carcinogenesis and cell immortalization. Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of this enzyme. The objective of this study was to evaluate the use of real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR) analysis for the quantification of hTERT in tumor and nontumorous tissue samples.

METHODS

Matched samples of tumor and adjacent nontumorous mucosa samples from 57 patients with completely resected colorectal carcinoma (International Union Against Cancer Stage I–IV) who underwent complete resection (R0) were quantified for hTERT mRNA expression using real‐time RT‐PCR. The expression levels were correlated with histopathologic findings and with survival. The median follow‐up was 76 months.

RESULTS

hTERT mRNA was expressed in all tumor samples and in all samples of adjacent mucosa. In 12 patients (21%), there was higher hTERT expression in tumor samples compared with nontumorous samples. Compared with tumor samples, the expression of hTERT in samples of nontumorous mucosa decreased with age (P= 0.06). hTERT mRNA expression in both tumor tissue and adjacent mucosa was correlated significantly with the histologic grade of colorectal carcinoma (P< 0.04 andP< 0.05, respectively). Patients with hTERT expression in tumor tissue in relation to the adjacent mucosa of > 0.57 had a significantly poorer overall survival compared with patients with lower hTERT ratios (P< 0.02). In addition to the established prognostic factor lymphatic vessel invasion, the hTERT ratio proved to be of independent prognostic value (P< 0.05).

CONCLUSIONS

The prognostic potential of hTERT in patients with colorectal carcinoma and the correlation of hTERT with tumor grade underlines the role of hTERT as a molecular marker for biologic tumor staging. Cancer 2002;95:2103–11. © 2002 American Cancer Society.

DOI 10.1002/cncr.10939
The diagnostic accuracy of the age‐adjusted and prostate volume‐adjusted biopsy method in males with prostate specific antigen levels of 4.1–10.0 ng/mL
Authors: Ito Kazuto , Ohi Masaru , Yamamoto Takumi , Miyamoto Shigeto , Kurokawa Kohei , Fukabori Yoshitatsu , Suzuki Kazuhiro , Yamanaka Hidetoshi
Published: November 2002

BACKGROUND

The authors evaluated a new age‐adjusted and prostate volume‐adjusted biopsy method for the detection of prostate carcinoma through the transperineal and the transrectal approaches in men with PSA levels of 4.1–10.0 ng/mL.

METHODS

The value of the adjusted biopsy method was calculated by using the following four factors: 1) life expectancy in Japanese men in 1998, 2) prostate volume estimated by transrectal ultrasonography, 3) tumor doubling time (4 years), and 4) tumor volume that influenced death (20 cc). The number of biopsy sites was set at 8–20. Between August, 1999 and December, 2001, 100 men age ≤ 79 years with prostate specific antigen (PSA) levels of 4.1–10.0 ng/mL underwent age‐adjusted and volume‐adjusted, systematic prostate biopsy.

RESULTS

The detection rate for the adjusted biopsy method was 46% (46 of 100 men). The clinical stage of prostate carcinoma was Stage II in 85% of patients and Stage III in 15% of patients. If routine six‐sextant biopsy had been performed in all of the men who underwent adjusted systematic biopsy, then 15 of 46 patients (33%) with prostate carcinoma would have been missed. The detection rates of prostate carcinoma in men who underwent adjusted biopsies were relatively high, especially in men with PSA levels of 6.1–10.0 ng/mL, men age ≤ 64 years, men with prostate volumes ≥ 50 cc, and men with PSA density (PSAD) levels ≤ 0.15 ng/mL/cc compared with the detection rates from six‐sextant and directed biopsies. The high detection rates were observed from biopsy sites at the posterior aspect of the lateral lobe through both the transperineal approach and the transrectal approach and at the anterior aspect of the transition zone through the transperineal approach.

CONCLUSIONS

The age‐adjusted and prostate volume‐adjusted prostate biopsy method was more useful for detecting clinically significant disease compared with the traditional six‐sextant biopsy method. This adjusted biopsy method was especially useful in patients age ≤ 64 years, patients with large prostate volumes (≥ 50 cc), and patients with PSAD levels ≤ 0.15 ng/mL/cc. The authors recommend that patients undergo an additional transition zone biopsy at the anterior aspect through the transperineal approach. Cancer 2002;95:2112–9. © 2002 American Cancer Society.

