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Human leukocyte antigen (HLA) Class II antigens are variably expressed on acute myeloid leukemia (AML) blasts. The biological and clinical significance of HLA Class II antigen expression by AML cells is not known. Therefore, we sought to characterize cases of AML without detectable HLA-DR expression. Samples from 248 consecutive adult AML patients were immunophenotyped by multiparameter flow cytometry at diagnosis. HLA-DR antigens were not detected on AML cells from 43 patients, including 20 with acute promyelocytic leukemia (APL), and 23 with other subtypes of AML. All APL cases had t(15;17), but there were no characteristic chromosome abnormalities in non-APL cases. No direct expression of other antigens was identified in HLA-DR-negative APL and non-APL cases. Interestingly, cells from three HLA-DR-negative non-APL patients had similar morphology to that of the hypogranular variant of APL. This morphology, however, was not present in any HLA-DR-positive AML cases. Treatment response was similar in the 23 HLA-DR-negative non-APL and the 205 HLA-DR-positive patients. Finally, relapse was infrequently associated with changes in HLA-DR antigen expression, as the HLA-DR antigen was lost at relapse in only 4% of HLA-DR-positive cases, and was gained at relapse in only 17% of HLA-DR-negative cases. We conclude that HLA-DR-negative AML includes approximately equal numbers of APL and non-APL cases, and that the morphology of HLA-DR-negative non-APL cases can mimic the hypogranular variant of APL. The diagnosis of APL cannot be based on morphology and lack of HLA-DR antigen expression; rather, it requires cytogenetic or molecular confirmation.

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 pr...

To determine the pathological, clinical, and therapeutic factors which had prognostic significance in women with extraovarian primary peritoneal carcinoma (EOPPC).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).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 (P0.001,0. 001, 0.004, and 0.012, respectively). In multivariate analysis, only performance status (P0.001) 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.

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.

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) × 4, followed by monthly paclitaxel (135 mg/m 2 ) and cisplatin (75 mg/m 2 ) × 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.

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. J. Surg. Oncol. 1998;68:144–148. © 1998 Wiley-Liss, Inc.

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.

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. Cancer 1997; 80:892-8. © 1997 American Cancer Society.

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-α (IFN-α) and IFN-γ, 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 × 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-α (STAT1 and STAT3) and IFN-γ (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-γ, 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.

PURPOSE c-mpl, the human homolog of v-mpl, is the receptor for thrombopoietin. Given that c-mpl expression carries an adverse prognosis in myelodysplastic syndrome and given the prognostic significance of expression of other growth factor receptors in other diseases, we attempted to determine whether c-mp/mRNA expression is a prognostic factor in acute myeloid leukemia (AML). PATIENTS AND METHODS We analyzed bone marrow samples from 45 newly diagnosed AML patients by reverse-transcription polymerase chain reaction. RESULTS Samples from 27 patients (60%) expressed c-mpl mRNA (c-mpl+); their clinical and laboratory features were compared with those of the 18 patients without detectable levels of c-mpl(c-mpl-). No significant differences in age, sex, leukocyte count, French-American-British subtype, or karyotype group were found. c-mpl+ patients more commonly had secondary AML (41% v 11%; P = .046) and more commonly expressed CD34 (67% v 12%; P = .0004). There was no significant difference in complete remission (CR) rate. However, c-mpl+ patients had shorter CR durations (P = .008; median, 6.0 v > 17.0 months). This was true when only de novo AML patients were considered and when controlling for age, cytogenetics, or CD34 expression. There was a trend toward shorter survival in c-mpl+ patients (P = .058; median, 7.8 v 9.0 months). CONCLUSION These data suggest that c-mpl expression is an adverse prognostic factor for treatment outcome in adult AML that must be considered in the analysis of clinical studies using thrombopoietin in AML.

Previous attempts to characterize harvested marrow and peripheral blood stem cell (PBSC) in order to predict time to and quality of engraftment post autologous bone marrow transplant (autoBMT) have included use of in vitro colony forming unit (CFU) assays. These assays are hampered by interlaboratory variability and are not uniformly predictive. CD34 quantification by flow cytometric technique has also been used to assess the quality of harvested marrow and PBSC. However, a lack of standardization has hampered direct comparison of published reports. We sought to characterize these early lineage-committed CD34+ progenitor cells from non-ficolled harvested marrow with six progenitor cell (PC) panels containing CD34 antibody plus two additional early lineage markers, using multiparameter flow cytometry. The specific gating technique including simultaneous CD34-PE vs. side scatter and forward vs. side scatter, was verified using morphologic analyses of sorted CD34+ cells. An ungated file was initially acquired to assess total CD34+ content. A second file using a CD34 threshold was then acquired to resolve lineage-committed subsets. The % CD34+ cells as well as cells/μl of bone marrow was calculated using cell counts at the time of marrow harvest. Bone marrow (mean total cell dose = 3.8 × 108/kg), obtained from 42 normal donors for allogeneic transplantation was first analyzed. CD34+ cells comprised a mean 1.3% of non-ficolled marrow, with 328 CD34+ cells/μl, and mean CD34+ cells collected was 4.8 × 108/kg. While no significant differences in total cells harvested nor proportion of CD34+ cells was found, a significant decrease in CD34 cells/μl ( = 233, P = .0012) was found in cancer patients. The percentage of CD19+ and CD38+ progenitor cells was significantly increased, while CD5+ and CD71+ cells were decreased. The proportions of all other early lineage-committed CD34 subsets were not different. Measurement of lineage-committed CD34 progenitor cells is a useful technique to characterize harvested marrow and PBSC, and may be applied to predict time and quality of engraftment post ablative conditioning regimens. © 1996 Wiley-Liss, Inc.

