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THE OUTCOME OF COMBINED-MODALITY TREATMENTS FOR STAGE I AND II PRIMARY LARGE B-CELL LYMPHOMA OF THE MEDIASTINUM
Linh N. Nguyen, M.D., Chul S. Ha, M.D., Mark Hess, B.B.A., Jorge E. Romaguera, M.D., Johnn T. Manning, M.D., Fernando Cabanillas, M.D. and James D. Cox, M.D.

Purpose: Primary mediastinal large B-cell lymphoma (PML) has clinicopathologic features distinct from those of other diffuse large-cell lymphomas. However, the optimal treatment for this tumor is evolving, and in particular, the role of radiation therapy remains undefined. We conducted a retrospective review to evaluate the role of radiation therapy in this disease.

Methods and Materials: The medical records of 40 consecutive patients with Ann Arbor Stage I or II PML treated at our institution from January 1980 to December 1995 were reviewed. There were 18 patients with Stage I disease and 22 patients with Stage II disease; 62.5% were women and 37.5% were men. The median age was 32.4 years (range, 17-74 years). The tumor scores were 0 in 1 patient, I in 5 patients, II in 13 patients, III in 7 patients, IV in 4 patients, and unknown in 10 patients. The International Prognostic Index (IPI) was 0 in 10 patients, I in 26 patients, II in 2 patients, and unknown in 2 patients. All patients were treated with doxorubicinbased chemotherapy, and 35 patients received radiation therapy. For most patients who received radiation therapy, an involved field or a modified-mantle field was used, and a dose of 40 Gy in 20 fractions or 39.6 Gy in 22 fractions was administered. Univariate analysis was performed to identify prognostic factors.

Results: The median follow-up in surviving patients was 56 months (range, 19-194 months). The actuarial 5-year relapse-free survival (RFS) rate and overall survival (OS) rate for all patients were 67% and 72%, respectively. Thirty-five patients achieved a complete response; 32 of these patients received radiation therapy. The patterns of failure for the complete responders were as follows: locoregional failure alone for 1 patient (at the margin of the radiation field); distant failure alone for 5 patients; and both locoregional (in-field) and distant failure for 1 patient. There were no failures after 2.5 years. None of the 5 patients who never achieved a complete response had local control, and all died with disease. Only 2 of the 5 completed the planned course of radiation therapy; both had massive mediastinal disease. There was no treatment-related death from the initial chemotherapy or radiation therapy. One patient developed a second malignancy (sarcoma) within the radiation field after 13 years. The tumor score was a significant predictor of RFS (p = 0.016) and OS (p = 0.006), but the IPI did not prove to be a significant predictor.

Conclusion: We recommend consolidative radiation therapy in view of the excellent local control and the lack of significant toxicity. Modified mantle or involved field appears to be an adequate volume, and 39.6-40 Gy appears to be an adequate dose. The tumor score is a significant prognostic factor.

Key words: Mediastinal large B-cell lymphoma, Lymphoma, Radiation therapy, Combined modality treatment.

THE INFLUENCE OF THE RADICALITY OF RESECTION AND DOSE OF POSTOPERATIVE RADIATION THERAPY ON LOCAL CONTROL AND SURVIVAL IN CARCINOMAS OF THE UPPER AERODIGESTIVE TRACT
Leo Pfreundner, M.D., Jochen Willner, M.D., Alexander Marx, M.D., Florian Hoppe, M.D., Gabriele Beckmann, M.D. and Michael Flentje, M.D.

Purpose: To evaluate dose concepts in postoperative irradiation of carcinomas of the upper aerodigestive tract according to the radicality of resection.

Patients and Methods: In a retrospective analysis, the charts of 257 patients with histologically-proven carcinoma of the upper aero tgestive tract (40 T1, 80 T2, 53 T3, 84 T4 tumors, with nodal involvement in 181 cases) were reviewed according to the radicality of resection and dose of irradiation administered. Sixty-four patients had tumor-free resection margins (> 3 mm), 66 patients had close resection margins (< 3 mm), and 101 patients had R1 resections, and 26 patients had R2 resections. A median dose of 56 Gy was applied to the primary tumor bed and the cervical lymphatics (2 Gy/fraction, 5 fractions/week). In cases of Rl or R2 resection, or of close margins (< 3 mm), the tumor bed or, respectively, tumor residuals were boosted with doses up to a median of 66 Gy. Locoregional tumor control and survival was investigated by uni- and multivariate analyses according to T-, N-stage, grade of resection, total dose of radiation, and presence or absence of extracapsular tumor spread and lymphangiosis carcinomatosa.