DOI 10.1002/cncr.10941
Cancer incidence in parents who lost a child
Authors: Li Jiong , Johansen Christoffer , Hansen Dorthe , Olsen Jørn
Published: November 2002

BACKGROUND

It has been debated whether psychological stress causes cancer, but the scientific evidence remains contradictory. The objective of this study was to investigate whether the death of a child is related to cancer risk in bereaved parents.

METHODS

The authors undertook a follow‐up study based on national registers. All 21,062 parents who lost a child from 1980 to 1996 were recruited for the exposed cohort together with 293,745 randomly selected, unexposed parents. Cox proportional hazards regression models were used to evaluate the relative risk of cancer incidence up to 18 years after the bereavement. The main outcomes of interest were all incident cancers, breast carcinoma, smoking‐related malignancies (International Classification of Diseases [ICD] 7 codes 140, 141, 143–149, 150, 157, 160–162, 180, and 181), alcohol‐related malignancies (ICD7 codes 141, 143–146, 148–150, 155, and 161), virus/immune‐related malignancies (ICD7 codes 155, 171, 191, 200–202, and 204), lymphatic/hematopoietic malignancies (ICD7 codes 200–205), and hormone related malignancies (ICD7 codes 170, 172, 175, and 177).

RESULTS

The authors observed a slightly increased overall cancer risk in bereaved mothers (relative risk [RR], 1.18; 95% confidence interval [95%CI], 1.01–1.37; P = 0.028) at 7–18 years of follow‐up. There was an increased risk for smoking‐related malignancies (RR, 1.65; 95%CI, 1.05–2.59; P = 0.010) among bereaved mothers during the 7–18 years of follow‐up. The authors observed no significantly increased relative risk of breast carcinoma, alcohol‐related malignancies, virus/immune‐related malignancies, or hormone‐related malignancies.

CONCLUSIONS

The current data suggest that the death of a child was associated with a slightly increased overall cancer risk in mothers and that the increase may be related to stress‐induced adverse life styles. Cancer 2002;95:2237–42. © 2002 American Cancer Society.

DOI 10.1002/cncr.10943
Overexpression of the insulin‐like growth factor I receptor in human colon carcinomas
Authors: Weber Matthias M. , Fottner Christian , Liu Sun Bin , Jung M. Christina , Engelhardt Dieter , Baretton Gustavo B.
Published: November 2002

BACKGROUND

High concentrations of insulin‐like growth factor (IGF)‐I and IGF‐II have been demonstrated in human colonic adenocarcinomas and exert mitogenic effects through paracrine/autocrine interactions with the IGF‐I receptor (IGF‐IR). However, definitive studies of IGF‐IR expression in these tissues have not been performed.

METHODS

To study changes in the levels of the IGF‐IR in colorectal carcinoma, we analyzed the expression of IGF‐IR in 40 paired samples of normal and carcinomatous colonic tissue by quantitative reverse‐transcription–polymerase chain reaction (RT‐PCR), immunohistochemistry, and ligand binding.

RESULTS

As measured by RT‐PCR, the IGF‐IR mRNA ratio in paired tumor and adjacent normal mucosa was higher than 2.0 in 32 of 40 (80%) samples. The overall mean IGF‐IR mRNA level was five‐fold higher in tumor versus adjacent normal mucosa (P < 0.0001). Overexpression of IGF‐IR in colon carcinomas was confirmed at the protein level by immunohistochemistry and receptor‐binding studies. Colon carcinoma cells exhibited a positive staining for IGF‐IR in 91% of all tumors (30 of 33) whereas the adjacent normal colonic epithelial cells showed only a very faint or no significant IGF‐IR immunoreactivity. Radioligand assays and Scatchard analysis in both tissue types revealed a single class of high‐affinity IGF‐IR–binding sites with a similar dissociation constant (Kd; 0.14 ± 0.02 nmol/L, n = 18). However, specific 125IGF‐I–binding and receptor concentrations were elevated in tumor membranes compared with normal mucosa (33.6 ± 5.6 vs. 22.7 ± 3.4 fmol/mg protein, P < 0.05). IGF‐I affinity crosslinking and sodium dodecyl sulfate–polyacrylamide gel electrophoresis displayed specific bands corresponding to the size of the normal α‐subunit of the IGF‐IR that were more intense in carcinomatous samples. IGF‐II mRNA levels were significantly elevated in colorectal carcinomas (P < 0.0001). The IGF‐II mRNA ratio in tumor versus normal tissue was elevated more than twofold in 28 of 40 paired samples and a positive correlation was observed between the overexpression of IGF‐II and IGF‐IR in the tumors.