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, N1–3, 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 5 mm in size. Conclusion: Most metastatic lymph nodes were

To prospectively correlate dynamic contrast enhancement at magnetic resonance (MR) imaging with mammographic and pathologic features of suspect breast lesions.Forty-nine patients with 51 breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo (SPGR) MR imaging at 1.5 T, as well as excisional biopsy or cyst aspiration.Twenty-two of 22 (100%) invasive carcinomas 8 mm or more in diameter, including three (12%) not evident on dense mammograms, enhanced 2.0 or more times the unenhanced intensity. One of three predominantly ductal carcinomas in situ and 10 of 26 (38%) benign lesions enhanced 2.0 or more times. Time-intensity curves were not statistically significantly different among enhancing carcinomas, fibroadenomas, or other benign lesions and showed no statistically significant correlations with pathologic size, nodal status, or hormone receptor status of invasive carcinomas.MR imaging enhancement of 2.0 or more times had high sensitivity (100%) for invasive carcinomas 8 mm or more in diameter, with moderate specificity (65%). Time-intensity curves showed no significant difference between enhancement of benign and malignant lesions.

An autopsy series on the patterns of occurrence of second primary non-mammary malignancies (SPNM) in breast cancer patients is presented. SPNM occurred in 11.4% of breast cancer patients at a mean interval of 83.9 months. Seventy-five per cent of them occurred by the first decade following breast cancer. The most common system of SPNM occurrence was the female genital system, followed by the gastrointestinal system. The single organs most commonly involved were the colon and rectum, ovary and uterine cervix. There was no evident association between administration of radiotherapy or chemotherapy for the breast cancer and the risk for SPNM development except in the case of post-radiation sarcomas at or near the site of post-mastectomy radiotherapy. Death was caused by the breast cancer in 28.7% of patients and by the SPNM in 53.5%. In 10.6% of the cases the SPNM was clinically interpreted as metastatic breast cancer until autopsy.

In this retrospective review of 58 patients (12 females and 46 males) with pulmonary metastases of squamous cell carcinoma of the head and neck treated between January 1, 1970, and December 31, 1989, we evaluated their clinical courses and analyzed the outcomes of those who underwent pulmonary resection. For the entire group of patients, factors predictive of survival in those patients with a diagnosis of pulmonary metastases included pulmonary resection of metastases (p = 0.0001), locoregional control of the head and neck primary tumor at the time of diagnosis of pulmonary metastases (p = 0.007), TNM stage of the head and neck primary tumor (p = 0.02), a single nodule seen on the chest radiograph (p = 0.02), and disease-free interval (DFI) from the primary tumor of the head and neck of 2 years or more (p = 0.05). Twenty-four of 58 patients underwent thoracotomy for resection of metastases. Four (17%) were found to have a second primary tumor of the lung. Of the 20 remaining patients who underwent explorative surgery for possible pulmonary resection, 18 (90%) underwent complete resection of all malignant disease with an estimated 5-year survival of 29%. In these patients, a DFI of less than 1 year was associated with a 5-year survival rate of 0%, whereas a DFI of 1 to 2 years was associated with a 5-year survival rate of 43% and a DFI of 2 years or longer had a 5-year survival rate of 33%. The number of malignant pulmonary nodules that were resected ranged from one to five and was not significant in predicting survival (p = 0.19). Of eight patients who underwent the resection of more than one malignant pulmonary nodule, 50% survived 2 years, but none survived 5 years. Resection of a solitary pulmonary metastasis from squamous cell carcinoma of the head and neck resulted in long-term survival in selected patients. Important prognostic factors included locoregional control of the head and neck primary tumor, the number of nodules seen on chest radiograph, the TNM stage of the primary tumor, and the DFI from the head and neck primary tumor. The value of resection in patients with more than one malignant pulmonary nodule remains to be defined for this group of patients.

