Nurses' attitudes toward clinical trials at a comprehensive cancer center.

PURPOSE/OBJECTIVES: To identify nurses' attitudes and beliefs toward cancer clinical trials and their perceptions about factors influencing patients' participation in these trials. DESIGN: Descriptive. SETTING: National Cancer Institute-designated comprehensive cancer center. SAMPLE: 417 nurses employed at the cancer center were surveyed; 250 (60%) subjects responded. METHODS: 59-item questionnaire. MAIN RESEARCH VARIABLES: Nurses' attitudes toward clinical trials and perceptions of patient understanding of and influences on participation in clinical trials. FINDINGS: 96% of nurses reported that participation in clinical trials is important to improving standards of care; only 56% believed that patients should be encouraged to participate in trials if they had cancer. In multiple regression analyses, older age and being a research nurse were significant predictors of positive attitudes toward clinical trials. Work setting also was a significant predictor of nurses' perceptions of patients' understanding of treatment. Overall, nurses reported that an investigational therapy should have at least a 50% chance of success prior to being offered to patients. CONCLUSIONS: Nurses generally reported that clinical trials are important to improve standards of care; however, attitudes concerning patient participation in clinical trials and perceptions of patient understanding differed by work setting. Nurses have high expectations regarding the benefits of investigational therapy. IMPLICATIONS FOR NURSING PRACTICE: Nurses play a critical role in the care of participants in cancer clinical trials. Targeted interventions that involve nurses to enhance appropriate patient accrual, patient understanding, and patient decision making should result in improved patient care in centers conducting clinical trials.

Validation of a new classification system for curatively resected colorectal adenocarcinoma.

BACKGROUND: The parameters within which colorectal adenocarcinoma is currently staged are often insufficient for decisions regarding therapy after potentially curative surgery. Consequently, oncologists make frequent use of additional prognostic indicators when assessing individual prognosis and selecting patients for adjuvant systemic treatment. Follow-up programs are generally uniform for all patients, regardless of disease stage and prognosis. As a result, patients with a favorable prognosis are needlessly subjected to stressful, costly follow-up too early and too frequently. This study was conducted to validate a new classification system that is a superior predictor of individual prognosis following curative surgery and may serve as a guide for personalized, cost-effective postoperative management and follow-up. METHODS: A total of 231 American colorectal carcinoma patients who underwent curative resection were retrospectively staged according to a new classification (containing 4 stage-groups) for curatively resected colorectal adenocarcinoma. This classification is based on statistical analysis of the impact on prognosis of numerous characteristics of 363 consecutive Israeli colorectal carcinoma patients who underwent curative resection. All the patients in both cohorts had had surgery at least 5 years previously. The new classification is based on three histologic variables (venous invasion, depth of primary tumor penetration, and regional lymph node status) and a scoring system that correlates higher numeric score with worse prognosis. In both cohorts, the new classification was compared with the Dukes, Astler-Coller, and TNM staging systems for patient distribution and survival (both disease free and cancer-related survival). RESULTS: In both cohorts, the 4 stage-groups of the new classification differed significantly in both the rate of and the time to first recurrence and cancer-related death, with progression from Group 4 to Group 1. Groups of high risk lymph node negative patients were defined, and lymph node positive patients were subdivided according to prognosis. It is suggested that, by using this new classification as a guide, selection for adjuvant systemic treatment may be refined, and postoperative follow-up may be personalized and therefore more cost-effective. CONCLUSIONS: The new classification for curatively resected colorectal adenocarcinoma, based on an analysis of the Israeli cohort and validated in the American cohort, is superior to the Dukes, Astler-Coller, and TNM staging systems as a predictor of individual prognosis, most probably because it incorporates the microscopic forerunner of distant, hematogenous spread (i.e., venous invasion) with the locoregional parameters of extent of disease (i.e., T and N values). It is suggested that the new classification may serve as a guide for more refined selection of patients for adjuvant systemic treatment and for individualized and more cost-effective postoperative follow-up. The new classification is simple and easy to use, requires no sophisticated equipment or tests, and can be applied in any health care system worldwide.

New approach to the substaging of node-positive colorectal adenocarcinoma.