CONCLUSIONS

Our results demonstrate that, in addition to IGF‐II, a strong overexpression of IGF‐IR is found in the majority of colorectal carcinomas, supporting the hypothesis of an important role of the IGF system in the pathogenesis of colorectal carcinoma. Cancer 2002;95:2086–95. © 2002 American Cancer Society.

DOI 10.1002/cncr.10945
Long‐term outcome of patients with insular carcinoma of the thyroid
Authors: Pellegriti Gabriella , Giuffrida Dario , Scollo Claudia , Vigneri Riccardo , Regalbuto Concetto , Squatrito Sebastiano , Belfiore Antonino
Published: November 2002

BACKGROUND

Insular thyroid carcinoma was described originally as a tumor with aggressive behavior. However, whether a predominant insular component is an independent factor for poor prognosis is unclear.

METHODS

The authors compared the clinical behavior of tumors in three groups of patients with thyroid carcinoma—13 patients with insular thyroid carcinoma, 18 patients with follicular thyroid carcinoma, and 26 patients with papillary thyroid carcinoma—who were selected based on similar tumor size and similar age. Disease free survival and disease specific deaths were assessed in the three groups with a Kaplan–Meier analysis and were compared using the log‐rank test. Cox regression analysis was used to evaluate the influence of histotype and other prognostic factors on the occurrence of distant metastases and disease specific death.

RESULTS

Patient follow‐up ranged from 5.2 months to 190.0 months. At last follow‐up, only 1 of 13 patients (7.7%) with insular carcinoma, compared with 8 of 18 patients (44.4%) with follicular carcinoma and 12 of 26 patients (46.1%) with papillary carcinoma, were disease free. The disease specific death rate was 61.5% among patients in the insular carcinoma group compared with 16.7% and 15.4% among patients in the follicular carcinoma group (P = 0.006) and the papillary carcinoma group (P = 0.025), respectively. At multivariate analysis, the insular histotype was the only variable that was related independently to disease specific death (hazard ratio = 4.27; P = 0.005). Distant metastases occurred in 84.6% of patients in the insular carcinoma group compared with 50% and 19.2% of patients in the follicular carcinoma group (P = 0.039) and the papillary carcinoma group (P = 0.0003), respectively. All metastases from patients with insular carcinomas (n = 11 patients) showed radioiodine uptake, but a clinical benefit from this treatment was observed only in 1 patient.

CONCLUSIONS

Patients with insular thyroid carcinoma have a poorer outcome compared with patients of similar age who have differentiated types of thyroid carcinoma with tumors of a similar size. Because radioiodine rarely is effective in the treatment of patients with metastatic insular thyroid carcinoma, novel and possible multimodal therapies should be explored for the treatment of patients with these aggressive tumors. Cancer 2002;95:2076–85. © 2002 American Cancer Society.

DOI 10.1002/cncr.10947
Prognostic significance of thymidine kinase activity in bladder carcinoma
Authors: Mizutani Yoichi , Wada Hiromi , Yoshida Osamu , Fukushima Masakazu , Kamoi Kazumi , Miki Tsuneharu
Published: November 2002

BACKGROUND

Thymidine kinase (TK) plays a key role in the complimentary or alternative salvage pathway of pyrimidine synthesis. Little is known about the significance of TK activity in bladder carcinoma. The authors examined the activity of TK in 55 patients with bladder carcinoma to determine the prognostic significance of TK activity.

METHODS

TK activity in nonfixed, fresh‐frozen specimens of bladder carcinoma and normal bladder tissue was determined by using the diethylaminoethanol cellulose disc method.