Objective To report the use of wide-area 5-aminolevulinic acid photodynamic therapy to treat numerous basal cell carcinomas (BCCs) and basaloid follicular hamartomas (BFHs). Design Report of cases. Setting Roswell Park Cancer Institute. Patients Three children with BCCs and BFHs involving 12% to 25% of their body surface areas. Interventions Twenty percent 5-aminolevulinic acid was applied to up to 22% of the body surface for 24 hours under occlusion. A dye laser and a lamp illuminated fields up to 7 cm and 16 cm in diameter, respectively; up to 36 fields were treated per session. Main Outcome Measures Morbidity, patient response, and light dose–photodynamic therapy response relationship and durability. Results Morbidity was minimal, with selective phototoxicity and rapid healing. After 4 to 7 sessions, with individual areas receiving 1 to 3 treatments, the patients had 85% to 98% overall clearance and excellent cosmetic outcomes without scarring. For laser treatments, a sigmoidal light dose–response relationship predicted more than 85% initial response rates for light doses 150 J/cm2or more. Responses were durable up to 6 years. Conclusion 5-Aminolevulinic acid photodynamic therapy is safe, well tolerated, and effective for extensive areas of diffuse BCCs and BFHs and appears to be the treatment of choice in children.

PURPOSE The pulmonary effects of concurrent radiation therapy and chemotherapy were studied in patients enrolled in a phase I trial for esophageal cancer. MATERIALS AND METHODS Pulmonary function tests were performed prospectively before and after combined-modality therapy (oxaliplatin, 5-fluorouracil, and radiation therapy) in 20 patients with esophageal cancer. Cumulative and differential lung DVH analysis from 0 to 5400 cGy in 25-cGy intervals was performed for the last 15 patients. Correlation between radiation exposure in various dose ranges and percent reduction in pulmonary function tests was calculated as an exploratory analysis. RESULTS Significant reductions in carbon monoxide diffusion capacity corrected for hemoglobin (12.3%) and total lung capacity (2.5%) were evident at a median of 15.5 days after radiation therapy. DVH analysis revealed that the single dose of maximum correlation between lung volume radiation exposure and lung function reduction was less than 1000 cGy for all pulmonary functions. The percent lung volume that received a total dose between 700 and 1000 cGy maximally correlated with the percent reductions in total lung capacity and vital capacity, and the absolute lung volume that received a total dose between 700 and 1000 cGy maximally correlated with the percent reductions in total lung capacity, vital capacity, and carbon monoxide diffusion capacity. DISCUSSION Significant declines in carbon monoxide diffusion capacity and total lung capacity are evident immediately after the administration of conformal radiation therapy, oxaliplatin, and 5-fluorouracil for esophageal cancer. Other lung functions remain statistically unchanged. The percent or absolute lung volume that received a total dose between 700 and 1000 cGy may be significantly correlated with the percent decline of carbon monoxide diffusion capacity, total lung capacity, and vital capacity. These associations will be evaluated further in a follow-up study.

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. Cancer 1999;86:782–92. © 1999 American Cancer Society.

Background: Future developments in adjuvant modalities may require substaging of nodepositive 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

Since pelvic exenteration for the treatment of recurrent gynecologic malignancy first was described, reported rates of morbidity and mortality have declined steadily. However, the factors responsible for this decline have never been clearly delineated.We reviewed the charts of 154 patients who underwent pelvic exenteration for gynecologic malignancy between 1954 and 1994. Charts were abstracted for details of the surgical procedure, pathologic findings, postoperative management, short- and long-term complications, time to recurrence, and overall survival.Seventy-two patients (47%) experienced 95 identifiable postoperative complications, resulting in death in 22 patients (14%). The rate of infectious complications declined to a statistically significant degree between the first two decades and latter two decades of the study (odds ratio [OR] 0.28. 95% CI 0.11-0.69). The use of routine prophylactic antibiotics was associated with this decline in infectious complications (OR 0.25, 95% CI 0.07-0.83). The use of preoperative subcutaneous heparin was associated with a reduction in thrombotic complications from 5 of 100 patients to 0 of 54 patients (P = .11), as well as a significant reduction in overall risk of complications (OR 0.53, 95% CI 0.33-0.85) and risk of postoperative mortality (OR 0.19, 95% CI 0.05-0.80). There was a significant reduction in overall risk of postoperative complications with both intensive care unit monitoring postoperatively (OR 0.65, 95% CI 0.43-0.99) and routine postoperative monitoring with a pulmonary artery catheter (OR 0.61, 95% CI 0.38-0.98).Routine use of prophylactic antibiotics, prophylactic subcutaneous heparin, and intensive postoperative monitoring appear to have reduced morbidity from pelvic exenteration.

The receptor for megakaryocyte growth and development factor (MGDF), also known as thrombopoietin, has recently been cloned. MGDF stimulates platelet production and maturation both in vitro and in vivo. MGDF may thus have a role in attenuating the thrombocytopenia associated with acute myeloid leukemia (AML) and its therapy. However, there is concern that MGDF might induce AML blast proliferation and thereby increase the risk of treatment failure. To address this concern, we studied the expression of c-mpl mRNA and c-Mpl protein by blasts from AML patients. In addition we examined the in vitro effect of MGDF as well as the combined effect of MGDF and granulocyte colony-stimulating factor (G-CSF) or stem cell factor (SCF) on leukemic blast proliferation, recruitment into S-phase, induction of programmed cell death and activation of signal transducers and activators of transcription (STAT) proteins. Our results demonstrate that blasts from a substantial proportion of cases of AML express the receptor at either the mRNA or protein level. Moreover, the function of the MGDF receptor was demonstrated by activation of STAT proteins following exposure to MGDF. Nevertheless, blast proliferation in response to MGDF was rare, and the proliferative effect of MGDF was less than that of G-CSF or SCF. Furthermore, MGDF did not prevent programmed cell death induced by cytarabine. Finally, there appeared to be no correlation between receptor expression by AML blasts and functional response to MGDF. Based on these data, it would appear that clinical trials of MGDF may be undertaken safely in patients with AML.