Results: An overall 3- and 5-year survival rate of 60% and 45%, respectively, was achieved. Rates for freedom rom ocoregional recurrence were 77% and 72% at 3 and 5 years, respectively. The survival rates according to the grade of resection at 5 years were 67% for patients resected with tumor-free margins, 59% for patients resected with close margins, 26% for patients with R1 resection, and 27% for patients with R2 resection. Within a median follow-up period of 4.7 years for living patients, a total of 67 recurrences (26%) were observed (in 9% of patients resected with tumor-free margins, in 27% with close margins, in 37% of RI resected, and in 19% of R2 resected patients). Freedom from locoregional recurrence at 3 years was achieved in 100% of the patients resected with tumor-free margins, in 92% of patients resected with close surgical margins, in 87% of RI and 69% of R2 resected patients. In multivariate Cox-regression analysis, the variables grade of resection (p = 0.00031) and total dose of irradiation (p = 0.0046) were found as factors influencing locoregional control. Variables influencing survival according to multivariate analysis are T-stage (p = 0.0057), N-stage (p = 0.024), grade of resection (p = 0.000015), total dose of irradiation (p < 0.000000). Extracapsular tumor spread and lymphangiosis carcinomatosa are factors of borderline significance (p = 0.055, p = 0.066).

Conclusion: In postoperative radiotherapy of head and neck carcinomas, doses adapted to the risk of locoregional recurrent disease should be applied. Patients with R1 and R2 resections should be treated with doses of more than 68 Gy (2 Gy/fraction, 5 fractions/week) (with close margins [< 3 mm] more than 66 Gy) to achieve an improvement in locoregional control and survival.

Key words: Head and neck cancer, Postoperative radiotherapy, Resection margins, Radiation dose.

LARYNGEAL AND HYPOPHARYNGEAL CANCERS AND OCCUPATIONAL EXPOSURE TO FORMALDEHYDE AND VARIOUS DUSTS: A CASE-CONTROL STUDY IN FRANCE
Laurent Laforest, Danièle Luce, Paquerette Goldberg, Denis Bégin, Michel Gérin, Paul A Demers, Jacques Brugère, Annette Leclerc

Objectives: A case-control study was conducted in France to assess possible associations between occupational exposures and squamous cell carcinomas of the larynx and hypopharynx.

Methods: The study was restricted to men, and included 201 hypopharyngeal cancers, 296 laryngeal cancers, and 296 controls (patients with other tumour sites). Detailed information on smoking, alcohol consumption, and lifetime occupational history was collected. Occupational exposure to seven substances (formaldehyde, leather dust, wood dust, flour dust, coal dust, silica dust, and textile dust) was assessed with a job exposure matrix. Exposure variables used in the analysis were probability, duration, and cumulative level of exposure. Odds ratios (ORs) with their 95% confidence intervals (95% CIs) were estimated by unconditional logistic regression, and were adjusted for major confounding factors (age, smoking, alcohol, and when relevant other occupational exposures).

Results: Hypopharyngeal cancer was found to be associated with exposure to coal dust (OR 2.31, 95% CI 1.21 to 4.40), with a significant rise in risk with probability (p < 0.045 for trend) and level (p < 0.007 for trend) of exposure. Exposure to coal dust was also associated with an increased risk of laryngeal cancer (OR 1.67, 95% CI 0.92 to 3.02), but no doseresponse pattern was found. A significant relation, limited to hypopharyngeal cancer, was found with the probability of exposure to formaldehyde (p < 0.005 for trend), with a fourfold risk for the highest category (OR 3.78, 95% CI 1.50 to 9.49). When subjects exposed to formaldehyde with a low probability were excluded, the risk also increased with duration (p < 0.04) and cumulative level of exposure (p < 0.14). No significant association was found for any other substance.

Conclusion: These results indicate that exposure to formaldehyde and coal dust may increase the risk of hypopharyngeal cancer.

Key words: laryngeal cancer; hypopharyngeal cancer; occupational exposure; job exposure matrix; formaldehyde; coal dust.

SUPRACRICOID LARYNGECTOMY WITH CHEP: FUNCTIONAL RESULTS AND OUTCOME
Roberto A. Lima, MD, Emilson Q. Freitas, MD, Jacob Kligerman, MD, Fernando L. Dias, MD, Mauro M. Barbosa, MD, Geraldo M. SA, MD, Izabella C. Santos, MD and Terence Farias, MD, Rio de Janeiro, Brazil

Objectives: To assess whether supracricoid laryngectomy with cricohiodoepiglottopexy could successfully reach the cure and preserve the voice in glottic laryngeal cancer, we studied 27 patients with T2/T3 squamous cell carcinoma of the larynx treated in our institution with cricohiodoepiglottopexy.

Study Design: A retrospective analysis has been carried out between 1995 through 1997. We classified 11 patients as MOW and 16 patients as MOW. Nineteen patients had bilateral selective lateral neck dissection, 3 patients had unilateral lateral neck dissection, and 5 patients had undissected neck. Survival was analyzed under the Kaplan-Meyer method.

