bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of developmental toxicology of aspirin (Acetylsalicylic Acid) in rats using selected dosing paradigms
Authors: Gupta Utpal , Cook Jon C. , Tassinari Melissa S. , Hurtt Mark E.
Published: April 2003

BACKGROUND: Analysis of the literature for nonsteroidal anti‐inflammatory drugs (NSAIDs) suggests that a low incidence of developmental anomalies occurs in rats given NSAIDs on specific days during organogenesis. Aspirin (acetylsalicylic acid [ASA]), an irreversible cyclooxygenase 1 and 2 inhibitor, induces developmental anomalies when administered to Wistar rats on gestational day (GD) 9, 10, or 11 (Kimmel CA, Wilson JG, Schumacher HJ. Teratology 4:15–24, 1971). There are no published ASA studies using the multiple dosing paradigm of GDs 6 to 17. Objectives of the current study were to compare results between Sprague–Dawley (SD) and Wistar strains when ASA is administered on GD 9, 10, or 11; to compare the malformation patterns following single and multiple dosings during organogenesis in SD rats; and to test the hypothesis that maternal gastrointestinal toxicity confounds the detection of low incidence malformations with ASA when a multiple dosing paradigm is used. METHODS: ASA was administered as a single dose on GD 9 (0, 250, 500, or 625 mg/kg), 10 (0, 500, 625, or 750 mg/kg), or 11 (0, 500, 750, or 1000 mg/kg) and from GD 6 to GD 17 (0, 50, 125, or 250 mg/kg a day) in the multiple dose study to SD rats. Animals were killed on GD 21, and fetuses were examined viscerally. RESULTS: The literature evaluation suggested that NSAIDs induce ventricular septal defects (VSDs) and midline defects (MDs) in rats and diaphragmatic hernia (DH), MDs, and VSDs in rabbits (Cook JC et al., 2003); hence, the present study focused on these malformations, even though ASA induces several other low‐incidence malformations. In single dose studies, DH, MD, and VSD were induced on GDs 9 and 10. VSD also was noted following treatment on GD 11. In contrast, DH and MD were noted in the multiple dose study design only in the high‐dose group, and VSD was noted across all dose groups. CONCLUSIONS: High concordance in major developmental anomalies between Wistar and SD rats were noted with the exception of VSD in the SD rats and hydrocephalus in the Wistar rats. Variations and malformations were similar when ASA was administered as a single dose or during the period of organogenesis (GDs 6 to 17). It was also evident that, by titrating the dose to achieve a maximum tolerated dose, malformations that normally occur at low incidence, as reported from previous single dose studies, could also be induced with ASA given at multiple doses. Birth Defects Research (Part B) 68:27–37, 2003. © 2003 Wiley‐Liss, Inc.
Relationship between cyclooxygenase 1 and 2 selective inhibitors and fetal development when administered to rats and rabbits during the sensitive periods for heart development and midline closure
Authors: Cappon G. D. , Cook J. C. , Hurtt M. E.
Published: April 2003

BACKGROUND: A review of the scientific literature suggested the occurrence of low‐level incidences of ventricular septal defect (VSD) and midline defect (MD) in rat fetuses and diaphragmatic hernia (DH), VSD, and MD in rabbit fetuses after maternal exposure to nonsteroidal anti‐inflammatory drugs (NSAIDs). Aspirin, an NSAID that irreversibly inhibits cyclooxygenase 1 (COX‐1) and COX‐2, induces DH, VSD, and MD when administered as one dose during the sensitive periods of development in rats. Unlike aspirin, other NSAIDs, including selective COX‐2 inhibitors, reversibly inhibit COX activity. To evaluate whether the dysmorphogenesis observed after maternal NSAID exposure correlates with COX‐1 or COX‐2 inhibition, a series of compounds with different capacities to inhibit COX‐1 and COX‐2 were administered to pregnant rats and rabbits during the sensitive period for heart development and midline closure. METHODS: The compounds selected, ranked from the most COX‐2 selective to the most COX‐1 selective based on COX inhibition in a human whole blood assay, were CJ‐19,209, meloxicam, diclofenac, diflunisal, ibuprofen, and ketorolac. Rat dams were treated on gestation days (GDs) 9 and 10, and rabbit does were treated on GDs 9, 10, and 11. The doses selected for evaluation represented the maximum tolerable dose for the compound, with the exception of CJ‐19,209, which was dosed at 1000 mg/kg. Fetuses were collected by cesarean section on GDs 21 and 29 for rats and rabbits, respectively, and all fetuses were examined for external and visceral developmental anomalies. RESULTS: In rabbits, diflunisal induced DH, VSD, and MD (omphalocele) and single incidences of VSD and MD (gastroschisis) were noted in the ibuprofen group; no other developmental findings were associated with treatment. In rats, ibuprofen, diflunisal, and ketorolac induced increases in the incidence of VSD. In general, the induction of developmental defects was associated with compounds that selectively inhibit COX‐1 or have a high ratio of COX‐1 to COX‐2 inhibition. CONCLUSIONS: Inhibition of COX‐1 may be involved in the disruption of heart development, whereas the selective inhibition of COX‐2 (as assessed with CJ‐19,209) appears to have no effect on heart development and midline closure in rats and rabbits. Birth Defects Research (Part B) 68:47–56, 2003. © 2003 Wiley‐Liss, Inc.
Multidrug resistance proteins in rhabdomyosarcomas
Authors: Komdeur Rudy , Klunder Jenneke , van der Graaf Winette T. A. , van den Berg Eva , de Bont Eveline S. J. M. , Hoekstra Harald J. , Molenaar Willemina M.
Published: April 2003

BACKGROUND

Pediatric rhabdomyosarcomas (RMS) have a more advantageous prognosis after multimodality treatment compared with adult RMS, which might be related to a decreased sensitivity to chemotherapy in adults. Resistance to chemotherapy might be conveyed by the multidrug resistance (MDR)‐associated proteins P‐glycoprotein (P‐gp), multidrug resistance‐associated protein 1 (MRP1), and lung resistance‐related protein (LRP). It was therefore suggested that these proteins were expressed differently in pediatric and adult patients.