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) × 4 followed by monthly cisplatin (50 mg/m 2 ), cyclophosphamide (750 mg/m 2 ), and doxorubicin (50 mg/m 2 ) for 10 cycles. In trial 2, patients received induction with weekly cisplatin (1 mg/kg) × 4 followed by monthly cisplatin (75 mg/m 2 ) and paclitaxel (135 mg/m 2 ) 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.

Purpose. To determine whether dynamic magnetic resonance (MR) imagingenhancement parameters are associated with vessel density of malignant andbenign breast lesions. Materials and methods. Forty-five patients with 48breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo(SPGR) MR imaging followed by excisional biopsy and Factor VIII staining andvessel density measurement in the lesions. Results. The vessel densitieswere not significantly different in 25 malignant breast lesions as comparedto 23 benign breast lesions. Among all 48 lesions, greater MR enhancementshowed an association with increased vessel density. Seventy-four percent ofall lesions with MRI enhancement amplitude greater or equal to three timespost-precontrast ratio had vessel densities greater than the median of 172as compared to 34% of lesions with enhancement amplitude less thanthree times, p = 0.02. The rate and washout of MR enhancement showedno significant association with vessel density. Conclusion. Although thereis an overall significant association between greater MRI enhancementamplitude and vessel density, MRI gadolinium enhancement of breast lesionsis not an accurate predictor of vessel density.

A prospective study was undertaken to evaluate associations among mammographic normal dense and fatty tissue, benign histologic findings, and cellular proliferative activity determined by DNA S phase percentages. Mammographic and histologic findings of benign, normal dense and fatty tissue contained in 100 excised specimens were cross-tabulated with flow cytometric DNA S phase percentages of needle aspirates obtained under radiographic guidance. Histologic evidence of atypia or hyperplasia was present in 21 (32%) of 66 fatty tissue samples and 11 (32%) of 34 dense tissue samples (p = NS). The median S phase percentages were identical for mammographic fatty and dense tissue (median % S phase = 5.35). The frequency of high S phase percentages (above the median) was not significantly different for tissue containing atypia or hyperplasia, 47% (15 of 32), as compared to tissue containing other benign histology, 52% (35 of 68) (p = NS). These frequencies were similar in women 49 and younger or 50 and older. These data show that mammographic normal dense and fatty tissues contain similar frequencies of histologic atypia or hyperplasia and low and high cellular proliferative activity determined by DNA S phase percentages in women aged 49 and younger and 50 and older.

Previously, we reported an effective chemotherapeutic combination regimen for non-small cell lung carcinoma (NSCLC) : cisplatinum, doxorubicin, cyclophosphamide, CCNU, and vincristine (PACCO). Forty-one patients with a diagnosis of NSCLC Stages III-A and III-B were entered into the protocol of neoadjuvant PACCO chemotherapy. Following two courses of chemotherapy, the patients were evaluated for surgical therapy. The overall response rate to the chemotherapy was 60%. Subsequently, 65% of the patients underwent surgical resection. The overall estimated median survival was 18 months. The survival of patients in III-A was 36 months and that of III-B was 18 months (95% confidence lower bounds for III-A : 8 months and for III-B : 13 months). There was one chemotherapy-related mortality but no surgical mortality. Neoadjuvant chemotherapy with PACCO regiment offers an alternative to chemoradiation therapy, without increasing the surgical mortality, and should be validated in a randomized clinical trial. For successful neoadjuvant chemotherapy of Stage III NSCLC, chemotherapy combination which would give a high response rate without significant side effects must be chosen. © 1995 Wiley-Liss, Inc.

PURPOSE: It is commonly believed that the right lobe of the liver is the most frequent site of colorectal liver metastases. However, direct evidence for this is lacking in the literature. This study was designed to document and evaluate the pattern of liver metastases according to liver segments. METHODS: A retrospective medical records review of 270 patients with hepatic metastases from colorectal adenocarcinoma was performed to determine the pattern of metastases according to Couinaud's segments. There was operative confirmation of liver metastases in 202 patients (75 percent). A total of 1,166 segments were involved with liver metastases and were used in this analysis. Segment I was excluded from calculations because of its dual blood supply. When groups contained different numbers of Couinaud's segments an appropriate correction was made in the statistical comparison. RESULTS: There were 736 (63 percent) right lobe segments (V,VI, VE, VIE) and 430 (37 percent) left lobe segments (II, III, IV) involved with metastases (P