Results: Five patients had postoperative complications, 2 were treated with a total laryngectomy. The remaining 25 patients kept the normal airway, swallowing, and speech. None of the patients in the neck dissection group had neck metastasis. Two patients had recurrences, 1 with local recurrence was treated with a total laryngectomy and is alive without disease; the other patient had neck recurrence, was treated with radical neck dissection plus radiotherapy, and is dead of the disease. One patient had a second tumor in oropharynx treated with palliative radiotherapy and is dead of the disease. Three years disease-free survival was 75% for T2 and 79% for T3.

Conclusions: This technique is useful in the treatment of selected cases of T3/T2 glottic cancer regarding the extent of disease. The incidence of complications in need of a complete laryngectomy does not compromise the functionality of this technique. The survival is comparable to patients who submitted to total laryngectomy and near-total laryngectomy, regarding the extent of the lesion.

EPIDEMIOLOGY OF BLOODSTREAM INFECTIONS AT A CANCER CENTER

Eduardo Velasco, MD, PhD, Luiz Claudio Santos Thuler, MD, MSc, PhD, Carlos Alberto de Souza Martins, MD, Márcio Nucci, MD, PhD, Leda Maria Castro Dias, RN and Vânia Maria da Silva Castro Gonçalves, RN

Context: Cancer patients are at unusually high risk for developing bloodstream infections (BSI), which are a major cause of in-hospital morbidity and mortality.

Objective: To describe the epidemiological characteristics and the etiology of BSI in cancer patients.

Design: Descriptive study.

Setting: Terciary Oncology Care Center.

Participants: During a 24-month period all hospitalized patients with clinically significant BSI were evaluated in relation to several I clinical and demographic factors.

Results: The study enrolled 435 episodes of BSI (349 patients). The majority of the episodes occurred among non-neutropenic patients (58.6%) and in those younger than 40 years (58.2%). There was a higher occurrence of unimicrobial infections (74.9%). nosocomial episodes (68.3%) and of those of undetermined origin (52.8%). Central venous catheters (CVC) were present in 63.2% of the episodes. Overall, the commonest isolates from blood in patients with hematology diseases and solid tumors were staphylococci (32% and 34.7%, respectively). There were 70 episodes of fungemia with a predominance of Candida albicans organisms (50.6%). Fungi were identified in 52.5°.6 of persistent BSI and in 91.4% of patients with CVC. Gram-negative bacilli prompted the CVC removal in 45.5% of the episodes. Oxacillin resistance was detected in 26.3% of Staphylococcus aureus isolates and in 61.8% of coagulase-negative Staphylococcus. Vancomycin-resistant enterococci were not observed. Initial empirical antimicrobial therapy was considered appropriate in 60.5% of the cases.

Conclusion: The identification of the microbiology profile of BSI and the recognition of possible risk factors in high-risk cancer patients may help in planning and conducting more effective infection control and preventive measures, and may also allow further analytical studies for reducing severe infectious complications in such groups of patients.

Key words: Bloodstream infection. Cancer. Epidemiology. Microbiology.

LOSS OF PTEN EXPRESSION LEADING TO HIGH AKT ACTIVATION IN HUMAN MULTIPLE MYELOMAS
Teresa Hyun, Alan Yam, Salvatore Pece, Xiaozhen Xie, Jie Zhang, Toru Miki, J. Silvio Gutkind and Weiqun Li

Mouse plasma cell tumor (PCT) and human multiple myeloma (MM) are terminal B-cell malignancies sharing many similarities. Our recent work demonstrated that activation of the insulin-like growth factor receptor (IGF-IR)/insulin receptor substrate (IRS)/ phosphatidylinositol 3' kinase (PI 3’K) pathway was evident in the tumor lines derived from both species. Although PI 3’K activity was higher in mouse tumor lines than that in human tumors, activation of Akt serine/threonine kinase was markedly lower in mouse lines. This discrepancy prompted us to test the status of PTEN tumor suppressor gene, as it has been shown to be a negative regulator of PI 3’K activity. Although all the mouse lines expressed intact PTEN, 2 of the 4 human lines (047 and OPM2) possessing the highest Akt activity lost PTEN expression. Sequencing analysis demonstrated that the PTEN gene contains a deletion spacing from exon 3 to exon 5 or 6 in the 047 line and from exon 3 to 7 in the OPM2 line. Restoration of PTEN expression suppressed IGF-I-induced Akt activity, suggesting that loss of PTEN is responsible for uncontrolled Akt activity in these 2 lines. Despite the expression of PTEN with the concomitant low Akt activity in all mouse PCT lines, their p70S6K activities were generally higher than those in 3 human MM lines, arguing for specific negative regulation of Akt, but not p70S6K by PTEN. These results suggest that p70S6K and Akt may be differentially used by the plasma cell tumors derived from mice and humans, respectively.

