Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin.

BACKGROUND: An elevated international normalized ratio (INR) increases the risk for major hemorrhage during warfarin therapy. Optimal management of patients with asymptomatic elevations in INR is hampered by the lack of understanding of the time course of INR decay after cessation of warfarin therapy. OBJECTIVE: To identify predictors of the rate of INR normalization after excessive anticoagulation. DESIGN: Retrospective cohort study. SETTING: Outpatient anticoagulant therapy unit. PATIENTS: Outpatients with an INR greater than 6.0 were identified from August 1993 to September 1998. Patients in whom two doses of warfarin were withheld and a follow-up INR was obtained on the second calendar day were enrolled. No patient received vitamin K(1). MEASUREMENTS: The INR was measured 2 days after an INR greater than 6.0 was recorded. RESULTS: Of 633 study patients with an initial INR greater than 6.0, 232 (37%) still had an INR of 4.0 or greater after two doses of warfarin were withheld. Patients who required larger weekly maintenance doses of warfarin were less likely to have an INR of 4.0 or greater on day 2 (adjusted odds ratio per 10 mg of warfarin, 0.87 [95% CI, 0.79 to 0.97]). Other risk factors for having an INR of 4.0 or greater on day 2 included age (odds ratio per decade of life, 1.18 [CI, 1.01 to 1.38]), index INR (odds ratio per unit, 1.25 [CI, 1.14 to 1.37]), decompensated congestive heart failure (odds ratio, 2.79 [CI, 1.30 to 5.98]), and active cancer (odds ratio, 2.48 [CI, 1.11 to 5.57]). CONCLUSIONS: Steady-state warfarin dose, advanced age, and extreme elevation in INR are risk factors for prolonged delay in return of the INR to within the therapeutic range. Decompensated congestive heart failure and active cancer greatly increase this risk.

Factors influencing serum CA125II levels in healthy postmenopausal women.

Our objective was to identify factors that correlate with CA125 concentrations in healthy postmenopausal women and to introduce recommendations for reporting and interpreting individual CA125 assay results. We analyzed repeated serum CA125 levels, as measured by the CA125II assay, in 18,748 postmenopausal women who participated in the ST: Bartholomew's/Royal London Hospital Ovarian Cancer screening trial from 1986 to 1994 and were not diagnosed with ovarian cancer during the 12-year follow-up period. We found that race is a substantial predictor of normal levels of CA125, with average CA125II concentration from African (median, 9.0; 95% range, 4.0-26.0 units/ml) and Asian women (median, 13.0; range, 5.9-33.3 units/ml) lower than that in Caucasian women (median, 14.2; range, 6.0-41.0 units/ml; P < 0.001). Women with a hysterectomy have lower CA125II values (median, 13.6; range 5.5-39.0 units/ml; P < 0.001), and women with a prior cancer diagnosis other than ovarian cancer have higher levels of CA125 II (median, 16.0; range, 6.0-49.0 units/ml; P < 0.003). Regular smoking and caffeine consumption decrease CA125 levels (P < 0.001). A woman's age, age at menarche, age at menopause, and history of a previous ovarian cyst (P < 0.05) are also predictive of baseline CA125 levels. Parity, history of hormone replacement therapy or unilateral oopherectomy, and previous use of oral contraceptives or talcum powder are not significant predictors of CA125 concentrations (P > 0.05). We concluded that clinically significant differences in individual patient characteristics need to be reflected in the screening algorithms that use CA125II so that designed performance characteristics (sensitivity and specificity) are maintained in practice.

Tumor markers in screening for ovarian cancer.