F.2a and B.2, cell clones of the human squamous cell carcinoma SCC-12, were examined to characterize their interactions through the expression of growth factors. F.2a was nontumorigenic yet B.2 was fully tumorigenic when injected into the flanks of athymic nude mice. Combination injections of F.2a and a subtumorigenic level of B.2 produced tumors. F.2a and B.2 overexpressed the 4.8-kb transcript for transforming growth factor-alpha (TGF-alpha) as well as the 10.5- and 5.8- kb transcripts for the epidermal growth factor receptor. Neither clone expressed the transcript for epidermal growth factor, while both expressed transcripts for insulin-like growth factor-I (IGF-I) of 8.15, 4.9, and 1.6 kb and transcripts for its receptor of 8.5 and 6.5 kb. Conditioned medium (CM) from either clone stimulated the growth of itself and the other clone in tissue culture. Both clones produced intracellular TGF-alpha detectable by immunohistochemical staining, but not detectable in CM by enzyme-linked immunosorption assay. IGF-I was detected at low levels in CM by radioimmunoassay. Neutralizing antibodies to TGF-alpha but not IGF-I partially inhibit the growth of both clones in tissue culture. These results suggest that (1) TGF-alpha is active in autocrine signaling (2) IGF-I is not directly stimulatory, and (3) additional factors, as yet unidentified, are present in CM and enhance tumor growth. It is concluded that human squamous cell carcinoma SCC-12 is composed of tumorigenic and nontumorigenic clones which interact to enhance growth.

Leucovorin (LV) is commonly used as a modulator of 5-fluorouracil (5-FU) cytotoxicity. In patient with colon cancer, the addition of LV to 5-FU improves response rates, and in some trials has improved survival in advanced disease and in the adjuvant setting. Leucovorin is generally administered as a racemic mixture, but the isomers differ substantially in pharmacokinetics and biological activity, with 6S-LV the predominant active component. The current study was undertaken to determine the effect of 6R on the pharmacokinetics of 6S-LV, and to characterize the toxicity and antitumor effect of 5-FU when administered with 6S-LV to patients with advanced colorectal carcinoma. Thirty patients were treated with weekly 5-FU plus high dose 6S-LV. To determine the effects of 6R-LV on the pharmacokinetics of S6-LV, 20 patients were randomly assigned to receive either 250 mg/m2 6S-LV or 500 mg/m2 6R,S-LV as a 2 hour IV infusion on day -2, and the other preparation on day -1, with pharmacokinetics measured each day. The presence of 6R-LV had no effect on the AUC, Clp, Cmax, or terminal phase t1/2 of 6S-LV. The overall response rate was 40% (C.I. 23-60%). The most frequent toxicities were gastrointestinal. In this small cohort, scheduled and delivered dose intensity was positively associated with response (p = 0.05). These results show that there is no pharmacokinetic advantage to the use of 6S-LV rather than 6R,S-LV as a modulator of 5-FU.

Using a fluorometric assay, mean drug levels of Adriamycin were significantly higher in the normal canine liver following bolus injection of this drug via the hepatic artery or portal vein as compared to hepatic tissue levels following systemic intravenous administration (P < 0.001). However, the variations in tissue levels observed after hepatic artery (± 16.8 mcg/gm tissue) or portal vein (± 21.1 mcg/gm) infusion were significantly wider than those observed after systemic (± 1.3 mcg/gm) administration (P = 0.03). Using C14-labeled drugs, regional infusion of Adriamycin through the hepatic artery or portal vein resulted in significantly higher mean drug levels in the liver than after systemic intravenous administration, but the difference was more pronounced with bolus infusion of the drug than 1-hour infusion. 5-FU bolus or 1-hour infusion in the hepatic artery resulted in significantly higher mean drug levels in the liver compared to peripheral intravenous administration, but this was not so with the 3-hour infusion. The above experiments confirm previous studies that regional chemotherapy results in higher drug levels in the regional tissues compared to systemic administration. They also: (1) demonstrate the spotty drug distribution in the regional tissues after regional administration, a potentially correctable problem, and (2) suggest that the advantage of intra-arterial infusion may be more pronounced within a certain range of infusion times. © 1994 Wiley-Liss, Inc.

Seventy-two consecutive patients with disseminated soft tissue sarcoma in the abdomen were prospectively placed in a program of debulking surgery. The tumor was completely resectable in 64% of the patients. Following the first exploration, the median survival was 23 months for those with resection of metastases and 9 months for those without resection (p less than or equal to 0.01); the former group had a survival rate of 28% at 3 years, 18% at 4 years, and 4% at 5 years (44%, 37%, and 10%, respectively, for low-grade sarcomas, i.e., grade I or II sarcomas), whereas in the latter group, none survived for 3 years. In the group with resection, patients with grade III tumors had a median survival longer by 6 months, and those with low-grade tumors by 28 months (p less than or equal to 0.001), over the respective median survival of patients with unresectable tumors. Metastasectomy appeared to prolong survival in all patients and significantly so in patients with low-grade tumors and those with long disease-free intervals.