TEL-AML1 FUSION GENE FREQUENCY IN PAEDIATRIC ACUTE LYMPHOBLASTIC LEUKAEMIA IN BRAZIL
I. Q. Magalhães, M. S. Pombo-de-Oliveira, C. A. Bennett, J. C. Cordoba, J. Dobbin, A. M. Ford and M. F. Greaves

We analysed 67 samples from Brazilian children of diverse ethnic origins with acute lymphoblastic leukaemia (ALI,) for the presence of the TEL-AMLI fusion gene transcripts using reverse transcription polymerase chain reaction (RT-PCR). All 12 positive cases (20 ‘7r of the 60 Bcell precursor ALL) had common (CD 10+) ALL with a mean age of 4 years (range 1-10 years). We conclude that the frequency, age, distribution and clinical features of the TEL-AML I fusion gene-positive ALL is similar in the diverse ethnic backgrounds of the Brazilian children to that in other countries with predominantly white Caucasian or oriental ethnicity. Apparent exceptions to this generality are discussed.

Keywords: TEL-AML l fusion gene. common acute lymphoblastic leukaemia, Brazil.

INCIDENCE OF P14^ARF GENE DELETION IN HIGH-GRADE ADULT AND PEDIATRIC ASTROCYTOMAS
Elizabeth W. Newcomb, PhD, Michelle Alonso, BA, Tammy Sung, BSc and Douglas C. Miller, MD, PhD

The INK4a-ARF locus encodes 2 separate proteins through differential splicing of alternative first exons to produce p16^INK4a (exon 1a) and p14^ARF (exon 1b) products in human cells. The p16^INK4a protein inhibits the cyclin D-dependent kinases (CDK) that control the phosphorylation of the Rb protein and cell proliferation. The p14ARF gene product can complex with and sequester the MDM2 protein within the nucleus, thus modulating the activity of the p53 protein. Loss of p16^INK4a expression would disrupt the retinoblastoma (Rb)/p16^INK4a/cycIin D-dependent kinase (CDK4) pathway, whereas loss of p14ARF expression would inactivate both the Rb and p53/MDM2/p14ARF pathways through MDM2, which can complex with either Rb or p53. Loss of the p16^INK4a gene on 9p21 has been documented in a wide range of human tumors, including one third of glioblastomas. However, in tumors showing homozygous loss of exon 2 of the p16^INK4a gene, loss of exon 1b of the p14^ARF gene has not been established. In this study, we have assessed deletion of the p14^ARF gene in 29 pediatric and 107 adult high-grade astrocytomas and 9 glioma cell lines, using multiplex PCR analysis for exon 1 0. We found homozygous deletions for exon la and exon 1b in 3 of 29 (10%) of the pediatric cases (2 grade III, 1 grade Ice, 25 of 107 (23%) of the adult cases (6 grade III and 19 grade Ice, and 8 of 9 (89%) of the glioma cell lines. Therefore, loss of the INK4a-ARF locus in high-grade astrocytomas may contribute to the highly malignant behavior and treatment resistance of these tumors through elimination of multiple checkpoint cell cycle control proteins.

Key words: astrocytoma, glioblastoma, p16^INK4a , p14^ARF, INK4a-ARF locus.

Abbreviations: CDT, cyclin-dependent kinase; DMSO, dimethylsulfoxide; PCP, polymerase chain reaction; PBL, peripheral blood lymphocytes.

CLINICAL CLASSIFICATION AND STAGING
Jeffrey E. Gershenwald, MD, David Fischer, MD and Antonio C. Buzaid, MD

For clinicians and researchers to make meaningful comparisons across patient populations, a cancer staging system must be standardized, uniformly accepted, and widely applied. It must be simple, practical, and must accurately reflect the prognosis of patients. Developing a staging system for melanoma is particularly difficult, however, because its biologic behavior is so often unpredictable. Nevertheless, researchers have modified the cutaneous melanoma staging system several times over the past five decades as a direct result of the identification of increasingly powerful prognostic determinants. The current staging is based on today’s well-established prognostic factors, but future changes are inevitable as the understanding of the clinical progression of melanoma metastasis is refined.

This article provides a brief historical perspective and critical review of the staging systems for cutaneous melanoma. Recent advances in the surgical staging of patients with primary melanoma are introduced (e.g., sentinel lymphadenectomy, and future directions are discussed.

The article emphasizes the details of the current staging system and makes practical recommendations for stage-specific evaluation according to patient presentation.

SURVIVAL AFTER OPERATIONS FOR COLORECTAL CANCER IN PATIENTS AGED 75 YEARS OR OVER
Jyrki T. Mäkelä, Heikki Kiviniemi and Seppo Laitinen

Objective: To define factors that predict mortality and survival in patients with colorectal cancer who are aged 75 or over.