Tumor markers are used for multiple purposes in clinical care, including screening asymptomatic subjects, differential diagnosis of symptomatic patients, treatment planning, prognosis during and immediately following treatment, and monitoring for recurrence. Generally, tumor markers have found most clinical utility in monitoring for recurrence of disease (1). Bast and coinvestigators discovered CA125 in 1979 using monoclonal antibody techniques (2), and subsequently demonstrated its utility in monitoring treatment and recurrence of ovarian cancer (3). CA125 is the most widely used ovarian tumor marker, and is currently approved in the United States for monitoring of disease to determine if second-look surgery is required. Tumor markers have not gained wide acceptance for early detection of disease with the one exception of PSA for prostate cancer in the U.S. The lack of acceptance is mainly because of the difficult hurdles a screening strategy must overcome, and few tumor markers have shown sufficient promise in overcoming these hurdles to put them to the test in a randomized controlled trial. Because of the low incidence of most cancers, sample sizes for prospective randomized screening trials are huge, so that sufficient numbers of disease specific events occur by the end of the trial. The significant costs entailed in clinical trials of this size imply that only very promising approaches to screening warrant prospective investigation. For ovarian cancer, three large trials are underway, two trials are planning to randomize 120,000 women followed for 7-8 yr (4,5), and an NCI trial will randomize 74,000 women followed for 16 yr (6).

Performance of ultrasound as a second line test to serum CA125 in ovarian cancer screening.

OBJECTIVE: To assess the performance of ultrasonography in a multimodal ovarian cancer screening strategy. DESIGN: Prospective ovarian cancer screening trial between December 1986 and June 1993. SETTING: General practice, occupational health departments and an ovarian cancer screening clinic at a London teaching hospital. POPULATION: Postmenopausal women, > or = 45 years with a raised CA125. METHODS: Volunteers with a CA125 > or = 30 U/mL underwent a pelvic ultrasound. Scans were classified as normal, abnormal (ovarian volume > or = 8.8 mL) or equivocal (normal volume with abnormal morphology). Abnormal ovarian morphology was subclassified as simple cyst (single, thin walled cyst with no septa or papillary projections) or complex (all other abnormalities). Volunteers with abnormal scans were referred for a gynaecological opinion. Follow up was via the cancer registry and postal questionnaires. MAIN OUTCOME MEASURES: Sensitivity, specificity and positive predictive value of different ultrasound criteria for detection of index cancer (e.g. primary invasive epithelial carcinoma of the ovary and fallopian tube). RESULTS: Seven hundred and forty-one women underwent 1,219 scans and 20 index cancers occurred during a median follow up of 6 x 8 years. The sensitivity for detection of ovarian cancer of different ultrasound criteria was 100% for abnormal morphology, 89 x 5% for abnormal volume and 84% for complex morphology. The highest specificity (97%) and positive predictive value (37 x 2%) was achieved using complex morphology. CONCLUSION: A variety of ultrasound criteria can achieve high sensitivity, specificity and positive predictive value for index cancers in postmenopausal women with an elevated CA125. Use of ovarian morphology to interpret ultrasound may increase sensitivity and use of complex ovarian morphology may increase the positive predictive value.

Ultrasound assessment of ovarian cancer risk in postmenopausal women with CA125 elevation.

We have previously shown that, in asymptomatic post-menopausal women, serum CA125 elevation is associated with a 36-fold increase in risk of ovarian cancer. This study was undertaken to assess the value of pelvic ultrasound for further stratification of ovarian cancer risk. Of 22,000 post-menopausal women, aged > or = 45 participating in an Ovarian Cancer Screening Trial, 741 with a CA125 > or = 30 U ml(-1) underwent pelvic ultrasonography. Twenty index cancers (primary invasive epithelial carcinomas of the ovary and fallopian tube) were diagnosed amongst these 741 women during a median follow-up of 6.8 years. Ultrasound results separated the women with CA125 elevation into two groups. Those with normal ovarian morphology had a cumulative risk (CR) of index cancer of 0.15% (95% confidence interval (CI) 0.02-1.12) which is similar to that of the entire population of 22,000 women (0.22%, 95% CI 0.18-0.30). In contrast, women with abnormal ovarian morphology had a CR of 24% (15-37) and a significantly increased relative risk (RR) of 327 (156-683). Ultrasound can effectively separate post-menopausal women with raised CA125 levels into those with normal scan findings who are not at increased risk of index cancer and those with abnormal findings who are at substantially increased risk of index cancer.