• A blinded prospective study of 34 patients with colorectal adenocarcinoma using the Fab I fragment of the anticarcinoembryonic antigen monoclonal antibody type IMMU-4 labeled with technetium 99m was conducted to compare, on a lesion-by-lesion basis, the findings of radioimmunoscintigraphy, preoperative computed tomography, and exploratory celiotomy. Of 115 lesions detected at surgery, 113 were adenocarcinoma. Radioimmunoscintigraphy detected 59 lesions and computed tomography detected 62; both studies combined detected 72. Twenty-nine (54%) lesions missed by radioimmunoscintigraphy and 24 (45%) missed by computed tomography were 1 cm or smaller. When both studies were combined, the sensitivities were 90%, 24%, and 42%, and the specificities were 52%, 86%, and 61% for hepatic, extrahepatic intra-abdominal, and pelvic lesions, respectively. In 10 patients, additional information obtained with the radioimmunoscintigram could have altered the treatment of these patients. In this study, radioimmunodetection scan was complementary to computed tomographic scan in the examination of patients with colorectal carcinoma. ( Arch Surg. 1992;127:1321-1324)

In the planning of a clinical trial to compare the proportion of responses to two treatments one determines the sample size to yield the desired power of achieving a significant difference at a pre-selected type I error under the assumption that the expected treatment difference exceeds a prescribed minimum. To achieve a practicable sample size, an investigator may be tempted to require a large treatment difference and thereby risk the chance of missing a somewhat smaller but clinically important difference. We obtain in this paper an expression for this loss of power if the true treatment difference is smaller than the minimum used to plan the study. The expression does not explicitly depend on the sample size and for most practical purposes does not depend on the actual response rates but rather varies only as a function of the fractional difference between the required minimum and true treatment difference. With provision of a prior distribution for this fractional difference, we can use the expression to calculate an expected power for the study. An illustration considers the case where the prior follows a beta distribution.

From June, 1972, to December, 1976, 40 patients with FIGO (International Federation of Gynaecology and Obstetrics) Stage IIB carcinoma of the uterine cervix were entered into a prospective, double-blind, randomized study to evaluate the possible radiation-potentiating properties (i.e., improved survival) of the S-phase cell cycle-specific inhibitor of DNA synthesis, hydroxyurea. All patients were documented to be without aortic lymph node metastasis by pretherapy staging para-aortic lymphadenectomy. All 40 patients were followed up for longer than 5 years (5.2 to 9.2 years) or until death. The double-blind code was not broken until all patients had been followed up for a minimum of 2 to 5 years. Leukopenia (white blood cell count less than 2,500 mm3) was significantly increased in the patients given hydroxyurea as compared to those given placebo (P less than 0.0001). There was no statistically significant difference relative to anemia, thrombocytopenia, radiation-induced skin reaction, and radiation-induced intestinal reaction between the patients given placebo or those given hydroxyurea. Life-table survival for the patients given hydroxyurea was 94% as compared to 53% for the patients given placebo (P = 0.006). Only one (5%) patient given hydroxyurea died of cervical cancer. Of the other patients who died in the group given hydroxyurea, all were confirmed by postmortem examination to have been without recurrent cervical cancer. In contrast, 45% (nine) of the patients given placebo died of cervical cancer.

The effectiveness of screening random asymptomatic women for breast cancer using mammography has been analyzed using a new mathematical-computer technology. The technology is based on a general mathematical theory of screening recently developed by Blumenson combined with a mathematical model for breast cancer developed by Blumenson and Bross over the past decade. The technology makes it relatively simple to try alternative strategies for age at onset of screening, screening interval, etc. and to calculate the relative effectiveness of the strategy. When the benefits of alternative strategies with periodic screening beginning at different ages were compared with the increasing risk of iatrogenic disease from multiple exposure to low levels of radiation, it was concluded that screening of asymptomatic women should begin no earlier than age 50.

The frequency distributions of litter sizes at birth for eight sublines derived from the same Ha(ICR) mouse stock with or without selection for large litters have their modes at even numbers of young. Each of the eight sublines produced a majority of even-numbered litters. An upward integral shift relationship among the medians of the frequency distributions was established. These findings are interpreted to mean that, in response to continued plus selection, ovarian and uterine performance of the Ha(ICR) bipartite reproductive system tends to be maximal bilaterally, which results in an excess of even-numbered litter sizes.

Between January 1974 and November 1978, 41 consecutive increased risk (age less than 24 months or less than 120 months, or leukocyte count greater than 30,000/mm3) patients with acute lymphoblastic leukemia (ALL) were entered on two consecutive treatment protocols which employed intermediate dose methotrexate (IDM). IDM was employed for central nervous system prophylaxis and systemic intensification. It was anticipated that the avoidance of prophylactic cranial irradiation would result in a lower incidence of longterm central nervous system sequelae. Twenty-two children and adolescents were entered on the first study (IDM X 3) which employed three courses of IDM (500 mg/m2) and six doses of intrathecal (IT) methotrexate (MTX). Nineteen children and adolescents were entered on the second study (IDM X 6) which employed six courses of IDM (3-500 mg/m2 and 3-1500 mg/m2), six doses of IT MTX and three additional doses of triple IT chemotherapy (MTX, cytosine arabinoside, and hydrocortisone or dexamethasone). The cumulative percentage of patients who remained in continuous complete remission was 30% for IDM X 3 and 57% for IDM X 6. This difference was statistically significant (P = 0.046; and BM + CNS, I-using IDM X 6. The cumulative incidence of primary CNS relapse was 36.4% for IDM X 3 and 29.9% for IDM X 6. This difference was not statistically significant (P = 0.44). The use of more intensive therapy with IDM and triple IT chemotherapy did improve the duration of continuous, complete remission but did not decrease the incidence of primary CNS relapse in increased risk patients.