Design: Retrospective study.

Setting: University hospital, Finland.

Subjects: 231 patients aged 75 or over who were admitted to hospital with colorectal cancer during the 14-year period 1980-93. Main outcome measures: Morbidity, mortality, recurrence, and survival.

Results: In-hospital mortality after any kind of operation was 8/211 (4%), and 8/175 (5%) of those who had their tumours resected. Morbidity was 35/ 175 (20%). Factors associated with mortality were weight loss, Dukes’stage, extent of resection, and type of operation. Overall 5-year survival was 28%, overall l0-year survival was 4%, and median survival was 33 months (range 0-150). Survival was most closely related to Duke’s stage, extent of resection, and recurrent disease on univariate analysis, but multivariate analysis identified only mode of recurrence (p < 0.0001), recurrent disease (p < 0.004), and extent of resection (p < 0.009) as independent predictors of survival. The recurrence rate after radical resection was 49/141 (35%) and the median disease-free interval was 10 months (range 4-64). Mortality after resection for recurrent cancer was 3/17 (18%) and morbidity 5/17 (29%).

Conclusion: Age alone is not a risk factor for postoperative mortality or a predictor of long-term survival. Low mortality and acceptable long-term survival can be achieved in patients aged 75 or over if those with extensive distant metastases, and those whose general condition is too poor to stand a major operation, are treated conservatively.

Key words: colorectal cancer, surgery, survival, elderly patients.

OPERATIONS FOR EXTRAHEPATIC BILE DUCT CANCERS: ARE THE RESULTS REALLY IMPROVING?
Gert Lindell, Lars Hansson, Sigmund Dawiskiba, Roland Andersson, Jan Axelson and Ingemar Ihse

Objective: To find out if our results for the treatment of extrahepatic bile duct cancer have improved we reviewed our latest patients as a comparison to a previously reported series from this department.

Design: Retrospective study.

Setting: Tertiary referral centre, Sweden.

Subjects: 102 patients who presented with extrahepatic bile duct cancer 1979-1995.

Main outcome measures: Morbidy, mortality, and short and long tern survival.

Results: 16 patients had various types of resection, which were radical in 14 according to the surgeon and in 10 according to the pathologist. One patient (6 %) died in hospital, and 11 (44 %) developed complications. 13 patients had other operations that did not involve resection, 23 had laparotomy alone, 61 had biliary drainage either by percutaneous transhepatic cholangiography (PTC) or endoscopy, and 10 had no active treatment. One patient of the 16 (6 %) who had resections has survived for more than five years and another one is still alive after 40 months.

Conclusion: Long term survival has not improved for patients with extrahepatic bile duct cancer in our hospital during the last decades.

Key words: bile duct cancer, long term survival, postoperative complications, resection.

SURVIVAL AFTER RESECTION OF MULTIPLE HEPATIC COLORECTAL METASTASES

Background: Hepatic resection is potentially curative in selected patients with colorectal metastases. It is a widely held practice that multiple colorectal hepatic metastases are not resected, although outcome after removal of four or more metastases is not well defined.

Methods: Patients with four or more colorectal hepatic metastases who submitted to resection were identified from a prospective database. Number of metastases was determined by serial sectioning of the gross specimen at the time of resection. Demographic data, tumor characteristics, complications, and survival were analyzed.

Results: From August 1985 to September 1998, 155 patients with four or more metastatic tumors (range 4-20) underwent potentially curative resection by extended hepatectomy (39%), lobectomy (42%), or multiple segmental resections (19%). Operative morbidity and mortality were 26% and 1%, respectively. Actuarial 5-year survival was 23% for the entire group (median = 32 months) and there were 12 actual 5-year survivors. On multivariate analysis, only number of hepatic tumors (P = .005) and the presence of a positive margin (P = .003) were independent predictors of poor survival.

Conclusions: Hepatic resection in patients with four or more colorectal metastases can achieve long-term survival although the results are less favorable as the number of tumors increases. Number of hepatic metastases alone should not be used as a sole contraindication to resection, but it is clear that the majority of patients will not be cured after resection of multiple lesions.

Key words: Colorectal hepatic metastases; Liver neoplasm; Liver resection; Prognosis.

DOES LAPAROSCOPIC CHOLECYSTECTOMY WORSEN THE PROGNOSIS OF UNSUSPECTED GALLBLADDER CANCER?
Leopoldo Sarli, MD, Sandro Contini, MD, Giuliano Sansebastiano, Sara Gobbi, MD, Renato Costi, MD and Luigi Roncoroni, MD

Background: Several reports claim that there is a risk that laparoscopic cholecystectomy (LC) might worsen the prognosis of unsuspected gallbladder cancer.

Hypothesis: Several factors rather than LC could influence prognosis.