RESULTS

The activity of TK was approximately two‐fold higher in bladder carcinoma specimens compared with normal bladder tissues. The TK activity in muscle‐invasive bladder carcinoma was two‐fold higher compared with the activity in superficial bladder carcinoma (Ta and T1). In addition, the activity of TK in T1 tumors was two‐fold higher compared with the TK activity in Ta tumors. The level of TK activity in Grade 3 bladder tumors was two‐fold higher compared with the activity in Grade 1 and Grade 2 tumors. Patients with Ta and T1 bladder carcinoma who had low TK activity had a longer postoperative tumor free period compared with the patients who had high TK activity during the 2 years of follow‐up. TK activity was correlated with the activity of thymidine synthase, which is a key enzyme for pyrimidine synthesis in the de novo pathway.

CONCLUSIONS

This study is the first to demonstrate that the level of TK activity is correlated with both disease stage and tumor grade in patients with bladder carcinoma and that elevated TK activity predicts early recurrence in patients with Ta and T1 disease. These results suggest that the level of TK activity may be used as a prognostic parameter and that TK may be a molecular therapeutic target in patients with bladder carcinoma. Cancer 2002;95:2120–5. © 2002 American Cancer Society.

DOI 10.1002/cncr.10948
HER‐2/neu status and tumor morphology of invasive breast carcinomas in Ashkenazi women with known BRCA1 mutation status in the Ontario Familial Breast Cancer Registry
Authors: Quenneville Louise A. , Phillips Kelly‐Anne , Ozcelik Hilmi , Parkes Robert K. , Knight Julia A. , Goodwin Pamela J. , Andrulis Irene L. , O'Malley Frances P.
Published: November 2002

BACKGROUND

The prevalence of BRCA1 germline mutations is greater in the Ashkenazi Jewish population than in the general North American population. The Ontario Familial Breast Cancer Registry collects clinical and family history data in familial breast carcinoma cases, and unselected Ashkenazi breast carcinomas, and acts as a tumor tissue repository.

METHODS

Using this resource, we examined the tumor morphology, hormone receptor status, and HER‐2/neu protein overexpression in Canadian Ashkenazi breast carcinoma patients whose germline BRCA1 mutation status is known.

RESULTS

Thirty‐eight tumors from 32 BRCA1 carriers and 354 tumors from 334 noncarriers were analyzed.The tumors in BRCA1 mutation carriers were more likely to be high grade (P < 0.0001) and estrogen receptor negative (P < 0.004). There was an increased frequency of typical medullary carcinomas in mutation carriers when all tumors were analyzed. However, this difference did not remain statistically significant when only the first tumor diagnosed in each patient was included in the analysis. There was no difference in HER‐2/neu protein overexpression between the two groups overall (P = 0.07). However, when the analysis was restricted to Grade III tumors, there were significantly fewer HER‐2/neu‐positive tumors in the mutation carriers versus noncarriers (3.1% vs. 21.5%, P = 0.012). No significant differences were found in the incidence of lymph node status, progesterone receptor status, lymphatic vessel invasion, degree of lymphocytic infiltration, or in the presence of ductal carcinoma in situ associated with the invasive tumors.

CONCLUSIONS

Increasing awareness of the morphologic and immunophenotypic features more commonly found in BRCA1‐associated breast carcinomas may lead to a wider use of these characteristics in genetic screening programs and provide further clues to their pathogenesis. Cancer 2002;95:2068–75. © 2002 American Cancer Society.

DOI 10.1002/cncr.10949
Factors influencing mortality among young women with second primary breast carcinoma
Authors: Bernstein Jonine L. , Lapinski Robert , Lynch Charles , Holford Theodore , Thompson W. Douglas
Published: November 2002

BACKGROUND

Tumor characteristics are strong predictors of survival among women with breast carcinoma, yet the variability in prognosis among women presenting with similar stages suggests other factors may also play an important role. We examine the prognostic significance of etiologic risk factors for breast carcinoma to determine whether factors that influence the development of breast carcinoma also affect the course of the disease among a prospective cohort of young women with bilateral breast carcinoma.

METHODS

The 369 U.S. women included in this study were from the Cancer and Steroid Hormone Study who were diagnosed with an invasive first primary breast carcinoma between 1980 and 1982 and a second primary breast carcinoma before 1999. Cox proportional hazards models were used to evaluate factors known and suspected to be associated with breast carcinoma and with survival, based on reporting at the time of the first primary.