BACKGROUND: Future developments in adjuvant modalities may require substaging of node-positive colorectal adenocarcinoma that is accurately indicative of individual prognoses, upon which therapeutic decisions (e.g., choice of agents and intensity of treatment) may be based. This study compares substaging of node-positive colorectal cancer by venous invasion with substaging by three currently used methods, with respect to the ability of each method to define patient subsets that differ significantly in both disease-free and cancer-related survival rates. METHODS: A total of 171 patients with node-positive colorectal cancer, who had undergone potentially curative resection at least 5 years earlier, were retrospectively substaged by the tumor, node, metastasis (TNM) N1/N2, Astler-Coller C1/C2, Gastrointestinal Tumor Study Group (GITSG) C1/C2, and venous invasion (positive/negative) methods. Disease-free and cancer-related survival curves were calculated (by the Kaplan-Meier method) and compared for statistical significance (using the log-rank test). RESULTS: The separation of disease-free and cancer-related survival curves using the four methods of substaging node-positive colorectal cancer was as follows: TNM, P = .16 (not significant) and P = .12 (not significant); Astler-Coller, P < .01 and P = .006; GITSG, P = .067 (not significant) and P = .03; venous invasion, P = .016 and P = .007, respectively. CONCLUSIONS: Numerical substaging of node-positive colorectal cancer (TNM and GITSG methods) is an inferior predictor of prognosis, compared with substaging by the T value (Astler-Coller) or venous invasion methods. We think that the latter method is the method of choice, because it separates patients who have only lymphatic metastasis from patients who display microscopic hematogenous spread as well. This separation obviously has biological/oncological significance, and it may have practical therapeutic implications in the future.

Phase I and pharmacokinetic study of weekly 5-fluorouracil administered with granulocyte-macrophage colony-stimulating factor and high-dose leucovorin: a potential role for growth factor as mucosal protectant.

Diarrhea is dose-limiting with weekly 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been associated with a decrease in chemotherapy-associated mucosal toxicity. This study was conducted to determine the maximum tolerated dose (MTD) of weekly 5-FU when administered with GM-CSF and high-dose LV. Patients were treated with intravenous LV 500 mg/m2 plus 5-FU weekly for six doses followed by a 2-week rest. GM-CSF 250 mg/m2 was administered subcutaneously 5 days each week. Cohorts were treated with 5-FU at 600, 700, and 800 mg/m2 weekly. Twenty-nine patients were treated. The MTD of 5-FU in this schedule was 700 mg/m2/week, with diarrhea dose-limiting. 5-FU delivered dose intensity at the MTD was 424 +/- 23.7 mg/m2/week, including rest periods. 5-FU and LV pharmacokinetics were not altered by concurrent treatment with GM-CSF. In a weekly schedule with high-dose LV and GM-CSF, the MTD of 5-FU and 5-FU delivered dose intensity were higher than previously reported with 5-FU and LV administered without GM-CSF.

Prolonged disease-free survival by maintenance chemotherapy among patients with recurrent platinum-sensitive ovarian cancer.

OBJECTIVE: The aim of this study was to determine the potential benefit and complications of prolonged salvage and maintenance chemotherapy among patients with recurrent epithelial ovarian cancer who achieve response to salvage chemotherapy. METHODS: Patients with recurrent platinum-sensitive epithelial ovarian cancer who were treated between 1982 and 1996 and achieved complete response to platinum-based salvage chemotherapy were offered prolonged (1 year) monthly salvage followed by maintenance (every 8 weeks) chemotherapy. Patients who accepted such treatment (n = 16) were compared to those who refused and discontinued therapy (n = 11) with regard to overall survival from time of initial diagnosis and overall and disease-free survival from time of recurrence. Chemotherapy-related toxicity in the study group was recorded. Survival curves were constructed according to the Kaplan and Meier method and survival curves were compared using the log-rank test. RESULTS: Patients in the study and control groups were similar with regard to age, stage, histology, grade, performance status, primary cytoreductive surgery, type of primary and salvage chemotherapy, and method of assessment of tumor response. The study group had a significantly longer disease-free interval from date of recurrence than the control group (median: 35.0 versus 6.0 months, respectively, P = 0.001). The study group had longer overall survival from date of recurrence than the control group. However, the difference did not achieve statistical significance (median: 119 versus 90 months, respectively, P = 0.056). There was no significant difference between the study group and the control group as to survival from date of initial diagnosis (median: 157 versus 124 months, respectively, P = 0.28). Chemotherapy-related toxicity was minimal. CONCLUSIONS: Prolonged salvage and maintenance chemotherapy is a safe method of treatment that may extend disease-free interval among patients with platinum-sensitive recurrent epithelial ovarian cancer who achieve response to salvage chemotherapy. These preliminary results need to be confirmed by a larger prospective randomized trial.