Methods: A retrospective clinicopathologic study was performed on 20 patients, 9 patients (3 men and 6 women, aged from 36 to 75 years [mean age, 62.3 years]) undergoing LC and 11 patients (2 men and 9 women, aged from 53 to 91 years [mean age, 65.3 years]) undergoing open cholecystectomy (OC), with postoperatively diagnosed gallbladder cancer. The correlation was evaluated between cumulative survival rates and the following 7 prognostic factors: age, sex, histopathological grade, pathologic stage, occurrence of bile spillage, type of cholecystectomy (LC or OC), and additional surgical treatments.

Results: Seven patients (87%) after LC and 9 patients (82%) after OC had cancer recurrence: the difference is of no statistical significance (P=.9). There were no recurrences of cancer in the abdominal wall after either LC or OC. Survival rate was statistically correlated to tumor stage (P=.007) and to the occurrence of bile spillage (P=.002). Survival rate did not change according to whether the operation was carried out using LC or OC (P=.60).

Conclusion: These results would seem to lend support to the opinion that LC does not worsen the prognosis for unsuspected gallbladder cancer.

COMPARISON OF MINIMALLY INVASIVE ESOPHAGECTOMY WITH TRANSTHORACIC AND TRANSHIATAL ESOPHAGECTOMY
Ninh T. Nguyen, MD, David M. Follette, MD, Bruce M. Wolfe, MD, Philip D. Schneider, MD, PhD, Peter Roberts, MD and James E. Goodnight, Jr, MD, PhD

Hypothesis: Minimally invasive esophagectomy can be performed as safely as conventional esophagectomy and has distinct perioperative outcome advantages.

Design: A retrospective comparison of 3 methods of esophagectomy: minimally invasive, transthoracic, and blunt transhiatal.

Setting: University medical center.

Patients: Eighteen consecutive patients underwent combined thoracoscopic and laparoscopic esophagectomy from October 9, 1998, through January 19, 2000. These patients were compared with 16 patients who underwent transthoracic esophagectomy and 20 patients who underwent blunt transhiatal esophagectomy from June 1, 1993, through August 5, 1998.

Main Outcome Measures: Operative time, amount of blood loss, number of operative transfusions, length of intensive care and hospital stays, complications, and mortality.

Results: Patients who had minimally invasive esophagectomy had shorter operative times, less blood loss, fewer transfusions, and shortened intensive care unit and hospital courses than patients who underwent transthoracic or blunt transhiatal esophagectomy. There was no significant difference in the incidence of anastomotic leak or respiratory complications among the 3 groups.

Conclusion: Minimally invasive esophagectomy is safe and provides clinical advantages compared with transthoracic and blunt transhiatal esophagectomy.

PROGNOSIS AND SURGICAL MANAGEMENT OF PATIENTS WITH PALPABLE INGUINAL LYMPH NODE METASTASES FROM MELANOMA
T. M. D. Hughes, R. P. A’Hern and J. M. Thomas

Background: The appropriate management of melanoma metastatic to inguinal lymph nodes remains controversial. The aim of this study was to identify disease- and treatment-related factors that influence the outcome of patients undergoing therapeutic groin dissection for clinically detectable melanoma lymph node metastases.

Methods: A retrospective analysis was performed on data collected from the case records of patients who had a therapeutic inguinal lymph node dissection performed between 1984 and 1998.

Results: Some 132 patients were suitable for inclusion. Sixty patients had superficial inguinal lymph node dissection (SLND) and 72 had combined superficial inguinal and pelvic lymph node dissection (CLND). There was no difference in postoperative morbidity or major lymphoedema between SLND and CLND. The overall survival rate was 34 per cent at 5 years. On univariate analysis, age (P=0.003), the number of involved superficial lymph nodes (P=0.001) and the presence of extracapsular spread (P=0.003) were found to have a significant impact on survival. The presence or absence of pelvic lymph node metastases in patients who had CLND was a significant prognostic factor for survival (5-year survival 19 versus 47 per cent; P= 0.015).

Conclusion: The prognosis of patients with clinically detectable melanoma metastases to the groin is variable and related to the biological characteristics of each case. CLND provided additional prognostic information and optimal regional control with no increased morbidity compared with SLND.

MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 1 (MRP1) EXPRESSION IN NEUROBLASTOMA CELL LINES AND PRIMARY TUMORS
Hiroaki Goto, MD, Nino Keshelava, MD, Katherine K. Matthay, MD, John N. Lukens, MD, Robert B. Gerbing, MA, Daniel O. Stram, PhD, Robert C. Seeger, MD and C. Patrick Reynolds, MD, PhD

Background and Procedure: MRP1 expression by neuroblastomas was evaluated by Northern blot analysis in 21 cell lines and 90 primary untreated tumors. Cytotoxicity assay in cell lines was performed for five anticancer drugs used in treating neuroblastoma.