RESULTS

One hundred sixty women died during the 16–18‐year follow‐up period. The adjusted 1, 5, 10, and 15‐year survival rates following diagnosis of second primary breast carcinoma were 94%, 70%, 55%, and 49%, respectively. Survival rates werepoorest among the youngest women, those diagnosed with a second primary within 5 years of their first, poor African American women, women with either primary diagnosed at a later stage, those with less than 12 years of school, single women, and those with major weight gain between age 18 and adulthood.

CONCLUSIONS

This study provided little evidence that important etiologic factors for breast carcinoma predict mortality following diagnosis of a second primary breast carcinoma. Cancer 2002;95:2051–8. © 2002 American Cancer Society.

DOI 10.1002/cncr.10950
Phase II trial combining paclitaxel with 24‐hour infusion cisplatin for chemotherapy‐naïve patients with locally advanced or metastatic breast carcinoma
Authors: Hsu Chiun , Huang Chiun‐Sheng , Chao Tsu‐Yi , Lu Yen‐Shen , Bu Ching‐Fang , Chen Mary M. , Chang King‐Jeng , Cheng Ann‐Lii
Published: November 2002

BACKGROUND

Both paclitaxel and cisplatin are active as second‐line chemotherapy for patients with breast carcinoma. A synergistic cytotoxicity of these two drugs has been demonstrated in vitro. This study sought to determine the efficacy of combining these two drugs in the treatment of chemotherapy‐naïve patients with breast carcinoma.

METHODS

The inclusion criteria for the study were 1) women with histologically proven breast carcinoma; 2) locally advanced disease, as defined by American Joint Committee on Cancer (AJCC) Stage T4 (locally advanced breast carcinoma [LABC]) or clinically proven metastases (metastatic breast carcinoma [MBC]); and 3) no prior cytotoxic chemotherapy. The regimen consisted of paclitaxel 175 mg/m2 intravenously by 3‐hour infusion immediately followed by cisplatin 50 mg/m2 intravenously by 24‐hour infusion on Day 1 and repeated every 3 weeks. After a maximal response to chemotherapy was achieved, patients with LABC underwent resection of their primary tumor if the procedure was not contraindicated.

RESULTS

From July, 1999 to January, 2001, 46 patients were enrolled into this study (28 patients with LABC and 18 patients with MBC). Their median age was 49.5 years (range, 29.8–65.5 years). A total of 205 cycles of chemotherapy were given. All patients were evaluable for toxicity, and 45 patients were evaluable for response. There were 3 complete responses (CRs) and 24 partial responses (PRs), for an overall response rate of 58.7% (95% confidence interval, 44.5–72.9%). Grade 4 hypersensitivity (asthma) to paclitaxel occurred in one patient. Grade 3–4 nausea and emesis and Grade 3–4 myelosuppression occurred in six patients and four patients, respectively. Of the 28 patients with LABC, 2 patients achieved a CR, and 14 patients achieved a PR. Twenty‐seven patients underwent mastectomy patients after chemotherapy. A pathologic CR was documented in one patient. Postoperatively, 23 patients with LABC received adjuvant chemotherapy, and 18 patients with LABC received adjuvant radiotherapy. During a median follow‐up of 14.6 months, 5 of 28 patients with LABC developed recurrent disease, and 2 patients died of progressive disease, whereas 3 of 18 patients with MBC died of progressive disease.

CONCLUSIONS

The combination of paclitaxel by 3‐hour infusion and cisplatin by 24‐hour infusion appears to be an active and well‐tolerated regimen for chemotherapy‐naïve patients with LABC or MBC. Cancer 2002;95:2044–50. © 2002 American Cancer Society.

DOI 10.1002/cncr.10951
Classifying local disease recurrences after breast conservation therapy based on location and histology
Authors: Huang Eugene , Buchholz Thomas A. , Meric Funda , Krishnamurthy Savitri , Mirza Nadeem Q. , Ames Frederick C. , Feig Barry W. , Kuerer Henry M. , Ross Merrick I. , Singletary S. Eva , McNeese Marsha D. , Strom Eric A. , Hunt Kelly K.
Published: November 2002

BACKGROUND

To distinguish true local recurrences (TR) from new primary tumors (NP) and to assess whether this distinction has prognostic value in patients who develop ipsilateral breast tumor recurrences (IBTR) after breast‐conserving surgery and radiotherapy.