Prognostic factors in extraovarian primary peritoneal carcinoma.

OBJECTIVE: To determine the pathological, clinical, and therapeutic factors which had prognostic significance in women with extraovarian primary peritoneal carcinoma (EOPPC). METHODS: A retrospective, clinicopathologic study was conducted of 75 women diagnosed with EOPPC. Diagnosis and assessment of prognostic pathological factors were based on the Gynecologic Oncology Group (GOG) criteria. Univariate and multivariate analyses were used to assess the following factors for their effect on overall survival: age, parity, presenting symptoms and signs, ascites, CA 125 level, history of oophorectomy, maximum ovarian dimension, histologic type, architectural and nuclear grades, number of mitosis and psammoma bodies, depth of ovarian invasion, estrogen and progesterone receptors (positive, negative), p53 overexpression (present, absent), performance status (GOG criteria), stage (FIGO criteria for ovarian cancer), debulking surgery (optimal versus suboptimal), first-line chemotherapy (platin-based without paclitaxel versus platin/paclitaxel), secondary cytoreduction, and second-line chemotherapy (paclitaxel-based versus no paclitaxel). RESULTS: The median overall survival of all patients was 23.5 months (95% CI 18.6, 39.8 months). The 5-year survival was 26.5% (SE 6.7%). p53 overexpression and estrogen and progesterone receptor positivity were demonstrated in 42.4, 50.0, and 6.3%, respectively. In univariate analysis, performance status, primary debulking surgery, stage, and age were significant on overall survival (P < 0.001, <0. 001, 0.004, and 0.012, respectively). In multivariate analysis, only performance status (P < 0.001) and primary debulking surgery (P = 0. 03) were independent prognostic factors. Conclusions. Overall survival in women with EOPPC is affected significantly by performance status and primary debulking surgery as independent variables. To improve survival, efforts should be made to achieve optimal tumor cytoreduction at primary surgery.

Correlation between extreme drug resistance assay and response to primary paclitaxel and cisplatin in patients with epithelial ovarian cancer.

OBJECTIVE: The extreme drug resistance (EDR) assay has been correlated with failure of response to chemotherapy in greater than 99% of patients. The goal of this study is to correlate the results of the EDR assay to response to first-line paclitaxel/cisplatin among patients with epithelial ovarian cancer. METHODS: Seventy-five of 100 patients with epithelial ovarian cancer for whom EDR assay was performed were treated with weekly induction cisplatin (1 mg/kg body wt) x 4, followed by monthly paclitaxel (135 mg/m2) and cisplatin (75 mg/m2) x 6 and were evaluable for correlation of response to chemotherapy and EDR assay. Specimens for EDR assay were obtained at primary surgery and the EDR assay was performed by Oncotech, Inc. Response to chemotherapy was correlated to EDR assay results regarding paclitaxel and cisplatin. RESULTS: Among 75 evaluable patients, the prevalence of EDR to paclitaxel was 20.0% (n = 15) and to cisplatin it was 2.7% (n = 2). Only 1 patient (1.3%) exhibited EDR to both paclitaxel and cisplatin. Surgical assessment of response was performed in 42 patients; 33 patients were clinically evaluable. The overall response rate was 85.3%. The overall response rate for patients whose tumors demonstrated no EDR to either paclitaxel or cisplatin did not differ significantly from that for patients whose tumors demonstrated EDR to at least one of these two drugs (86.4% versus 81.3%, respectively, P = 0.692). Similarly, the complete surgical response rate for both groups did not differ significantly (25.4% versus 12.5%, respectively, P = 0. 34). A single patient whose tumor exhibited EDR to both paclitaxel and cisplatin had tumor progression. The sensitivity, specificity, positive predictive value, and negative predictive value of the EDR assay were 79.6, 27.0, 86.0, and 19.0%, respectively. CONCLUSIONS: EDR to paclitaxel does not preclude response to the combination of paclitaxel and cisplatin as primary therapy for patients with epithelial ovarian cancer. The role of the EDR assay in the primary management of patients with epithelial ovarian cancer remains to be determined.

Importance of lymph node metastases in primary peritoneal carcinoma.