Retinoic acid has been reported to act as an inhibitor and as an enhancer of mouse skin carcinogenesis in vivo. However, no in vitro cell transformation model has been reported to be sensitive to both effects. In an attempt to provide such a model, the effect of retinoic acid on an early step in carcinogen-induced transformation of mouse epidermal cell line 271c was measured using a recently described assay. The step observed is altered response to extracellular Ca2+ as an epidermal terminal differentiation signal. In six out of twelve experiments retinoic acid increased the frequency of altered colonies resulting from treatment with three chemical carcinogens. The enhancement effect was stronger after DMBA treatment than MNNG or MCA, resulting in up to a 13.7-fold increase in the frequency of colonies exhibiting altered terminal differentiation (TF). On the other hand, up to a 10-fold decrease in TF was observed in other experiments. Both the enhancement and inhibitory effects were greater at the higher doses of retinoic acid tested in the range of 10(-10) - 10(-7) M. Variations in cloning efficiency or surviving colony density did not account for the effects on TF. Enhancement effects tended to be observed at lower doses of carcinogen, or in experiments in which TF resulting from treatment with carcinogen alone was in the lower range observed. However, the factors determining each effect have yet to be defined. The enhancement effect of retinoic acid was not merely suppression of the phenotypic endpoint of the in vitro assays, because treatment of carcinogen-altered cells with retinoic acid or TPA in vitro also enhanced their tumorigenicity in vivo compared to acetone controls. These findings suggest that studies of the determinants of retinoid activity should be a prerequisite to their use in chemoprevention.

The occurrence of sepsis due to Streptococcus pneumoniae and Hemophilus influenza and of herpes zoster (HZ) was reviewed in a series of 72 consecutive, previously untreated children and adolescents with Hodgkin disease. There was not a statistically significant difference in the risk of developing sepsis within five years of diagnosis between patients who had (16.6%) or had not (6.2%) undergone splenectomy. Sepsis occurred most frequently among patients treated initially with total nodal irradiation and combination chemotherapy. The estimated risk of HZ during the first five years after diagnosis was 34%. Patients treated initially with irradiation and combination chemotherapy had a significantly greater risk of developing HZ than patients treated initially with only irradiation (P less than 0.05). Although trends were present which suggested that splenectomy and the extent of disease at diagnosis may influence the occurrence of HZ, these did not achieve statistical significance. Survival was not influenced by the occurrence of HZ.

Periodic screening programs for the early detection of chronic diseases such as cancer and heart disease may not always lead to a reduction in the number of deaths from the disease. Some improvement is usually possible with the use of a more sensitive detection test, or by lowering the age for the first screening examination, or by decreasing the period between examinations. However, the extent of the reduction in deaths that is attainable with these changes is limited by the underlying biological behavior of the disease as well as by the rate at which the disease is detected without the screening examination, i.e., by the “natural history” of the disease. The effectiveness of a periodic screening program is derived as a function of this natural history, the period between examinations, the sensitivity of the detection test, the age at the first examination, and the age distribution of the rate of the disease initiation in the screened population. A detailed discussion is given of how these results might be used to estimate the effectiveness of any planned periodic screening program. The analysis of a simple example suggests that for some diseases decreasing the interval between screening examinations may not lead to a significant lowering of the death rate, i.e., there may be a natural lower bound on the screening period.

When the technology used to screen a large population for a chronic disease is potentially harmful in itself, it becomes necessary to consider alternative screening strategies. These alternatives are compromises, since although less people are exposed to the danger of the screening technology, some who would have benefited from the examination never receive it. A previously developed mathematical model for mass screening programs is used to evaluate one type of compromise screening strategy, namely, a two stage screening examination with the first stage a harmless, relatively inaccurate test and the second stage the more accurate, potentially harmful examination. The formulas are then used to calculate the effectiveness of a one stage screening examination for breast cancer using mammography, relative to a two stage screening examination for which the first stage measures the erythrocyte sedimentation rate and the second stage is a mammography examination. It is shown that the numerical values obtained are not too far from a conjecture made in an earlier paper. It is concluded that a two stage screening examination should be used in any program which uses mammography to screen a large population of asymptomatic women for breast cancer.

