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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. more...

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. more...

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. more...

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. more...

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. more...

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 more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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 more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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 more...

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. more...

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. more...

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. more...

• 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) more...

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. more...

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. more...

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. more...

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. more...

Experiments made on the passage of cells through untreated and siliconized glass beads, and on the adhesion and spread of cultured cells on glass and Teflon surfaces show that, in the absence of serum and in its presence in low concentrations, cell adhesion and spread is sensitive to substratum wettability. On the other hand, in the presence of 100% serum, no differences in adhesive parameters are detectable. It is concluded that arguments correlating cell adhesion to surface wettability, and, by inference, surface free energy, are unsubstantiated in 100% serum, which may well approximate to the in vivo situation. The results also show no correlation between parameters of cell adhesion and cell separation, and thereby support the hypothesis that these are different processes. more...

Two-thousand, five-hundred and twenty-four bacterial isolates were tested against 11 new beta-lactam antibiotics in a prospective study conducted in a cancer center. E. coli, P. aeruginosa, and K. pneumoniae were the most common gram-negative organisms isolated, while S. aureus and Enterococcus were the most common organisms among the gram-positive. The new cephalosporins were more active than the semisynthetic penicillins against E. coli, P. aeruginosa, and K. pneumoniae (p less than 0.001). Mezlocillin had better activity than the other semisynthetic penicillins against most of the gram-negative organisms as well as the enterococci. As a result, mezlocillin was preferred as a beta-lactam agent to be employed with an aminoglycoside as empiric antibiotics for febrile patients with neoplasia. more...

We have observed that the ammonia levels in mammalian cell culture media are 10 to 100 times the mean level found in the blood of normal humans. At the moment of formulation of culture medium, the major source of ammonia is the serum component. Ammonia levels exceeding 5,000 μg/dl of NH 3 -N have been detected in stored serum samples. Upon storage, of complete culture media, significant quantities of ammonia were generated by the decomposition of glutamine and serum. The rates of generation of ammonia, in stored culture media, ranged from 0 to 89 μg/dl/day of NH 3 N depending on the temperature of storage (−80 °C to 37 °C). more...

Hydroxyurea was evaluated as a possible radiation sensitizer in 130 evaluable women with Stages IIB and IIIB (International Federation of Gynecology and Obstetrics) carcinoma of the uterine cervix. This was a prospective double-blind randomized study in which hydroxyurea or placebo was compared in conjunction with continuous or split-course radiation therapy. Of all patients with Stage IIB cancer without biopsy proof of aortic node metastasis, a significant improvement in survival (P less than 0.01) was achieved in the hydroxyura group (74.0%) as compared to the patients receiving placebo (43.5%). In women with Stage IIIB cervical cancer there was a trend toward longer survival in those receiving hydroxyurea (52.1%) as compared to those receiving placebo (33.3%). However, there was a statistically significant improvement in survival in those women with Stage IIIB cervical cancer who had staging done at operation, were found to have negative para-aortic nodes, and subsequently received continuous radiation therapy (90.9%) as compared to those receiving split-course therapy (29.4%) (P = 0.005). more...

Thyroid function was evaluated in a consecutively treated group of children and adolescents with Hodgkin disease who received incidental radiation to the thyroid gland. Ten of 27 (36.7%) were found to have elevated concentrations of thyroid-stimulating hormone (TSH). Two groups of patients had an increased incidence of thyroid dysfunction - those who had not had a pretreatment lymphangiogram and those who were less than 13 years of age at the time of neck irradiation. The estimated percentage of patients who did not have a pretreatment lymphangiogram who will develop TSH elevation was 67.7% and of patients who were 13 years of age or less when irradiated, 64.8%. Thyroid dysfunction developed in 6/7 patients who had both of these risk factors present. more...

A new simplified system for updating a cancer registry has been developed in the Biostatistics Department of Roswell Park Memorial Institute. It was designed to serve the needs of maintaining a registry for a cooperative cancer research group. The Data-Update Procedure at a Remote Terminal (DUPART) system has general value for registry applications. more...

A mathematical model is developed in order to examine the relationship between the spread of cancer and the movements of the constituent cells of the tumor. A distinction is made between the “visible” and the “invisible” spread of cancer in an area of tissue in terms of the number of tumor cells located in this area. The relevance of this distinction for the cure of cancer by surgical excision of the visible tumor is examined in some detail for the geometry of uterine cancer. The movements of the tumor cells are classified into (a) those which occur in the intercellular spaces (from ameboid movements, tumor pressure, etc.) and (b) those which are due to convection in the small vessels of the vascular system. The effect of these two types of movement on the spread of the cancer is examined by means of computer pictures generated from the mathematical model. more...

Biologists, in the laboratory, see cancer cells as individual entities while physicians, in the clinic, see them as tumor masses. A mathematical model is described which bridges the relationship between the observations in the clinic and the underlying movements of the individual tumor cells. For this purpose the model is developed according to the protocol of an actual study of patients with cancer of the endometrium and includes the effect of preoperative radiation treatment in reducing the visible size of the tumor. In this way it is possible to obtain a quantitative estimate of the radiation effect. The model is also used to estimate the motility of tumor cells in vivo and this is compared with measurements obtained in the laboratory. A short discussion is presented of how mathematical models could become useful tools for bridging the gap between discovery in the laboratory and application in the clinic. more...