BACKGROUND AND OBJECTIVES: The incidence and significance of lymph node involvement in patients with primary peritoneal adenocarcinoma (PPA) are unknown. The aim of the current study is to report on the incidence and significance of clinically or surgically detectable lymphadenopathy in women with PPA. METHODS: The study is a retrospective clinical review of patients with the confirmed diagnosis of PPA treated at Roswell Park Cancer Institute between 1982 and 1996. Patients with clinically or surgically detectable lymphadenopathy confirmed on histologic examination to be secondary to metastases from PPA were identified and compared to patients with negative lymph nodes with regard to clinicopathologic characteristics, treatment, response to treatment, and survival. RESULTS: Seventy-two patients with PPA were identified. Pelvic and periaortic lymph node biopsies or sampling were performed in 35% of the patients. In 8/72 patients (11%), lymphadenopathy was one of the presenting clinical or surgical findings. The clinicopathologic features, treatment, response to first-line chemotherapy, and estimated median overall survival were not different in patients with or without lymph node involvement (71.4% vs. 69.7%, P = 1.0, and 21.5 vs. 23.5 months, P = 0.14). CONCLUSIONS: Lymph node involvement is not an infrequent occurrence in patients with PPA and does not seem to be of adverse prognostic significance.

Octreotide does not prevent diarrhea in patients treated with weekly 5-fluorouracil plus high-dose leucovorin.

The somatostatin analog, octreotide, is effective in treating diarrhea associated with cancer chemotherapy. This study was undertaken to determine whether octreotide could be used as prophylaxis against chemotherapy-induced diarrhea and, thereby, permit increased dose intensity. Adult cancer patients were treated with a standard regimen of intravenous 5-fluorouracil (5-FU) (600 mg/m2) plus leucovorin (LV) (500 mg/m2) weekly x 6 weeks. In addition, 150 microg of octreotide was administered subcutaneously twice daily, beginning on the first day of chemotherapy and continuing for 43 days. Escalation of 5-FU was planned for successive cohorts based upon toxicity. Eleven patients were treated at the initial 5-FU dose level. In 10 evaluable patients, dose-limiting toxicities were diarrhea (two patients), fatigue (one patient), and hyperbilirubinemia (one patient). Diarrhea was experienced by six of 10 patients, and only three patients were able to receive six weekly chemotherapy treatments without dose reduction or delay. At a dose of 150 microg twice daily, octreotide did not prevent diarrhea associated with 5-FU plus LV, and 5-FU dose escalation was not possible. While octreotide is successful in the treatment of 5-FU-induced diarrhea, we were unable to demonstrate a role in toxicity prophylaxis.

Prospective sequential trials of induction weekly cisplatin followed by monthly cisplatin, doxorubicin, cyclophosphamide and paclitaxel and cisplatin in optimal (< or = 1 cm) stage III and IV ovarian cancer.

PURPOSE OF INVESTIGATION: This study was conduced to assess the results of paclitaxel plus cisplatin given over six months as firstline therapy in women with stage III and IV epithelial ovarian cancer with residual disease < 1 cm and compare it to our previous standard of cisplatin, adriamycin, and cyclophosphamide given over ten months in two sequential trials totaling 100 patients. METHODS: We compared induction weekly cisplatin (1 mg/kg x 4) followed by monthly cisplatin (50 mg/m2), doxorubicin (50 mg/m2) and cyclophosphamide (750 mg/m2) x 10 (n = 56) versus induction cisplatin (1 mg/kg x 4) followed by cisplatin (75 mg/m2) and paclitaxel (135 mg/m2) monthly over six months (n = 44). RESULTS: The two groups were similar in age, histologic subtypes, grade, performance status, and substage. The mean dose of cisplatin in the PAC patients was 617.1 (+/-92.7) mg/m2 as compared to 567.1 (+/-89.2) mg/m2 in the TP patients (p < 0.0001). Surgical response was assessed in 83.9% of the PAC and 86.4% of the TP patients. The incidence of nausea and vomiting, myelotoxicity and renal toxicity were similar in the two groups. Peripheral neuropathy occurred more frequently following TP (57% vs 16%; p = 0.001). Cardiac toxicity (grade 1) occurred in 39% of the PAC patients and in 4.5% of the TP patients (p < 0.001). The overall response rate (75% vs 88.7%), surgical response rate (67.9% vs 79.5%), complete surgical responses (37.5% vs 40.9%), estimated two-year survival (80.2% vs 79.6%), progression-free median survival (36 months vs 30.4 months) and two-year progression/recurrence rates (32.3% vs 46.9%), respectively, of PAC and TP patients were not statistically significant (p = NS). CONCLUSIONS: Given the discussed limitations of the study, compared with PAC, TP did not improve overall and surgical response rates, two-year survival, two year disease-free survival, or median time of recurrence in patients with optimal (< 1 cm) stage III and IV ovarian cancer and resulted in higher peripheral neuropathy rates.