METHODS

Between 1970 and 1994, 1339 patients underwent breast‐conserving surgery at The University of Texas M. D. Anderson Cancer Center for ductal carcinoma in situ or invasive carcinoma. Of these patients, 139 (10.4%) had an IBTR as the first site of failure. For the 126 patients with clinical data available for retrospective review, we classified the IBTR as a TR if it was located within 3 cm of the primary tumor bed and was of the same histologic subtype. All other IBTRs were designated NP.

RESULTS

Of the 126 patients, 48 (38%) patients were classified as NP and 78 (62%) as TR. Mean time to disease recurrence was 7.3 years for NP versus 5.6 years for TR (P = 0.0669). The patients with NP had improved 10‐year rates of overall survival (NP 77% vs. TR 46%, P = 0.0002), cause‐specific survival (NP 83% vs. TR 49%, P = 0.0001), and distant disease‐free survival (NP 77% vs. TR 26%, P < 0.0001). Patients with NP more often developed contralateral breast carcinoma (10‐year rate: NP 29% vs. TR 8%, P = 0.0043), but were less likely to develop a second local recurrence after salvage treatment of the first IBTR (NP 2% vs. TR 18%, P = 0.008).

CONCLUSIONS

Patients with NP had significantly better survival rates than those with TR, but were more likely to develop contralateral breast carcinoma. Distinguishing new breast carcinomas from local disease recurrences may have importance in therapeutic decisions and chemoprevention strategies. This is because patients with new carcinomas had significantly lower rates of metastasis than those with local disease recurrence, but were more likely to develop contralateral breast carcinomas. Cancer 2002;95:2059–67. © 2002 American Cancer Society.

DOI 10.1002/cncr.10952
Low bone density and high percentage of body fat among men who were treated with androgen deprivation therapy for prostate carcinoma
Authors: Chen Zhao , Maricic Michael , Nguyen Paul , Ahmann Frederick R. , Bruhn Roberta , Dalkin Bruce L.
Published: November 2002

BACKGROUND

Men with prostate carcinoma who are treated with androgen deprivation therapy (ADT) are reported to be at an increased risk of bone loss and weight changes due to the sudden disruption of hormonal levels. In the current case–control study, the authors examined the prevalence and magnitude of low bone density and obesity among men with prostate carcinoma who were treated with ADT.

METHODS

Sixty‐two men with prostate carcinoma who had been receiving ADT for 1–5 years were included as cases. Healthy men (n = 47) with a prostate specific antigen level < 4.0 ng/mL were recruited as controls. Body composition and bone mineral density (BMD) were measured using dual‐energy X‐ray absorptiometry. The average age was 74.3 years for the cases and 72.8 years for the controls.

RESULTS

The results of the current study demonstrate that prostate carcinoma cases had significantly higher body weight (86.5 kg vs. 80.6 kg), a higher percentage of body fat (30% vs. 26%), and a lower total body BMD (1.12 mg/cm2 vs. 1.17mg/ cm2) compared with controls (P < 0.05). Cases were more likely to be obese (27.4% vs 43%) and have low BMD at trochanter (32.3% vs. 10.6%), intertrochanter (48.4% vs. 29.8%), and total hip measurements (50.0% vs. 25.3%).

CONCLUSIONS

The results of the current study indicate that men with prostate carcinoma who are treated with ADT have a significantly increased risk of low bone density and obesity. Cancer 2002;95:2136–44. © 2002 American Cancer Society.

DOI 10.1002/cncr.10967
Serum endostatin predicts tumor vascularity in hepatocellular carcinoma
Authors: Dhar Dipok Kumar , Ono Takashi , Yamanoi Akira , Soda Yukiko , Yamaguchi Emi , Rahman Md Atikur , Kohno Hitoshi , Nagasue Naofumi
Published: November 2002

BACKGROUND

Tumor angiogenesis is a strong prognostic factor in patients with hepatocellular carcinoma (HCC). However, to the authors' knowledge, details regarding the serum levels of proangiogenic and antiangiogenic growth factors controlling this process are not yet known.