METHODS

The expression of P‐gp, MRP1, and LRP was assessed immunohistochemically in 45 specimens of untreated RMS: 29 were obtained from children younger than 16 years old and 16 were obtained from adults. All children had an embryonal or botryoid RMS. Among the adults, there were 10 embryonal, 3 alveolar, and 3 pleomorphic RMS. Samples were scored as negative or positive according to the percentage of immunoreactive tumor cells: 0.5 (1–5%), 1 (5–25%), 2 (26–50%), 3 (51–75%), or 4 (> 75%).

RESULTS

Expression of LRP was more pronounced in embryonal and pleomorphic RMS in adults compared with RMS in children. In addition, LRP expression correlated with age at diagnosis. Alveolar RMS had remarkably low LRP expression. Expression of P‐gp and MRP1 did not differ significantly between children and adults.

CONCLUSIONS

In this series of embryonal and pleomorphic RMS, an increased LRP expression was observed in adults, which may explain their worse response to chemotherapy reported in other studies. In alveolar RMS, a low LRP expression was observed, suggesting that other mechanisms are responsible for the resistant phenotype in most of these tumors. Cancer 2003;97:1999–2005. © 2003 American Cancer Society.

DOI 10.1002/cncr.11259
Phase I study of temozolomide and escalating doses of oral etoposide for adults with recurrent malignant glioma
Authors: Korones David N. , Benita‐Weiss Michal , Coyle Thomas E. , Mechtler Laszlo , Bushunow Peter , Evans Brandon , Reardon David A. , Quinn Jennifer A. , Friedman Henry
Published: April 2003

BACKGROUND

Although temozolomide is active against recurrent malignant glioma, responses in many patients are modest and short‐lived. Temozolomide may prove more effective in combination with other agents. Therefore, combination oral chemotherapy for these patients is a particularly attractive approach.

METHODS

The authors conducted a Phase I study of temozolomide in combination with escalating doses of oral etoposide (VP‐16) to determine the maximum tolerated doses of these two agents when given together. The temozolomide dose was fixed at 150 mg/m2 per day on Days 1–5. The oral VP‐16 was escalated in cohorts of 3 to 6 patients by numbers of days of VP‐16 administered: 50 mg/m2 per day, Days 1–5 (dose level 1), Days 1–8 (dose level 2), Days 1–12 (dose level 3), Days 1–16 (dose level 4), and Days 1–20 (dose level 5). Therapy was given in 28‐day cycles.

RESULTS

Of the 29 patients enrolled, 26 were fully evaluable and 3 were partially evaluable for toxicity. The 29 patients received a total of 92 cycles. The median age of the patients was 49 years (range, 28–76 years). Diagnoses included glioblastoma (n = 19), gliosarcoma (n = 3), anaplastic astrocytoma (n = 5), and anaplastic oligoastrocytoma (n = 2). The median time from diagnosis to disease recurrence was 8 months (3–188 months). Twenty patients were treated at the first disease recurrence, seven at the second, and two at the third. Twenty‐four patients (83%) were receiving anticonvulsants and 24 were receiving dexamethasone. All patients had received previous radiation, and 25 of 29 had been treated with chemotherapy previously. Of the 3 patients at dose level 1, none had dose‐limiting toxicity (DLT). Of the 6 patients at dose level 2, 1 patient had DLT: Grade 3 thrombocytopenia resulting in a > 2‐week delay in starting the next cycle of chemotherapy. Of the 6 patients at dose level 3, 1 patient had DLT: death due to pneumonia. There were 2 DLTs in the 7 patients at dose level 4: fever, neutropenia, and herpes zoster infection in 1 patient and death due to pneumonia in another. Seven patients had been started at dose level 5 when DLT was established at dose level 4: of the 5 fully evaluable and 2 partially evaluable patients at dose level 5, there was no DLT.

CONCLUSIONS

The maximum tolerated dose of temozolomide and oral VP‐16 in this heavily treated group of patients with recurrent malignant glioma is temozolomide 150 mg/m2 per day for 5 days and oral VP‐16 50 mg/m2 per day for 12 days. Cancer 2003;97:1963–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11260
Preoperative ultrasonographic identification of the sentinel lymph node in patients with malignant melanoma
Authors: Kahle Birgit , Hoffend Johannes , Wacker Jörg , Hartschuh Wolfgang
Published: April 2003

BACKGROUND

Dissection of the “sentinel lymph node” (SLN) as identified by lymphoscintigraphy is becoming increasingly important in the treatment of patients with malignant melanoma. The purpose of the current study was to determine whether the SLN also could be identified by ultrasound.

METHODS

Sixty‐seven patients with malignant melanoma (40 females and 27 males, with an average age of 48.8 years) in whom extirpation of the SLN was indicated underwent ultrasonography of the regional lymph nodes prior to preoperative lymphoscintigraphy. The location of the melanoma was the legs in 30 patients, the arms in 14 patients, and the trunk in 23 patients. During regional ultrasonography, the location of the lymph nodes that differed in the cortex/medulla ratio from the surrounding lymph nodes was marked on the skin corresponding to the planes of insonation (M1) when the probe was held vertically to the skin surface. After lymphoscintigraphy using technetium‐99m, the position of a gamma probe at which the highest count rate vertical to the skin surface was recorded also was marked (M2).