Results: MRP1 expression did not correlate with drug resistance or with MYCN RNA expression in cell lines. MRP1 expression was higher in drugsensitive cell lines established after chemotherapy relative to cell lines at diagnosis, but highly drug-resistant cell lines showed low MRP1 expression. Positive expression of MRP1 RNA in primary tumors was associated with a poorer survival relative to MRP1-negative tumors. However, MRP1 expression levels did not correlate with age, stage, MYCN amplification, or MYCN expression, and higher MRP1 expression was not associated with a worse outcome.

Conclusions: In neuroblastoma, positive MRP1 RNA expression at diagnosis has prognostic significance, but high drug resistance is conferred by mechanisms other than MRP1.

Key words: neuroblastoma, multidrug resistance, prognostic factors, MYCN oncogene, MRP1.

RISK OF UNFAVORABLE CHARACTER AMONG NEUROBLASTOMAS DETECTED THROUGH MASS SCREENING
Takeo Tanaka, Takafumi Matsumura, Tomoko Iehara, Tadashi Sawada and The Japanese Infantile Neuroblastoma Cooperative Study

Current study shows that about 50 %, of neuroblastomas (NBs) detected through mass screening had factor(s) indicating an unfavorable biological nature and that early intervention after the screening might improve clinical outcome of the patients. On the other hand, favorable properties were detected in the remaining half of the mass-screening NBs. Some of them might have the ability to regress spontaneously. Therapeutic modality should be determined according to their biological nature. Further investigation for their biologic properties is necessary to evaluate the benefits of the mass screening.

Key words: mass screening; neuroblastoma; prognostic factor; Ha-ras gene; trk A gene.

PROGNOSTIC SIGNIFICANCE OF KI-67 (MIB-1) PROLIFERATION INDEX IN CHILDHOOD PRIMITIVE NEUROECTODERMAL TUMORS OF THE CENTRAL NERVOUS SYSTEM
Michael A. Grotzer, MD, Birgit Geoerger, MD, Anna J. Janss, MD, PhD, Huaqing Zhao, MA, Lucy B. Rorke, MD and Peter C. Phillips, MD

Background: Primitive neuroectodermal tumors (PNET) of the central nervous system, including medulloblastomas, are the most common malignant brain tumors of childhood. Whereas some patients experience prolonged disease control after surgery and adjuvant therapy, others with tumors that appear comparable will relapse and eventually die from progressive disease.

Procedure: Because proliferative activity may provide a potential correlate of biologic aggressiveness, PNETs of 78 well-characterized patients were evaluated by Ki-67 (MIB-1) immunohistochemistry. Proliferation indices (PI) were determined by counting Ki-67 (MIB-1) positive tumor cells either in the highest staining region (hot spot PI), or in at least 15 randomly chosen fields (random PI).

Results: Twenty-five of 78 PNETs showed amore than twofold higher value of hot spot PI (median 9.3’G,; range 0.6-56%), compared to random PI (median 5.6 %; range 0.2-41.3 G0. Univari ate Cox regression analysis revealed that PNETs with a high hot spot PI had a significantly greater risk of progression and death than PNETs with a low hot spot PI (hazard ratio 1 .58, P= 0.04). The hazard ratio remained significant after adjusting for M-stage in multivariate analysis. In contrast to hot spot PI, random PI proved not to be a significant prognostic predictor.

Conclusions: Hot spot PI is a significant and independent prognostic factor in PNETs. Its assessment is uncomplicated, reliable, and may supplement routine histologic examination as a means for improving the accuracy of predicting the biologic behavior of childhood PNETs.

Key words: brain tumor; medulloblastoma; Ki-67; MIB-1; survival.

MEASURING SYMPTOM DISTRESS IN PATIENTS WITH LUNG CANCER
A pilot study of experienced intensity and importance of symptoms
Carol Tishelman, R.N., Dr.Med.Sci., Lesley F. Degner, R.N., Ph.D. and Bryan Mueller, R.N., B.N.

Patients with cancer experience high levels of symptom distress. Current measures of symptoms generally weight the importance of each symptom equally, and do not generally address the relative importance of different symptoms to patients. The purpose of this pilot study was to explore whether the assumption of equal weighting is warranted in measurements of symptom distress. Consecutive patients presenting with primary lung cancer at the Lung Medicine Unit of one Swedish hospital completed the Symptom Distress Scale and a Thurstone scale eliciting patients’ weightings of the symptoms’ relative importance three times: after first contact with the unit, then 1 and 2 months later. The results show that subjects weighted some symptoms as significantly more important than others, and the ordering of symptoms was found to differ by intensity and perceived importance in this group. Outlook was the symptom rated most important at T1. Fatigue received the highest intensity score, but ranked second lowest in importance. Kendall’s coefficient showed minimal agreement among these patients as to the specific order for the weighting of the importance of symptoms. In addition to theoretical relevance, this issue is clinically relevant in selecting symptoms that should be the focus of intervention and in determining how the success of interventions should be judged.