Two sequential studies for primary peritoneal carcinoma: induction with weekly cisplatin followed by either cisplatin-doxorubicin-cyclophosphamide or paclitaxel-cisplatin.

OBJECTIVES: The aim of the current study is to evaluate the results of therapy with induction with weekly cisplatin followed by the combination of cisplatin-doxorubicin-cyclophosphamide (PAC) or the combination paclitaxel-cisplatin (TP) as first-line chemotherapy in patients with primary peritoneal adenocarcinoma (PPA). METHODS: Between October 1988 and July 1996, 46 patients with PPA were treated with PAC (n = 25) or TP (n = 21) following cytoreductive surgery in two sequential trials. In trial 1, patients received induction with weekly cisplatin (1 mg/kg) x 4 followed by monthly cisplatin (50 mg/m2), cyclophosphamide (750 mg/m2), and doxorubicin (50 mg/m2) for 10 cycles. In trial 2, patients received induction with weekly cisplatin (1 mg/kg) x 4 followed by monthly cisplatin (75 mg/m2) and paclitaxel (135 mg/m2) over 24 hr for 6 cycles. Surgical assessment of response was performed in 15 (60.0%) and 13 (61.9%) patients in the PAC and TP trials, respectively. Estimated survival and progression-free survival distributions were calculated by the method of Kaplan and Meier. Survival curves were compared using the log rank test. RESULTS: There were no significant differences between patients in either treatment arm with respect to median age, substage, percentage of patients undergoing optimal cytoreductive surgery, median preoperative CA125 values, performance status, proportion of patients who had second-look procedures, or median cumulative doses of cisplatin. The incidence of nausea and vomiting as well as peripheral neuropathy was significantly higher among patients who received TP (P = 0.005 and 0.022, respectively). The overall response, surgical response, and complete surgical response were not statistically different among patients who received PAC and those who received TP (62.5% versus 70.0%, P = 0.75, 73.3% versus 76.9%, P = 0.1, and 13.3% versus 23.1%, P = 0.64, respectively). Patients who underwent optimal cytoreductive surgery demonstrated higher response than patients whose tumors could not be optimally cytoreduced (76.7% versus 42.9%, P = 0.04). There was no statistically significant difference in overall survival or time to progression/recurrence between the PAC and TP groups (median 21.5 versus 24.0 months, P = 0.68, and 17.3 versus 24.0 months, P = 0.59, respectively). In both treatment groups combined, 18 of 32 patients whose tumors were optimally cytoreduced and 3 of 14 patients whose tumors were suboptimally cytoreduced had surgically verified response. Patients who underwent optimal cytoreductive surgery exhibited longer survival than those who underwent suboptimal cytoreductive surgery (median 29.4 versus 18.6 months, P = 0.008). CONCLUSIONS: Both PAC and TP regimens are effective combinations in patients with PPA. The median survival was similar following PAC and TP but the responses and time to recurrence/progression were nonsignificantly better in the paclitaxel combination.

Serum CA-125 measurements > 65 U/mL. Clinical value.