RESULTS

In the inguinal region, the agreement between M1 and M2 was found to be 100% (40 of 40 SLNs) and was 72.5% in the axilla (29 of 40 SLNs). In patients with melanomas located on the leg, the location of M1 and M2 agreed in 97% of cases (36 of 37 lymph nodes in 30 patients); in patients with melanomas located on the arms, the agreement was 76% (13 of 17 lymph nodes in 14 patients) and in patients with melanomas located on the trunk, the agreement was 75% (21 of 28 lymph nodes in 23 patients). The position documented by ultrasound relative to the neighboring structures of the SLN was confirmed intraoperatively in all cases.

CONCLUSIONS

The results of the current study indicate that the SLN in patients with melanoma located on the limbs, especially the legs, are characterized by a specific sonomorphologic pattern. Preoperative sonography might constitute an important addition to lymphoscintigraphy in the planning of SLN biopsy. Cancer 2003;97:1947–54. © 2003 American Cancer Society.

DOI 10.1002/cncr.11261
Empiric risk of prostate carcinoma for relatives of patients with prostate carcinoma
Authors: Zeegers Maurice P.A. , Jellema Annemarie , Ostrer Harry
Published: April 2003

BACKGROUND

Although narrative reviews have concluded that there is strong support for familial clustering of prostate carcinoma, the association has never systematically been quantified in reviews. The purpose of this meta–analysis was to summarize and quantify the recurrence risk ratio with emphasis on the degree of relation, the specific relationship of the family member, the number of affected family members, and the age at diagnosis.

METHODS

Publications were identified through computerized database searches for epidemiologic studies published up to December 2002. In addition, references cited in original and review papers were examined. Three blinded reviewers extracted both qualitative and quantitative information from each paper. Using random effects meta–regression analyses, the authors calculated summary recurrence risk ratios (Sλ). The reviewers also evaluated changes in Sλ according to differences in study methodology.

RESULTS

Thirty–three epidemiologic studies were included in the current review. Sλ was 2.53 (95% confidence interval, 2.24–2.85) for first–degree family members. Sλ appeared to be greater for men with an affected brother than for men with an affected father. Sλ for men who had second–degree relatives with prostate carcinoma was only slightly elevated. The nature of the familial clustering is such that Sλ increases with decreasing age of the patient and family members, with increasing genetic relatedness of the affected relative, and with increasing number of individuals affected within a family.

CONCLUSIONS

The studies that were reviewed consistently demonstrate that family history is a significant risk factor for development of prostate carcinoma. Cancer 2003;97:1894–903. © 2003 American Cancer Society.

DOI 10.1002/cncr.11262
Clinical relevance of the expression of the CD31 ligand for CD38 in patients with B‐cell chronic lymphocytic leukemia
Authors: Ibrahim Sherif , Jilani Iman , O'Brien Susan , Rogers Anna , Manshouri Taghi , Giles Francis , Faderl Stefan , Thomas Deborah , Kantarjian Hagop , Keating Michael , Albitar Maher
Published: April 2003

BACKGROUND

CD31 (platelet endothelial cell adhesion molecule‐1 [PECAM‐1]) is the ligand for CD38, a transmembrane glycoprotein that is expressed on the surface of leukemic cells in many patients with B‐cell chronic lymphocytic leukemia (B‐CLL). In a previous study, the authors showed that CD38 expression was correlated with a poor prognosis in patients with B‐CLL. In the current study, blood samples from patients with B‐CLL were examined to identify CD31 surface marker expression, and CD31 expression was correlated with several other known prognostic variables, including CD38.

METHODS

Using flow cytometry, peripheral blood samples from 120 patients with B‐CLL were analyzed for CD31 and CD38 expression on CD19 positive leukemic B cells.

RESULTS

Thirteen of 120 patients (11%) had CD31 expression on < 20% of their B cells, and the remaining patients had various levels of CD31 expression. The median expression of CD31 was 76% of leukemic, CD19 positive cells. Levels of CD31 expression were not correlated with survival outcomes or with any of the known prognostic parameters when all patients were considered. Patients who had high CD38 expression (≥ 20%), as expected, had significantly shorter survival (P = 0.001) compared with patients who had low CD38 expression (< 20%). However, in patients with low CD38 expression, a subgroup with low CD31 expression (< 76%) had significantly longer survival compared with the survival for the entire group (P = 0.0001). Moreover, the survival pattern of patients with low CD38 expression and high CD31 expression was not significantly different from the survival pattern seen in patients with high CD38 expression.

CONCLUSIONS

CD31 expression further defined a subgroup of patients with B‐CLL who had a different survival outcome. Defining the interaction between CD31 expression and CD38 expression in patients with CLL will require further exploration. Cancer 2003;97:1914–9. © 2003 American Cancer Society.

DOI 10.1002/cncr.11264
Cytokeratin expression patterns in low‐grade papillary urothelial neoplasms of the urinary bladder
Authors: Ramos David , Navarro Samuel , Villamón Rafael , Gil‐Salom Manuel , Llombart‐Bosch Antonio
Published: April 2003

BACKGROUND

The differential expression patterns of cytokeratin 20 (CK20) and 34βE12 antigen in low‐grade papillary urothelial tumors of the bladder are discussed.

METHODS

A retrospective study of 120 patients with low‐grade papillary bladder tumors (45 neoplasms of low malignant potential and 75 low‐grade WHO G1 carcinomas) was performed. All tumors were graded in accordance with the 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) and 1999 WHO classifications. The mean follow‐up was 76.6 months (range, 36–168 mos), considering for prognostic purposes the time to first recurrence, or relapse‐free interval (RFI), and the total number of recurrent patients. Immunohistochemically, normal or abnormal CK20 and 34βE12 antigen expression patterns were determined for each patient. CK20 (clone IT‐Ks) and a high‐molecular weight cytokeratin (clone 34βE12) were the monoclonal antibodies used in the immunohistochemical study.