METHODS

Serum endostatin, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) levels were measured by the enzyme immunoassay method in prospectively collected samples from 33 HCC patients who had received no preoperative therapy. The angiogenic score (AS) and endostatin localization were evaluated using immunohistochemistry.

RESULTS

Significant decreases in serum endostatin (P = 0.0007) and bFGF (P = 0.0004) were observed in postoperative samples compared with the preoperative values. A very strong direct correlation was noted between VEGF and endostatin (P < 0.0001). Only the preoperative serum endostatin was found to have a significant (P = 0.0025) inverse correlation with the AS. Furthermore, the combined positivity for bFGF and VEGF and negativity for endostatin was found to have a significantly (P = 0.0069) positive correlation with AS. Significantly high levels of endostatin were noted in patients with trabecular‐type tumors (P = 0.0446) and in patients with hepatitis B infection (P = 0.0183). The serum endostatin level was found to be significantly (P = 0.0166) higher in living patients and patients with high serum endostatin levels had a tendency (P = 0.0871) toward long survival. Tissue endostatin expression was found to have a direct correlation with the serum endostatin level (P = 0.0117).

CONCLUSIONS

The measurement of serum endostatin can predict tumor vascularity and may serve as a promising tool in the antiangiogenic therapy for patients with HCC. Cancer 2002;95:2188–95. © 2002 American Cancer Society.

DOI 10.1002/cncr.10972
Estrogen receptor‐α distribution in the human hypothalamus in relation to sex and endocrine status
Authors: Kruijver Frank P.M. , Balesar Rawien , Espila Ana M. , Unmehopa Unga A. , Swaab Dick F.
Published: November 2002

The present study reports the first systematic rostrocaudal distribution of estrogen receptor‐α immunoreactivity (ERα‐ir) in the human hypothalamus and its adjacent areas in young adults. Postmortem material taken from 10 subjects (five male and five female), between 20 and 39 years of age, was investigated. In addition, three age‐matched subjects with abnormal levels of estrogens were studied: a castrated, estrogen‐treated 50‐year‐old male‐to‐female transsexual (T1), a 31‐year‐old man with an estrogen‐producing tumor (S2), and an ovariectomized 46‐year‐old woman (S8). A strong sex difference, with more nuclear ERα‐ir in women, was observed rostrally in the diagonal band of Broca and caudally in the medial mamillary nucleus. Less robust sex differences were observed in other brain areas, with more intense nuclear ERα‐ir in men, e.g., in the sexually dimorphic nucleus of the medial preoptic area, paraventricular nucleus, and lateral hypothalamic area, whereas women had more nuclear ERα‐ir in the suprachiasmatic nucleus and ventromedial nucleus. No nuclear sex differences in ERα were found, e.g., in the central part of the bed nucleus of the stria terminalis. In addition to nuclear staining, ERα‐ir appeared to be sex‐dependently present in the cytoplasm of neurons and was observed in astrocytes, plexus choroideus, and other non‐neuronal cells. ERα‐ir in T1, S2, and S8 suggested that most of the observed sex differences in ERα‐ir are “activational” (e.g., ventromedial nucleus/medial mamillary nucleus) rather than “organizational.” Species similarities and differences in ERα‐ir distribution and possible functional implications are discussed. J. Comp. Neurol. 454:115–139, 2002. © 2002 Wiley‐Liss, Inc.
Expression of synapsin III in nerve terminals and neurogenic regions of the adult brain
Authors: Pieribone Vincent A. , Porton Barbara , Rendon Beatrice , Feng Jian , Greengard Paul , Kao Hung‐Teh
Published: November 2002

We have examined the distribution of synapsin III in the adult mouse brain. Expression of synapsin III was observed in puncta throughout the brain, but demonstrated greater regional variation than that of synapsins I or II. This punctate staining is typical for synaptic vesicle proteins located at nerve terminals. These findings are also consistent with the well‐established role for synapsins in regulating neurotransmitter release. However, unexpectedly, synapsin III was also highly expressed in the cell body and processes of immature neurons in neurogenic regions of the adult brain, such as the hippocampal dentate gyrus, rostral migratory stream, and olfactory bulb. Many synapsin III‐positive neurons also reacted with an antibody directed toward polysialylated‐neuronal cell adhesion molecule, a marker of immature, migrating neurons. These results suggest that synapsin III may also play a role in adult neurogenesis. J. Comp. Neurol. 454:105–114, 2002. © 2002 Wiley‐Liss, Inc.
Projections of the claustrum to the primary motor, premotor, and prefrontal cortices in the macaque monkey
Authors: Tanné‐Gariépy Judith , Boussaoud Driss , Rouiller Eric M.
Published: November 2002