OBJECTIVE: To review the prevalence of various conditions associated with serum CA-125 values > 65 U/mL, to calculate the odds ratios of different ranges of high CA-125 in predicting cancer and to study the effect of menopause and the presence of a mass on the predictive value of high serum CA-125. STUDY DESIGN: A retrospective review of the diagnoses in 313 consecutive women seen at the Cleveland Clinic Foundation whose serum CA-125 was > 65 U/mL was performed. Statistical analysis was performed using crosstabulation, chi 2, Fisher's exact test and the odds ratio. RESULTS: In patients with serum CA-125 > 65 U/mL, gynecologic cancers, nongynecologic cancers and non-malignant conditions constituted 74.3%, 10.2% and 13.1% of diagnoses, respectively. In patients with serum CA-125 > or = 1,000 U/mL, the same conditions were responsible for 89%, 7% and 3% of diagnoses, respectively. Endometriosis and metastatic breast cancer were the most common benign condition and nongynecologic cancer associated with serum CA-125 > 65 U/mL. The presence of an abdominopelvic mass significantly increased the risk of malignancy (P < .00005). Approximately 90% of patients with CA-125 > 65 U/mL and no mass had nonmalignant disease. The diagnoses of serum CA-125 values > 65 U/mL varied significantly in premenopausal versus postmenopausal patients. Postmenopausal patients had a higher incidence of gynecologic (P = .002) and nongynecologic (P = .0008) cancers and lower incidence of benign conditions (P < .0005). The odds ratio that CA-125 levels were associated with cancer increased as the level of CA-125 increased. The odds ratio of malignant versus benign disease was significantly higher in post-menopausal patients for all intervals of CA-125 levels until the level of > or = 1,000 U/mL was reached. CONCLUSION: In patients seen at a tertiary center, serum CA-125 measurements > 65 U/mL were associated with nonmalignant conditions in 13% of patients. Although higher serum CA-125 levels were more associated with gynecologic malignancies, no level of CA-125 occurred exclusively with gynecologic cancers. In postmenopausal patients with serum CA-125 values > 65 U/mL and in patients with serum CA-125 values > 65 U/mL and an abdominopelvic mass, subspecialty consultation should be considered before proceeding to surgery.

p53 overexpression is not an independent prognostic factor for patients with primary ovarian epithelial cancer.

BACKGROUND: The clinical significance of p53 overexpression in patients with ovarian carcinoma is uncertain. Previous studies have yielded conflicting results and have been hampered by small patient populations, failure to account for other well-known prognostic variables in multivariate analysis, and failure to account for the grade of p53 overexpression. The aim of this study was to investigate the independent prognostic significance of p53 overexpression in patients with primary ovarian epithelial cancer (POEC). METHODS: Tumors obtained from 221 patients with primary ovarian epithelial cancer (POEC) (Stages I-IV) were studied for p53 overexpression semiquantitatively by immunohistochemical techniques. The median duration of follow-up of surviving patients was 7 years. The presence or absence and degree of p53 overexpression were correlated with the clinicopathologic features of the study population and overall survival. Survival curves were constructed according to the Kaplan-Meier method, and differences in survival were assessed with the log rank test. The prognostic significance of p53 overexpression for survival was assessed in a multivariate analysis with the Cox proportional hazards model. RESULTS: One hundred seven tumors (48.4%) exhibited p53 overexpression. The overexpression was graded as mild in 16.7% of cases, moderate in 5.9%, and strong in 25.8%. p53 overexpression was associated with advanced stage (P = 0.04), higher grade (P = 0.0003), serous histology (P = 0.0018), and patient age > 61 years (P = 0.013). In univariate analysis, p53 overexpression was a significant prognostic factor (P = 0.049 for any degree of overexpression, P = 0.03 for strong overexpression). However, in multivariate analysis, after adjustment for stage and size of residual tumor following cytoreductive surgery, p53 overexpression did not retain statistical significance. Survival curves for patients with different stages and grades of tumor differentiation did not demonstrate a difference in survival among patients with no p53 overexpression, compared with those who demonstrated any degree of p53 overexpression or compared with those who demonstrated strong p53 overexpression. CONCLUSIONS: p53 overexpression is not an independent prognostic factor for patients with primary ovarian epithelial cancer.

Angiogenesis and dynamic MR imaging gadolinium enhancement of malignant and benign breast lesions.

PURPOSE: To determine whether dynamic magnetic resonance (MR) imaging enhancement parameters are associated with vessel density of malignant and benign breast lesions. MATERIALS AND METHODS: Forty-five patients with 48 breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo (SPGR) MR imaging followed by excisional biopsy and Factor VIII staining and vessel density measurement in the lesions. RESULTS: The vessel densities were not significantly different in 25 malignant breast lesions as compared to 23 benign breast lesions. Among all 48 lesions, greater MR enhancement showed an association with increased vessel density. Seventy-four percent of all lesions with MRI enhancement amplitude greater or equal to three times post-precontrast ratio had vessel densities greater than the median of 172 as compared to 34% of lesions with enhancement amplitude less than three times, p = 0.02. The rate and washout of MR enhancement showed no significant association with vessel density. CONCLUSION: Although there is an overall significant association between greater MRI enhancement amplitude and vessel density, MRI gadolinium enhancement of breast lesions is not an accurate predictor of vessel density.