RESULTS

Seventy‐seven of 120 patients (64.2%) experienced a recurrence during follow‐up. In recurrence prediction, the differential expression pattern of both cytokeratins showed a high sensitivity (76.6% for CK20 and 80.5% for 34βE12 antigen) and a high positive predictive value (85.5% for CK20 and 75.6% for 34βE12 antigen), although specificity was higher for CK20 (76.7%) than it was for 34βE12 antigen (53.4%). Independent of adjuvant intravesical chemotherapy, these 2 markers showed a strong statistical correlation (p < 0.001) in univariate studies with both the prediction of disease recurrences and RFI.

CONCLUSIONS

CK20 and 34βE12 antigen have proved to be strong predictive markers of disease recurrences when considering different topographic expression profiles, and, in the authors' opinion, these profiles could be incorporated into follow‐up clinicopathologic strategies. Cancer 2003;97:1876–83. © 2003 American Cancer Society.

DOI 10.1002/cncr.11265
Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma
Authors: Hu Tsung‐Hui , Huang Chao‐Cheng , Lin Pey‐Ru , Chang Hsueh‐Wen , Ger Luo‐Ping , Lin Yu‐Wei , Changchien Chi‐Sin , Lee Chuan‐Mo , Tai Ming‐Hong
Published: April 2003

BACKGROUND

Inactivation of the tumor suppressor gene PTEN/MMAC1/TEP1, located on chromosome 10q23, is a common event in advanced stages of diverse human malignancies. However, the prognostic role of PTEN expression in patients with hepatocellular carcinoma (HCC) has not been characterized.

METHODS

One hundred five resected specimens were collected from patients with HCC. Expression levels of PTEN and p53 in clinical samples were analyzed by immunohistochemistry.

RESULTS

Immunohistochemical analysis of 105 HCC tissue specimens revealed that decreased or absence of PTEN immunostaining was found in 43 specimens (40.9%). Reduced PTEN expression levels were correlated with increased tumor grade (P = 0.017), advanced disease stage (P = 0.016), and elevated serum α‐fetoprotein (αFP) levels (P = 0.001). Kaplan–Meier analysis indicated that patients with reduced PTEN levels had shorter overall survival (P = 0.001) and higher recurrence rates (P = 0.0007) compared with patients who had intact PTEN expression. Examining p53 expression unveiled an inverse correlation between p53 overexpression and reduced PTEN expression in patients with HCC (P = 0.004). In addition, patients with p53 overexpression had shorter overall survival compared with patients who were without p53 overexpression (P = 0.0014). Univariate and multivariate analyses revealed that reduced PTEN expression was an independent prognostic factor for survival in patients with HCC.

CONCLUSIONS

The current study demonstrated that reduced PTEN expression levels are involved in the pathogenesis of HCC. Moreover, decreased PTEN expression was correlated with tumor progression, high αFP levels, p53 overexpression, and poor prognosis in patients with HCC. Cancer 2003;97:1929–40. © 2003 American Cancer Society.

DOI 10.1002/cncr.11266
Analysis of the Na,K‐ATPase α‐ and β‐subunit expression profiles of bladder cancer using tissue microarrays
Authors: Espineda Cromwell , Seligson David B. , James Ball William , Rao JianYu , Palotie Aarno , Horvath Steve , Huang Yunda , Shi Tao , Rajasekaran Ayyappan K.
Published: April 2003

BACKGROUND

The purpose of this study was to determine the clinical significance of Na,K‐ATPase α‐ and β‐subunit expression in a histopathologically well‐characterized group of patients representing a wide spectrum of tumor grades and disease stages with transitional cell carcinomas (TCC).

METHODS

Na,K‐ATPase α‐ and β‐subunit protein expression patterns were analyzed using immunohistochemistry on urothelial cancer tissue microarrays (TMA) of 146 patients diagnosed with urothelial carcinoma. For each subunit, the maximum staining intensity and the percentage of positive cells staining at the maximal intensity were analyzed.

RESULTS

Compared with the benign fields, the mean protein expression for both Na,K‐ATPase α‐ and β‐subunits were found to be decreased overall in in situ and invasive tumors, as well as in tumor‐adjacent dysplastic fields. When Na,K‐ATPase α‐ and β‐subunit expression levels were dichotomized into distinct groups, they were both found to be significant predictors of recurrence risk in multivariate logistic regression analysis (P = 0.0062, odds ratio [OR] = 2.6 and P = 0.013, OR = 0.43, for Na,K‐ATPase α‐ and β‐subunits, respectively). The authors also found that patients with high α‐ and low β‐subunit expression had a high risk for early recurrence, whereas patients with a low α‐ and high β‐subunit expression had a significantly longer median recurrence‐free time (17 months and 125 months, respectively, log rank statistics P = 0.0005).

CONCLUSIONS

The results suggested that Na,K‐ATPase α‐ and β‐subunit expression levels may be useful predictors of clinical outcomes such as recurrence‐free time of bladder cancer patients. Cancer 2003;97:1859–68. © 2003 American Cancer Society.

DOI 10.1002/cncr.11267
Refined prognostic evaluation in colon carcinoma using immunohistochemical galectin fingerprinting
Authors: Nagy Nathalie , Legendre Hugues , Engels Olivier , André Sabine , Kaltner Herbert , Wasano Kojiro , Zick Yehiel , Pector Jean‐Claude , Decaestecker Christine , Gabius Hans‐Joachim , Salmon Isabelle , Kiss Robert
Published: April 2003

BACKGROUND

Knowledge of the expression of the galectins in human colon carcinomas is mainly restricted to galectin‐3 and, to a lesser extent, galectin‐1. The current study analyzed the prognostic values contributed by galectin‐1, galectin‐3, galectin‐4, and galectin‐8 in cases of colon carcinoma.