Screening for ovarian cancer: a pilot randomised controlled trial.

BACKGROUND: The value of screening for ovarian cancer is uncertain. We did a pilot randomised trial to assess multimodal screening with sequential CA 125 antigen and ultrasonography. METHODS: Postmenopausal women aged 45 years or older were randomised to a control group (n=10,977) or screened group (n=10,958). Women randomised to screening were offered three annual screens that involved measurement of serum CA 125, pelvic ultrasonography if CA 125 was 30 U/mL or more, and referral for gynaecological opinion if ovarian volume was 8.8 mL or more on ultrasonography. All women were followed up to see whether they developed invasive epithelial cancers of the ovary or fallopian tube (index cancers). FINDINGS: Of 468 women in the screened group with a raised CA 125, 29 were referred for a gynaecological opinion; screening detected an index cancer in six and 23 had false-positive screening results. The positive predictive value was 20.7%. During 7-year follow-up, ten further women with index cancers were identified in the screened group and 20 in the control group. Median survival of women with index cancers in the screened group was 72.9 months and in the control group was 41.8 months (p=0.0112). The number of deaths from an index cancer did not differ significantly between the control and screened groups (18 of 10,977 vs nine of 10,958, relative risk 2.0 [95% CI 0.78-5.13]). INTERPRETATION: These results show that a multimodal approach to ovarian cancer screening in a randomised trial is feasible and justify a larger randomised trial to see whether screening affects mortality.

The percentage of free prostate specific antigen is an age-independent tumour marker for prostate cancer: establishment of reference ranges in a large population of healthy men.

OBJECTIVE: To define the reference range for the ratio of free to total prostate-specific antigen (fPSA%) in a population of healthy men with no clinically evident prostate cancer and to assess the influence of age on this tumour marker, thus determining the utility of fPSA% in enhancing the discriminatory power of PSA to differentiate healthy men and patients with benign prostatic hyperplasia from those with prostate cancer. SUBJECTS AND METHODS: In a prospective cohort study between May and August 1996, 1160 white men aged 20-89 years (957 were 40-69 years old, 82% of all subjects) from nine European and eight non-European countries were assessed. None of the participants who had a history of prostate cancer had undergone prostatectomy. A standard clinical examination including a digital rectal examination was performed to exclude the presence of prostate cancer. Transrectal ultrasonography was not an inclusion criterion, as it was not available in every case. Total PSA (tPSA) and free PSA (fPSA) were determined in 61 laboratories using the appropriate Enzymun-Test for tPSA and fPSA (Boehringer Mannheim Diagnostics, Mannheim, Germany). Serum tPSA, fPSA and fPSA% were then assessed as a function of the subjects' age. RESULTS: The serum tPSA and fPSA were significantly different among age decades 2-8 (P < 0.001), with increasing median values, indicating that both variables depend on age. The recommended upper reference limit (95th percentile) for tPSA is 1.78 ng/mL for men aged 30-39 years, 1.75 ng/mL for 40-49 years, 2.27 ng/mL for 50-59 years, 3.48 ng/mL for 60-69 years and 4.26 ng/mL for 70-79 years. The fPSA% was not significantly different between decades 3-8 (P = 0.06). Those aged 20-29 years had a slightly higher median value (P = 0.03) than the other age groups. The recommended lower reference limit (fifth percentile) for fPSA% is 12.6%. CONCLUSION: The fPSA% for clinically relevant age groups in healthy men was independent of age, which simplifies the use and interpretation of this relatively new tumour marker.

Acetaminophen and other risk factors for excessive warfarin anticoagulation.