Characterization of interleukin-10 receptor expression on B-cell chronic lymphocytic leukemia cells.

B-cell chronic lymphocytic leukemia (B-CLL) cells accumulate in vivo in the G0/G1 phase of the cell cycle, suggesting that their malignant expansion is due, at least in part, to a delay in cell death. However, the cellular or molecular factors responsible for a delay in B-CLL cell death are unknown. B-CLL cells do express receptors for interferon-alpha (IFN-alpha) and IFN-gamma, and activation of both has been shown to promote B-CLL survival in vitro by preventing apoptosis. The interleukin-10 (IL-10) receptor is another member of the IFN receptor family, but its ligand, IL-10, has been reported to induce apoptosis in B-CLL cells. In the current study, we undertook a biochemical analysis of IL-10 receptor expression on freshly isolated B-CLL cells and characterized the functional responsiveness of IL-10 binding to its constitutively expressed receptor. We show that B-CLL cells bind IL-10 with significant specificity and express between 47 and 127 IL-10 receptor sites per cell, with a dissociation constant in the range of 168 to 426 x 10(-12) mol/L. Ligand binding and activation of the IL-10 receptor expressed on B-CLL cells results in the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 proteins. This pattern of STAT protein phosphorylation is identical to IL-10 receptor activation on normal cells and similar to IFN-alpha (STAT1 and STAT3) and IFN-gamma (STAT1) receptor activation in CLL. Further, in consecutive samples of fresh blood obtained from patients with B-CLL cells, the addition of IL-10 inhibited B-CLL proliferation, enhanced B-CLL differentiation, but did not induce apoptosis. Indeed, IL-10, like IFN-gamma, was able to significantly reduce the amount of B-CLL cell death caused by hydrocortisone-induced apoptosis. We conclude that cytokines, which signal through the interferon family of receptors, have comparable functional effects on B-CLL cells.

Cathepsin D and dynamic magnetic resonance imaging gadolinium enhancement in malignant and benign breast lesions.

Our purpose was to determine whether the expression of cathepsin D, a proteolytic enzyme implicated in basement membrane degradation, is associated with dynamic magnetic resonance imaging (MRI) enhancement of breast lesions. Forty-five patients with 48 breast lesions underwent gadolinium-enhanced spoiled gradient recalled echo MRI followed by excisional biopsy and cathepsin D staining and semiquantitative measurement in the lesions. There was no significant difference in cathepsin D staining of 25 malignant and 23 benign breast lesions. A significant association was seen between high cathepsin D staining and positive axillary lymph nodes in invasive carcinomas. Nine of nine (100%) node-positive carcinomas had high cathepsin D, as compared to three of seven (43%) node-negative carcinomas (P = 0.02). No significant associations were observed between cathepsin D staining and MRI enhancement amplitude, rate, or washout. Cathepsin D has no effect upon MRI gadolinium enhancement of malignant and benign breast lesions but is associated with positive axillary lymph nodes in invasive carcinomas.

Granulocyte-macrophage colony-stimulating factor as infection prophylaxis in high-risk oncologic surgery.

BACKGROUND: A method of augmenting host defenses against bacterial pathogens could result in a decrease in postoperative infections. Given its effects on leukocyte proliferation and function, it is possible that prophylactic granulocyte-macrophage colony-stimulating factor (GM-CSF) could reduce the incidence and severity of infections in high-risk surgical patients. The current study was undertaken to determine the safety and hematologic effects of perioperative GM-CSF. METHODS: Cancer patients undergoing operations with a high risk of postoperative infection were treated perioperatively for 10 days with subcutaneous GM-CSF. Cohorts were treated with GM-CSF at 125 micrograms/m2/day (12 patients) and 250 micrograms/m2/day (11 patients). RESULTS: There were no severe or life-threatening toxicities associated with GM-CSF. Mean maximum neutrophil counts during the first 5 postoperative days were 16.3 +/- 9.14 and 24.5 +/- 7.60 at 125 and 250 micrograms/m2, respectively (P = 0.04). Only one wound infection was diagnosed during this study. CONCLUSIONS: GM-CSF may be safely administered perioperatively at doses that augment neutrophil number and function. An ongoing randomized clinical trial will determine the impact of GM-CSF on postoperative infection.