METHODS

The authors selected 55 colon carcinomas (including 10 Dukes A, 16 Dukes B, 15 Dukes C, and 14 metastatic tumors that the authors labeled “Stage D”). The immunohistochemical levels of expression of the four galectins were determined quantitatively by means of computer‐assisted microscopy.

RESULTS

The data from the current study indicate that the four galectins under study are associated with significant and separate prognostic values that depend on the Dukes stage of the colon tumor. In particular, the authors observed a significant prognostic value associated with galectins‐1, ‐3, and ‐4 in Dukes A and B colon tumors. In addition, significant prognostic value also was associated with galectin‐8 in Dukes C and D colon tumors. The prognostic values associated with the levels of expression of galectin‐1 and galectin‐4 in Dukes A and B tumors appear to be independent of the Dukes stage. The same feature was observed when galectin‐4 and galectin‐8 were analyzed in the complete series.

CONCLUSIONS

The data from the current study strongly suggest that galectins‐1, ‐3, and ‐4 may be involved in the early stages of human colon carcinoma development and that galectin‐8 is involved in the later stages. Cancer 2003;97:1849–58. © 2003 American Cancer Society.

DOI 10.1002/cncr.11268
Histopathologic score predicts recurrence free survival after radical surgery in patients with stage IA2–IB1–2 cervical carcinoma
Authors: Grisaru Dan A. , Covens Allan , Franssen Edmee , Chapman William , Shaw Patricia , Colgan Terence , Murphy Joan , DePetrillo Denny , Lickrish Gordon , Laframboise Stefane , Rosen Barry
Published: April 2003

BACKGROUND

The authors evaluated clinical and pathologic factors that predicted for recurrence after patients underwent radical surgery for International Federation of Gynecology and Obstetrics (FIGO) Stage IA2–IB1–2 cervical carcinoma and developed a simple method of scoring those predictive factors to quantify outcome.

METHODS

An analysis was conducted of a prospective radical surgery cervical carcinoma data base. A Cox proportional hazards regression analysis was done for each of the individual factors to estimate individual risk ratios using all available data for each factor. Stepwise and best‐model options were used to identify the best combinations as predictors and to calculate adjusted risk ratios. Based on the information obtained, each patient was assigned a categorical score to predict recurrence. The variables used for the score were dichotomized. The differences between the scores in time to recurrence were evaluated using the log‐rank test to compare the time to recurrence curves that were generated with the Kaplan–Meier method.

RESULTS

Eight hundred seventy‐one patients were included in the study, and 66 patients who developed recurrent disease after a median follow‐up of 49 months. Tumor size, maximum depth of invasion, pelvic lymph node status, tumor grade, and capillary lymphatic space (CLS) were single predictors for recurrence, and the score, which was based on combinations of these factors, predicted the disease free survival. Maximum depth of invasion, pelvic lymph node status, and CLS were the best combined predictors for recurrence, and they were used to form a second, precise scoring system to predict disease free survival (P < 0.0001; log‐rank test).

CONCLUSIONS

The scoring system based on maximal depth of invasion, CLS, and pelvic lymph node metastases identified four strata of patients with distinct recurrence free survival. The incremental presence of each factor decreased recurrence free survival after patients underwent radical surgery. Patients with the presence of all three factors had a 5‐year recurrence free survival rate of 65%. These patients would be suitable for studies of postoperative adjuvant therapy to improve outcome. Cancer 2003;97:1904–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11269
Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1‐mm thick)
Authors: Khayat David , Rixe Olivier , Martin Ginette , Soubrane Claude , Banzet Martine , Bazex Jacques‐André , Lauret Philippe , Vérola Olivier , Auclerc Gérard , Harper Peter , Banzet Pierre
Published: April 2003

BACKGROUND

This study addressed the question of whether limited surgery for primary malignant melanoma with a 2‐cm margin is as good as a 5‐cm margin. An update of a 16‐year follow‐up is provided.

METHODS

Nine European Centers, over a period of 5 years, prospectively randomized 337 patients with melanoma measuring less than 2.1 mm in thickness to undergo a local excision with either a 2‐cm or a 5‐cm margin. Three hundred twenty‐six patients were eligible for statistical analysis. Excluded from the trial were patients older than 70 years; those with melanomas from the toe, nail, or finger; and those with acral‐lentiginous melanoma. A separate randomization was performed to independently test an adjuvant treatment with a nonspecific immunostimulant, isoprinosine, compared with observation. The median follow‐up time was 192 months (16 years) for the estimation of survival and disease recurrences.

RESULTS

There were 22 tumor recurrences in the 2‐cm arm and 33 in the 5‐cm arm. The median time to disease recurrence was 43 months and 37.6 months, respectively. The 10‐year disease‐free survival rates were 85% for the group with a 2‐cm margin and 83% for the group with a 5‐cm margin. There was no difference in the 10‐year overall survival rates (87% vs. 86%). Isoprinosine did not demonstrate any activity in this setting.

CONCLUSIONS

The authors concluded that for melanoma less than 2.1‐mm thick, a margin of excision of 2 cm is sufficient. A larger margin of 5 cm does not appear to have any impact on either the rate or the time to disease recurrence or on survival. Cancer 2003;97:1941–6. © 2003 American Cancer Society.

DOI 10.1002/cncr.11272
Dose escalation study of tezacitabine in combination with cisplatin in patients with advanced cancer
Authors: Flaherty Keith T. , Stevenson James P. , Gallagher Maryann , Giantonio Bruce , Algazy Kenneth M. , Sun Weijing , Haller Daniel G. , O'Dwyer Peter J.
Published: April 2003

BACKGROUND

The authors performed a dose escalation study of cisplatin and the novel deoxycytidine analog, tezacitabine, to determine the maximum tolerated dose of the combination.