CONTEXT: Warfarin is highly effective in preventing thromboembolism, but increases the risk of hemorrhage, particularly at an international normalized ratio (INR) greater than 4.0. Identifying causes of excessive anticoagulation in clinical practice could help target patients at risk for elevated INRs. OBJECTIVE: To determine causes of INRs greater than 6.0 in a clinical practice setting. DESIGN: Case-control study. SETTING: Outpatient anticoagulant therapy unit. PATIENTS: Outpatients followed up prospectively from April 1995 to March 1996 who had been taking warfarin for more than 1 month, had a target INR of 2.0 to 3.0, and were able to be interviewed within 24 hours of their reported INR. Case patients had INRs greater than 6.0; controls were randomly selected from patients having INRs between 1.7 and 3.3. MAIN OUTCOME MEASURES: Factors associated with INRs greater than 6.0, including medication use, recent diet, illness, alcohol consumption, and actual warfarin use. RESULTS: A total of 93 cases and 196 controls were interviewed; they did not differ in age, indication for warfarin, length of therapy, warfarin dose, number of prescription medications, or previous INR or long-term INR variability. Acetaminophen ingestion was independently associated in a dose-dependent manner with having an INR greater than 6.0 (P for trend <.001). For the highest-dose category of acetaminophen intake, 9100 mg/wk or more, the odds of having an INR greater than 6.0 were increased 10-fold (95% confidence interval [CI], 2.6-37.9). Other factors independently associated with an INR greater than 6.0 were new medication known to potentiate warfarin (odds ratio [OR], 8.5; 95% CI, 2.9-24.7), advanced malignancy (OR, 16.4; 95% CI, 2.4-111.0), recent diarrheal illness (OR, 3.5; 95% CI,1.4-8.6), decreased oral intake (OR, 3.6; 95% CI, 1.3-9.7), and taking more warfarin than prescribed (OR, 8.1; 95% CI, 2.2-30.0). Higher vitamin K intake (OR, 0.7; 95% CI, 0.5-0.9) and habitual alcohol consumption of from 1 drink every other day to 2 drinks a day (OR, 0.2; 95% CI, 0.1-0.7) were associated with decreased risk. CONCLUSIONS: These data suggest that acetaminophen is an underrecognized cause of overanticoagulation in the outpatient setting. Several other clinically important risk factors were identified. Increased monitoring of INR values when such risk factors are present or modification of the risk factors themselves should reduce the frequency of dangerously high levels of anticoagulation.

Prevalence of antineutrophil cytoplasmic antibodies in a large inception cohort of patients with connective tissue disease.