The claustrum is interconnected with the frontal lobe, including the motor cortex, prefrontal cortex, and cingulate cortex. The goal of the present study was to assess whether the claustral projections to distinct areas within the frontal cortex arise from separate regions within the claustrum. Multiple injections of tracers were performed in 15 macaque monkeys, aimed toward primary motor area (M1), pre‐supplementary motor area (pre‐SMA), SMA‐proper, rostral (PMd‐r) and caudal (PMd‐c) parts of the dorsal premotor cortex (PM), rostral (PMv‐r) and caudal (PMv‐c) parts of the ventral PM, and superior and inferior parts of area 46. The distribution of retrogradely labeled neurons showed no clear segregation along the rostrocaudal axis of the claustrum; they were usually located along the entire anteroposterior extent of the claustrum. For all motor cortical areas, there was a general trend of the labeled neurons to occupy the dorsal and intermediate parts of the claustrum along the dorsoventral axis. The same territories were labeled after injection in area 46, but in addition numerous labeled neurons were found in the most ventral part of the claustrum. At higher resolution, however, there was clear evidence that the territories projecting to pre‐SMA and SMA‐proper formed separate, interdigitating, clusters along the dorsoventral axis. A comparable local segregation was observed for the two subdivisions of area 46, whereas there was more local overlap among the subareas of PM. The projections from the claustrum to the multiple subareas of the motor cortex and to area 46 arise from largely overlapping territories, with, however, some degree of local segregation. J. Comp. Neurol. 454:140–157, 2002. © 2002 Wiley‐Liss, Inc.
Neurochemical characterization of receptor‐expressing cell populations by in vivo agonist‐induced internalization: Insights from the somatostatin sst2A receptor
Authors: Csaba Zsolt , Simon Axelle , Helboe Lone , Epelbaum Jacques , Dournaud Pascal
Published: November 2002

Characterization of both neurochemical phenotype of G protein‐coupled receptor (GPCR)‐expressing cells and receptor compartmentalization is a prerequisite for the elucidation of receptor functions in the central nervous system. However, it is often prevented by the diffuse and homogeneous distribution of receptor immunoreactivity. This is particularly true for the somatostatin (SRIF) sst2A receptor, which is largely distributed in the mammalian brain. By using this receptor as a model, we investigated whether receptor internalization, a biochemical property shared by numerous GPCRs, would reveal sst2A‐expressing cell populations in the rat dorsolateral septum (LSD), a region in which SRIF might play an important modulatory role. Thirty minutes to 1 hour after intracerebroventricular injection of the sst2A receptor agonist octreotide, numerous sst2A‐immunoreactive neurons and processes became apparent due to intracytoplasmic accumulation of intensely stained granules. Double‐immunolabeling experiments with synaptophysin and MAP2 provided evidence that internalized sst2A receptors are predominantly localized in the somatodendritic compartment. Revealing sst2A receptor‐expressing cell bodies permitted to analyze their neurotransmitter content. Quantitative analysis demonstrated an extensive overlap (∼85%) between SRIF‐ and sst2A‐expressing neuronal populations. Additionally, numerous SRIF‐immunoreactive axon‐like terminals were found in close apposition with sst2A‐positive cell bodies and dendrites. Taken together, these data suggest that the sst2A receptor is predominantly expressed in LSD neurons as a postsynaptic autoreceptor, thus providing novel neuroanatomic clues to elucidate SRIF neurotransmission in this region. More generally, in vivo agonist‐induced internalization appears as a rapid and powerful tool for the neurochemical characterization of GPCR‐expressing cell populations in the mammalian brain. J. Comp. Neurol. 454:192–199, 2002. © 2002 Wiley‐Liss, Inc.