METHODS

Twenty‐three patients with advanced cancer and good performance status were accrued to 3 dose levels of tezacitabine (150–270 mg/m2) and cisplatin (50 mg/m2). Using a 28‐day treatment cycle, both drugs were administered on Days 1 and 15.

RESULTS

Hematologic toxicity was the most frequently observed side effect and was dose limiting. Grade 3 or 4 neutropenia and thrombocytopenia complicated 75% and 31% of all cycles, respectively. Nonhematologic toxicities were mild. Among 18 evaluable patients, 2 with upper gastrointestinal tract tumors achieved partial responses and 4 had stable disease.

CONCLUSIONS

Based on dose‐limiting neutropenia and thrombocytopenia at the highest dose level, the recommended Phase II doses are 200 mg/m2 of tezacitabine and 50 mg/m2 of cisplatin. Cancer 2003;97:1985–90. © 2003 American Cancer Society.

DOI 10.1002/cncr.11273
Late anthracycline cardiotoxicity after childhood cancer
Authors: Sorensen Keld , Levitt Gill A. , Bull Catherine , Dorup Inge , Sullivan Ian D.
Published: April 2003

BACKGROUND

The objective of the current study was to examine the risk factors for progression in severity of anthracycline‐induced cardiac dysfunction, thereby providing information that is useful in refining cancer treatment regimes and guiding follow‐up.

METHODS

Serial echocardiograms were performed on 101 acute lymphoblastic leukemia survivors and 83 Wilms tumor survivors after a mean interval of 6.2 years and 6.7 years since last anthracycline dose, respectively, at first study, and after 10.3 years and 11.1 years, respectively, at second study. The paired data were contrasted with data from 100 normal subjects, and potential correlations with follow‐up interval, cumulative dose, cancer diagnosis, gender, age at diagnosis, and growth were explored using univariate and multiple regression techniques.

RESULTS

The most important predictor of worsening cardiac performance was total anthracycline dose. As a group, patients receiving < 240 mg/m2 showed no deterioration of left ventricular end systolic stress at > 10 years from the end of treatment.

CONCLUSIONS

Survivors who have received low‐dose anthracycline require cardiac surveillance infrequently. In good prognosis tumors, cumulative anthracycline dose should be maintained at < 250 mg/m2. Cancer 2003;97:1991–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11274
Quinidine impairs proliferation of neurofibromatosis type 2‐deficient human malignant mesothelioma cells
Authors: Utermark Tamara , Alekov Alexi , Lerche Holger , Abramowski Vincent , Giovannini Marco , Hanemann Clemens Oliver
Published: April 2003

BACKGROUND

Human malignant mesotheliomas (HMMs) are aggressive tumors that arise from the mesothelium. They respond poorly to conventional tumor treatment and outcome is often fatal. Inactivating mutations of the neurofibromatosis type 2 (NF2) tumor suppressor gene merlin have been described in nearly 60% of primary malignant mesothelioma and in approximately 20% of the mesothelioma cell lines. Studies regarding human NF2 schwannoma cells revealed a higher proliferation and a larger noninactivating K+ outward current compared with controls. The enhanced proliferation of merlin‐deficient NF2 schwannoma cells could be reduced in the presence of quinidine, a K+ channel blocker, whereas the proliferation of normal Schwann cells is not affected. The current study was undertaken to evaluate the effect of quinidine on the proliferation of HMM cell lines in relation to their NF2 status.

METHODS

Proliferation analyses using bromodeoxyuridine incorporation was performed by immunocytochemical staining and fluorescence assisted cell sorting. The patch‐clamp technique was applied for electrophysiologic characterization of the HMM cell lines. The cytochrome P450 2D6 locus, known to be mutated at high frequencies in NF2 patients and to be specifically inhibited by quinidine, was screened for mutations by cycle sequencing.

RESULTS

Quinidine selectively reduces the proliferation of merlin‐deficient HMM cell lines by causing a G0/G1 arrest, whereas the proliferation rates of merlin‐expressing HMM cell lines remain unchanged. The effect of quinidine on the proliferation of HMM cell lines appears to be correlated with the NF2 gene status but not with the K+ outward current. No relation to cytochrome P450 2D6 mutations was detected.

CONCLUSIONS

Quinidine or quinidine analogs are of potential therapeutic interest for the subset of merlin‐deficient mesothelioma tumors. Cancer 2003;97:1955–62. © 2003 American Cancer Society.

DOI 10.1002/cncr.11275
Angiosarcoma after breast‐conserving therapy
Authors: Monroe Alan T. , Feigenberg Steven J. , Mendenhall Nancy Price
Published: April 2003

BACKGROUND

Angiosarcoma arising in the irradiated breast after breast‐conserving therapy is being reported with increasing frequency. As more women undergo breast‐conserving therapy, the incidence can be expected to increase. Surgeons, medical oncologists, and radiation oncologists will be faced with difficult management decisions for this aggressive disease.

METHODS

A comprehensive review of all English‐language reports of angiosarcomas after breast‐conserving therapy was performed. Approximately 100 cases were reviewed for treatment details and outcome analysis was performed.

RESULTS

Surgical excision is associated with very high rates of disease recurrence (55 of 75 patients with at least 1 year of follow‐up; 73%). Local disease recurrences in the tumor bed or along the mastectomy scar are a component of almost all recurrences (96%). Distant metastases develop simultaneously or shortly after local recurrences. Hyperfractionated radiotherapy has successfully prevented local disease recurrences in a limited number of patients.

CONCLUSIONS

Angiosarcoma after breast‐conserving therapy is increasingly diagnosed in a small but significant portion of breast carcinoma survivors. The aggressive nature of this disease demands further investigation of adjuvant therapy to prevent recurrence of disease after surgery. Cancer 2003;97:1832–40. © 2003 American Cancer Society.