A recently developed model of the human granulopoietic system had been used to analyze the toxic effects of 5-fluorouracil administered to cancer patients. From this analysis there appeared to be a relationship between the level of the early leukopenic depression and the rate at which the drug kills cells in the marrow. In particular, it may be possible to estimate this kill rate from the extent of the maximal depression in the white blood count during the second or third week after treatment begins. This estimate may be useful when planning modifications in treatment in order to prevent the onset of hematologic crises.

A mathematical modeling procedure which links the known phases of granulocyte kinetics is developed. The procedure is comprehensive enough so that it can be used to analyze the implications at the clinical level of events occuring at the cellular level. A computer simulation that incorporates the concepts and experimental data of the model is described in detail. This simulation is used to study the pattern of leukopenia seen in cancer patients receiving chemotherapy. In particular, the relationship between the drug effect on marrow cells and the ensuing pattern of leukopenia in the peripheral blood is analyzed in detail.

The ideal goal of a screening program for breast cancer is to detect the disease at a stage when it is still curable by a simple lumpectomy. This goal would be possible if the tumor had an early latent period before it was vascularized. However, even if there existed a harmless screening examination that was sensitive enough to discover the cancer at this stage the benefit to be gained from a screening program would be highly dependent on the time the tumor spends in the latent stage as well as on the chance of false negatives at the examination. Calculations derived from a mathematical model suggest a variety of theoretically possible situations including: (1) For certain cancers screening every three years would offer almost as much benefit as screening every year; (2) A large increase in the sensitivity of a screening examination does not necessarily lead to a large increase in the benefit of a screening program; (3) For certain cancers the benefit of screening might remain low no matter how sensitive the examination used.

The ability of choline (C) to prevent hepatic toxicity due to chronic administration of 6-mercaptopurine (6-MP) was evaluated in male Wistar rats. Two dose levels of 6-MP and two dose levels of C were used. Choline did not prevent or diminish the hepatic accumulation of triglyceride when administered in combination with 6-MP. The 6-MP did impair the growth of the experimental animals, and this effect was antagonized by C administration. The data provided experimental support for the clinical observation of growth impairment in children treated with chronic antimetabolite therapy for acute lymphoblastic leukemia.

A steady state mathematical analysis of periodic mass screening programs to detect chronic diseases is extended to the transient state. One can now calculate the screening effectiveness, the number of cases, both discovered and undiscovered, and the extent of disease in these cases at any time after the screening program is started. A previously developed mathematical model for the growth and spread of human breast cancer is joined with this screening model to evaluate alternative screening strategies for breast cancer in large populations of asymptotic women. The screening effectiveness is calculated for examinations with different levels of detection sensitivity, for different intervals between examinations, and for different ages when screening begins. Tentative conclusions are that starting screening at age 40 has little advantage over starting at age 50, while there is some advantage to a screening interval of 12 months rather than 24 months.

Fifty-one previously untreated women with FIGO Stages III and IV ovarian adenocarcinoma underwent sequential monthly skin testing utilizing Keyhole Limpet Hemocyanian, Varidase, mumps, monilia, and a purified protein derivative Tuberculin (PPD) prior to each course of systemic chemotherapy (with or without Corynebacterium parvum). The purpose of the study was to evaluate the patients' ability to demonstrate a delayed cutaneous hypersensitivity reaction to these sensitizing antigens and response to therapy. There was no statistically significant correlation with response to therapy and: 1) Positive pretherapy skin test reactions vs anergy to pretherapy skin tests. 2) Negative pretherapy and positive post-therapy skin tests. 3) Anergy pre- and post-therapy vs positive skin tests pre- or post-therapy. 4) Age of the patient vs skin test reactivity. 5) Skin test reactivity to any one of the five antigens tested. 6) Skin test reactivity in response to therapy in those women also receiving Corynebacterium parvum. It is concluded that the battery of skin tests utilized do not predict the patient's response to systemic chemotherapy in advanced ovarian adenocarcinoma.

One hundred and three women with FIGO stage IB cervical carcinoma were treated either by radical hysterectomy and bilateral pelvic lymphadenectomy, or external pelvic radiation and intracavitary brachytherapy to deliver >6000 rads to point A. Surgical therapy was to be limited to stage IB tumors mea

The value of deep mathematical models for the predictive design of experiments is discussed and the principles are applied to an evaluative protocol in decisions concerning radical vs. total mastectomy in cases of self-contained breast cancer. The relation of clinical observations on the degree of malignancy to the underlying cellular phenomena that give rise to the condition are translated into algebraic language and the possible therapeutic strategies are plotted. In this particular situation of radical vs. total mastectomy analysis shows that the issue will most likely not be resolved even with analysis of 10000 cases. The use of predictive design can show which proposed studies are likely to achieve their research objectives and can provide guidance for future studies.

Mathematical models have been constructed which relate the depth of the culture fluid overlay to the oxygen available to mammalian cells cultured under static conditions. These models suggest that the maintenance of a given rate of oxygen utilization by some culture systems may be critically depended on this fluid depth and on the solubility and rate of diffusion of oxygen in the culture fluid. The importance of these concepts as applied to the isolation and growth of differentiated cells representative of the tissue of origin are noted.