Day surgery for cervical microdiscectomy: is it safe and effective?

The objective of this pilot study was to evaluate the safety and efficacy of cervical discectomy with fusion performed on an outpatient basis. The experimental group (50 consecutive patients) was studied prospectively and the outcomes were compared with 53 consecutive, retrospectively analyzed, admitted controls who underwent the same procedure. Outcomes for both groups were assessed by patient-response questionnaires and clinical examination. At follow-up times of 1.3 (outpatient) and 1.6 (inpatient) years, outcomes (outpatient/inpatient) expressed as percent successful were as follows: Relief of arm pain (80/70%); relief of neck pain (78/68%); relief of arm muscle weakness and atrophy (94/96%); return to normal activities (64/70%); return to work (65/68%); and satisfaction with the results of surgery (86/83%). No statistically significant differences between outpatients and inpatients were found for any of the outcome parameters studied. There was no mortality and the operative complication rate was 2% for each study group. The results indicate that conversion of cervical discectomy with fusion from an admitted to an ambulatory practice did not compromise the safety or efficacy of the surgical procedure. Potential economic savings to overall health costs of the United States that might result from such conversion could exceed $100 million annually.

Daily subcutaneous injection of low-dose interleukin 2 expands natural killer cells in vivo without significant toxicity.

We aimed to determine the toxicity and immunological effects of daily s.c. administered low-dose interleukin (IL) 2. Adult cancer patients received a single daily s.c. injection of IL-2 as outpatients for 90 consecutive days. Cohorts of four to nine patients were treated at escalating IL-2 dose levels until the maximum tolerated dose (MTD) was defined. Peripheral blood mononuclear cell phenotyping, IL-2 serum levels, and the presence of anti-IL-2 antibodies were investigated. Thirty-eight patients were treated at seven IL-2 dose levels ranging from 0.4 to 1.75 million International Units (mIU)/m2 daily. The MTD was 1.25 mIU/m2, with constitutional side effects, vomiting, and hyperglycemia dose limiting. Severe toxicity did not occur at or below the MTD, although mild local skin reaction and mild constitutional side effects were common. Objective tumor regressions were not observed during this Phase I trial. Low-dose IL-2 resulted in natural killer (NK) cell (CD3(-) CD56(+)) expansion at all dose levels. This effect was dose dependent (P < 0.01), ranging from a 154 to 530% increase over baseline. Peak NK levels were achieved at 6-8 weeks and sustained through 12 weeks of therapy. As predicted by in vitro studies of IL-2 receptor structure-activity relationships, the subset of NK cells that constitutively express high-affinity IL-2 receptors (CD3(-)CD56(bright+)) showed more profound dose-dependent expansion, with increases ranging from 368 to 2763% (P = 0.015). NK expansion occurred at peak IL-2 levels <10 pM (2.3 IU/ml). Three patients developed nonneutralizing anti-IL-2 antibodies. Thus, we concluded that selective expansion of NK cells may be achieved in vivo with daily s.c. injections of low-dose IL-2 with minimal toxicity.

Clinical significance of colorectal cancer: metastases in lymph nodes < 5 mm in size.

BACKGROUND: The clinical significance of metastases in small lymph nodes is not known. Our objective was to evaluate possible relationships between the number and size of lymph node metastases and survival after potentially curative colorectal resection. METHODS: A retrospective chart review was performed in patients with Dukes'C (any T, N(1-3') M0) colorectal cancers from July 31, 1971 to December 31, 1987. All specimens underwent the lymph node clearing technique. Statistical analysis was performed with the log rank test and the Cox proportional hazards model. RESULTS: In 77 patients there were 253 (8%) of 3,087 cleared lymph nodes with metastases. One hundred seventy-five (69%) of these metastatic nodes were 5 mm or less in diameter. The distal margin of resection (p = 0.011) and number of positive lymph nodes (p = 0.036) were statistically significant factors influencing overall survival. There was no significant difference in overall survival (p = 0.73) or disease-free survival (p = 0.56) whether the involved lymph nodes were < or > 5 mm in size. CONCLUSION: Most metastatic lymph nodes were < 5 mm in diameter. Based on our results, the size of lymph node metastases do not affect disease-free or overall survival in colorectal carcinoma.