DOI 10.1002/cncr.11277
False‐negative core needle biopsies of the breast
Authors: Shah Varsha I. , Raju Usha , Chitale Dhananjay , Deshpande Vikram , Gregory Nancy , Strand Vernon
Published: April 2003

BACKGROUND

A benign diagnosis in a core needle biopsy (CNBx) of the breast performed for a clinically and/or radiologically suspicious abnormality is often due to a nonrepresentative sample. However, the discordance may not be recognized, resulting in a logistic delay in the diagnosis.

METHODS

Twenty‐seven false‐negative CNBxs were identified in 952 consecutive CNBxs of the breast (653 benign, 266 malignant, and 33 atypical) performed during a 1‐year period. Biopsies were analyzed with respect to clinical and radiologic findings, biopsy type, type of malignancy, and interval between the original CNBx and final diagnosis. Four hundred thirty‐eight (67%) of the patients with a benign CNBx diagnosis either underwent excision or had a minimum of 1‐year follow‐up (mean, 35.6 months; median, 36 months).

RESULTS

The cancers missed on CNBx included 6 ductal carcinomas in situ, 17 invasive ductal carcinomas, 3 invasive lobular carcinomas, and 1 non‐Hodgkin lymphoma. The overall false‐negative rate was 9.1%. For palpable lesions, ultrasound‐guided CNBx had a lower rate of missed cancer (3.6%) compared with CNBx without image guidance (13.3%). The false‐negative rate for vacuum assisted CNBx biopsy was 7.6% (3.3% for the 11‐gauge needle, 22.2% for the 14‐gauge needle; 5.6% for nonpalpable mass lesions, 8.2% for microcalcifications). In all seven false‐negative CNBxs performed by radiologists, the discordance between the radiologic and pathologic findings was promptly recognized due to their standard follow‐up protocol. The discordance between the degree of clinical suspicion, radiologic impression, and the pathologic findings was not immediately recognized in 5 of 20 false‐negative CNBxs performed by surgeons (4 without radiologic guidance and 1 with ultrasound guidance), resulting in a delay in the diagnosis ranging from 112–336 days.

CONCLUSIONS

A false‐negative diagnosis of breast carcinoma was found to be more common in CNBx performed without image guidance but occurred to a lesser degree in image‐guided biopsies. A delay in diagnosis can be avoided by establishing a standard post‐CNBx follow‐up protocol. Cancer 2003;97:1824–31. © 2003 American Cancer Society.

DOI 10.1002/cncr.11278
Induction of intensive tumor suppression by antiangiogenic photodynamic therapy using polycation‐modified liposomal photosensitizer
Authors: Takeuchi Yoshito , Kurohane Kohta , Ichikawa Kanae , Yonezawa Sei , Nango Mamoru , Oku Naoto
Published: April 2003

BACKGROUND

The authors previously observed that antiangiogenic scheduling of photodynamic therapy (PDT) was effective in causing tumor regression through hemostasis. It would thus be expected that photosensitizer entrapped in polycation liposomes (PCLs) would be efficiently taken up in tumor‐derived angiogenic vascular endothelial cells due to the strong electrostatic adhesion between the polycation and the plasma membrane, thus resulting in enhanced phototherapeutic efficacy.

METHODS

Tumors and angiogenesis were induced by subcutaneous injection of Meth‐A sarcoma cells into 5‐week‐old male BALB/c mice. PDT treatment was performed by an intravenous (i.v.) injection of benzoporphyrin derivative monoacid ring A (BPD‐MA)‐entrapped liposomes or the PCLs (0.25 mg/kg in terms of BPD‐MA), followed by exposure to a laser light of 689 nm with 150 J/cm2 of fluence 15 minutes post injection.

RESULTS

As a result of PDT on angiogenesis‐model mice prepared by the dorsal air sac technique, neovascular destruction after laser irradiation was observed when BPD‐MA entrapped in PCLs was used. Furthermore, strong suppression of tumor growth was identified by the PCL‐mediated PDT treatment along with a prolonged life span for the mice. Destruction of angiogenic vessels and subsequent tumor cell apoptosis were observed after PCL‐mediated PDT treatment in an immunofluorescence study. Interestingly, the biodistribution of the injected BPD‐MA that was delivered by PCLs indicated invariable photosensitization levels in tumor tissues.

CONCLUSIONS

The study revealed that antiangiogenic PDT treatment using a low dose of BPD‐MA entrapped in PCLs efficiently induced the destruction of angiogenic vessels and subsequent tumor suppression by vessel occlusion. Cancer 2003;97:2027–34. © 2003 American Cancer Society.

DOI 10.1002/cncr.11283
Role of surgery for nonmetastatic abdominal rhabdomyosarcomas
Authors: Cecchetto Giovanni , Bisogno Gianni , Treuner Jorn , Ferrari Andrea , Mattke Adrian , Casanova Michela , Dall'Igna Patrizia , Zanetti Ilaria , Volpato Sandra , Siracusa Fortunato , Scarzello Gianni , Boglino Camillo , Carli Modesto
Published: April 2003

BACKGROUND

In the current study, the authors aim to evaluate clinical features and treatment results observed in patients from the German and Italian studies who had nonmetastatic abdominal rhabdomyosarcomas (RMS).