Key words: Cancer nursing; Lung cancer; Symptom distress.

QUALITY OF LIFE IN WOMEN WITH BREAST CANCER
A review of the literature and implications for nursing practice
Tone Rustøen, R.N., Ph.D. and Susanne Begnum, Dipl.Psych.

This article discusses the gap between an ever-increasing interest in research on the quality of life in patients with breast cancer and the lack of impact this research has had in the actual care of these women. A critical review of the literature is used to answer the question of how much can be accepted as established knowledge despite the often methodologically weak studies and contradictory results. Deficiency in research studies is no rationale for not improving nursing care in areas wherein there is an expressed need for support and assistance. Nurses are in contact with patients who have breast cancer at all stages of the disease and treatment, because they meet the women in the hospital, at the outpatient clinic, and in their homes. They play an important role in meeting the needs of these women. Ways of improving nursing practice at the different stages of the illness, from the pretreatment phase to posttreatment follow-up assessment, are discussed, and concrete suggestions made. This article addresses the women’s need both for adequate information and for social and emotional support.

Key words: Breast cancer; Nursing; Quality of life.

GEMCITABINE AND CISPLATIN VERSUS METHOTREXATE, VINBLASTINE, DOXORUBICIN, AND CISPLATIN IN ADVANCED OR METASTATIC BLADDER CANCER: RESULTS OF A LARGE, RANDOMIZED, MULTINATIONAL, MULTICENTER, PHASE III STUDY
H. von der Maase, S.W. Hansen, J.T. Roberts, L. Dogliotti, T. Oliver, M.J. Moore, I. Bodrogi, P. Albers, A. Knuth, C.M. Lippert, P. Kerbrat, P. Sanchez Rovira, P. Wersall, S.P. Cleall, D.F. Roychowdhury, I. Tomlin, C.M. Visseren-Grul and P.F. Conte

Purpose: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium.

Patients and Methods: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m 2 days 1, 8, and 15; cisplatin 70 mg/m 2 day 2) or standard MVAC every 28 days for a maximum of six cycles.

Results: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were wellbalanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI, 0.72 to 1.10), and response rote (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rote was 1 % on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively) and thrombocytopenia (57°/a v 21 %, respectively). On both arms, the RBC transfusion rote was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1 %, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue.

Conclusion: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.

ANASTROZOLE IS SUPERIOR TO TAMOXIFEN AS FIRST-LINE THERAPY FOR ADVANCED BREAST CANCER IN POSTMENOPAUSAL WOMEN: RESULTS OF A NORTH AMERICAN MULTICENTER RANDOMIZED TRIAL
J.M. Nabholtz, A. Buzdar, M. Pollak, W. Harwin, G. Burton, A. Mangalik, M. Steinberg, A. Webster and M. von Euler for the Arimidex Study Group

Purpose: The efficacy and tolerability of anastrozole (Arimidex; AstraZeneca, Wilmington, DE, and Macclesfield, United Kingdom) and tamoxifen were compared as first-line therapy for advanced breast cancer in 353 postmenopausal women.

Patients and Methods: The randomized, doubleblind, multicenter study was designed to evaluate anastrozole 1 mg once daily relative to tamoxifen 20 mg once daily in patients with hormone receptor-positive tumors or tumors of unknown receptor status who were eligible for endocrine therapy. Primary end points were objective response (OR), defined as complete (CR) or partial (PR) response, time to progression (TTP), and tolerability.

Results: Anastrozole was as effective as tamoxifen in terms of OR (21 % v 17% of patients, respectively); with clinical benefit (CR + PR + stabilization > 24 weeks) observed in 59% of patients on anastrozole and 46% on tamoxifen (two-sided P = .0098, retrospective analysis). Anastrozole had a significant advantage over tamoxifen in terms of TTP (median TTP of 11.1 and 5.6 months for anastrozole and tamoxifen, respectively; two-sided P = .005). The tamoxifen:anastrozole hazards ratio was 1.44 (lower one-sided 95% confidence limit, 1.16). Both treatments were well tolerated. However, thromboembolic events and vaginal bleeding were reported in fewer patients who received anastrozole compared with those who received tamoxifen (4.1 % v 8.2% [thromboembolic events] and 1.2% v 3.8% [vaginal bleeding], respectively).

Conclusion: Anastrozole satisfied the predefined criteria for equivalence to tamoxifen. Furthermore, we observed both a significant increase in TTP and a lower incidence of thromboembolic events and vaginal bleeding with anastrozole. These findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with advanced breast cancer.