METHODS

One hundred sixty‐one patients were observed; 78 registered in the German studies between October 1980 and August 1995, and 83 registered in the Italian studies between April 1975 and December 1995. The age range of the patients was 0–18 years (median, 4 yrs). The distribution of tumor sites was as follows: 32 intraperitoneal, 42 retroperitoneal, 75 pelvic, and 12 not otherwise specified (NOS). Most patients had a large and invasive primary mass (26 T1b, 114 T2b). The breakdown in histology was as follows: 116 embryonal, 34 alveolar, and 11 other (leiomyomatous, pleomorphic, and NOS); all cases were staged according to the Intergroup Rhabdomyosarcoma Studies (IRS) system. Nine Group I patients were treated after surgery with chemotherapy (CT) (radiotherapy [RT] was delivered to treat alveolar RMS in the 1991 German and 1988 Italian studies); 19 Group II patients received CT + RT (40–44 Gy); 133 Group III patients underwent neoadjuvant CT ± surgery and/or RT (54 Gy) + CT. Different CT regimens (based primarily on the administration of vincristine, dactinomycin, doxorubicin, and cyclophosphamide or ifosfamide) were adopted. RT was not recommended for patients age < 3 years.

RESULTS

The 10‐year overall survival (OS) and progression‐free survival (PFS) were 47.2% and 43.9%, respectively. The OS was related significantly to the following variables: histology (alveolar, 29.4% vs. nonalveolar, 52.1% [P = 0.0156]), tumor size (> 5 cm, 42.1% vs. < 5 cm, 81% [P = 0.005]), age (< 10 yrs, 51.4% vs. ≥ 10 yrs, 27.8% [P = 0.02]), complete surgery at diagnosis or after CT (±RT) (70.4% vs. 34.4% without it [P = 0.0015]). Most patients who achieved the delayed local control had responded well to neoadjuvant CT.

CONCLUSIONS

Tumor size, histology, age, and initial or delayed achievement of local control were important prognostic factors. Most relapsed patients had unfavorable outcomes. Cancer 2003;97:1974–80. © 2003 American Cancer Society.

DOI 10.1002/cncr.11285
Phase II trial of gemcitabine in patients with advanced sarcomas (E1797)
Authors: Okuno Scott , Ryan Louise M. , Edmonson John H. , Priebat Dennis A. , Blum Ronald H.
Published: April 2003

BACKGROUND

The current study was conducted to evaluate the antitumor activity and toxicity of gemcitabine in patients with advanced sarcoma.

METHODS

Twenty‐five patients with advanced sarcomas, who previously were untreated for metastatic disease, were treated on an Eastern Cooperative Oncology Group Phase II study. Patients ranged in age from 27 to 79 years, with a median age of 59 years. The most common histology was leiomyosarcoma (54%). The grades of the tumors were high in 40%, moderate in 24% and low in 12%. Gemcitabine was given at a dose of 1250 mg/m2 as a 30‐minute infusion weekly for 3 weeks followed by 1 week of rest.

RESULTS

One of the 25 patients (4%) (90% confidence interval [90% CI], 0–18%) achieved a partial response lasting 8 months. The estimated overall median survival was 15 months. The 1‐year estimated survival rate was 63% (90% CI, 47–84%). The estimated median progression‐free survival (PFS) was 13 months with a 1‐year PFS rate of 56% (90% CI, 41–76%). Grade 3–4 toxicities (by CTC criteria) were observed in all 25 patients. No lethal toxicity (Grade 5) related to treatment was found.

CONCLUSIONS

The results of the current study demonstrated that gemcitabine given at this schedule and dose in this population of patients with advanced sarcoma had limited activity. Cancer 2003;97:1969–73. © 2003 American Cancer Society.

DOI 10.1002/cncr.11290
Fibrolamellar hepatocellular carcinoma in children and adolescents
Authors: Katzenstein Howard M. , Krailo Mark D. , Malogolowkin Marcio H. , Ortega Jorge A. , Qu Wenchun , Douglass Edwin C. , Feusner James H. , Reynolds Marleta , Quinn John J. , Newman Kurt , Finegold Milton J. , Haas Joel E. , Sensel Martha G. , Castleberry Robert P. , Bowman Laura C.
Published: April 2003

BACKGROUND

Children with hepatocellular carcinoma (HCC) were treated on a prospective, randomized trial and were then analyzed to determine whether children with the fibrolamellar (FL) histologic variant of HCC have a more favorable presentation, increased surgical resectability, greater response to therapy, and improved outcome compared with children who have typical HCC.

METHODS

Forty‐six patients were enrolled on Pediatric Intergroup Hepatoma Protocol INT‐0098 (Pediatric Oncology Group Study 8945/Children's Cancer Group Study 8881) between August 1989 and December 1992. After undergoing initial surgery or biopsy, children with Stage I HCC (n = 8 patients), Stage III HCC (n = 25 patients), and Stage IV HCC (n = 13 patients) were assigned randomly, regardless of histology, to receive treatment either with cisplatin, vincristine, and fluorouracil (n = 20 patients) or with cisplatin and continuous‐infusion doxorubicin (n = 26 patients).

RESULTS

Ten of 46 patients (22%) had the fibrolamellar variant of HCC (FL‐HCC). For the entire cohort, the estimated 5‐year event free survival (EFS) rate (± standard deviation) was 17% ± 6%. There was no difference in outcome among patients who were treated with either regimen. The 5‐year EFS rate for patients with FL‐HCC was no different the rate for patients with typical HCC (30% ± 15% vs. 14% ± 6%, respectively; P = 0.18), although the median survival was longer in patients with FL‐HCC. There was no difference in the number of patients with advanced‐stage disease, the incidence of surgical resectability at diagnosis, or the response to treatment between patients with FL‐HCC and patients with typical HCC.

CONCLUSIONS

Children with FL‐HCC do not have a favorable prognosis and do not respond any differently to current therapeutic regimens than patients with typical HCC. Children with initially resectable HCC have a good prognosis irrespective of histologic subtype, whereas outcomes are poor uniformly for children with advanced‐stage disease. The use of novel chemotherapeutic agents and the incorporation of other treatment modalities are indicated to improve the dismal survival of pediatric patients with all histologic variants of advanced‐stage HCC. Cancer 2003;97:2006–12. © 2003 American Cancer Society.

DOI 10.1002/cncr.11292