BACKGROUND: Two types of antineutrophil cytoplasmic antibodies (ANCA), antiproteinase 3 antibodies (anti-PR3) and antimyeloperoxidase antibodies (anti-MPO), are useful in the diagnosis of such types of vasculitis as Wegener granulomatosis and microscopic polyangiitis. Connective tissue diseases frequently appear in the differential diagnosis of this spectrum of vasculitis. OBJECTIVE: To determine the prevalence of ANCA in patients with connective tissue disease. DESIGN: Blinded, controlled study of a 5-year inception cohort. SETTING: Tertiary-care university teaching hospitals. PATIENTS: 70 patients with rheumatoid arthritis, 70 patients with systemic lupus erythematosus, 45 patients with scleroderma, 36 patients with inflammatory myositis, 44 patients with the sjögren syndrome, 33 patients with the antiphospholipid syndrome, and 165 patients with early undifferentiated connective tissue disease (EUCTD). Serum was taken from 200 blood donors and 52 patients who had known vasculitis and positive results on tests for anti-PR3 or anti-MPO; these patients served as controls. MEASUREMENTS: The presence of anti-PR3 and anti-MPO was determined by combining the results of indirect immunofluorescence tests for cytoplasmic (C-ANCA) and perinuclear (P-ANCA) patterns with the results of enzymelinked immunosorbent assays (ELISAs) directed to measure antigen. RESULTS: Cytoplasmic ANCA was not detected in any study or control patient. Perinuclear ANCA was commonly detected among patients with lupus (31%) but was uncommon among patients in other groups (0% to 5%). In all cases, P-ANCA was associated with the presence of antinuclear antibodies. Atypical ANCA immunofluorescence patterns were fairly common in all groups (11% to 39%). Antiproteinase 3 was detected by ELISA in study patients (1 patient with rheumatoid arthritis, 1 with lupus, 1 with polymyositis, and 6 with EUCTD). Antimyeloperoxidase was detected by ELISA in 2 study patients (1 with rheumatoid arthritis and 1 with lupus). None of the patients with positive ELISA results had evidence of renal vasculitis during follow-up. When an ANCA scoring system that combines immunofluorescence and ELISA was used, the test specificity for vasculitis was 99.5% among patients with connective tissue disease. CONCLUSIONS: Patients with connective tissue disease are known to develop multiple autoantibodies; positivity for anti-PR3 and anti-MPO ANCA in such patients is highly specific for anti-PR3. However, P-ANCA immunofluorescence, which may have positive results because of the presence of antinuclear antibodies, is not a specific marker of anti-MPO. A rigorous ANCA testing system that combines the results of immunofluorescence with those of ELISA is highly specific for Wegener granulomatosis and related vasculitides even in patients with connective tissue disease.

An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation.

BACKGROUND: To avert major hemorrhage, physicians need to know the lowest intensity of anticoagulation that is effective in preventing stroke in patients with atrial fibrillation. Since the low rate of stroke has made it difficult to perform prospective studies to resolve this issue, we conducted a case-control study. METHODS: We studied 74 consecutive patients with atrial fibrillation who were admitted to our hospital from 1989 through 1994 after having an ischemic stroke while taking warfarin. For each patient with stroke, three controls with nonrheumatic atrial fibrillation who were treated as outpatients were randomly selected from the 1994 registry of the anticoagulant-therapy unit (222 controls). We used the international normalized ratio (INR) to measure the intensity of anticoagulation. For the patients with stroke, we used INR at admission; for the controls, we selected the INR that was measured closest to the month and day of the matched case patient's hospital admission. RESULTS: The risk of stroke rose steeply at INRs below 2.0. At an INR of 1.7, the adjusted odds ratio for stroke, as compared with the risk at an INR of 2.0, was 2.0 (95 percent confidence interval, 1.6 to 2.4); at an INR of 1.5, it was 3.3 (95 percent confidence interval, 2.4 to 4.6); and at an INR of 1.3, it was 6.0 (95 percent confidence interval, 3.6 to 9.8). Other independent risk factors were previous stroke (odds ratio, 10.4; 95 percent confidence interval, 4.4 to 24.5), diabetes mellitus (odds ratio, 2.95; 95 percent confidence interval, 1.3 to 6.5), hypertension (odds ratio, 2.5; 95 percent confidence interval, 1.1 to 5.7), and current smoking (odds ratio, 5.7; 95 percent confidence interval, 1.4 to 24.0). CONCLUSIONS: Among patients with atrial fibrillation, anticoagulant prophylaxis is effective at INRs of 2.0 or greater. Since previous studies have indicated that the risk of hemorrhage rises rapidly at INRs greater than 4.0 to 5.0, tight control of anticoagulant therapy to maintain the INR between 2.0 and 3.0 is a better strategy than targeting lower, less effective levels of anticoagulation.

Toward an optimal algorithm for ovarian cancer screening with longitudinal tumor markers.

Stored samples from women in the Stockholm screening study were reassayed for CA125II (Centocor, Malvern, PA) and OVX1. The postmenopausal women older than age 50 without ovarian cancer were randomly split into a training set to develop a screening test based on longitudinal marker levels and a second set to validate the test. The CA125II data from each woman is summarized by the slope and intercept from a linear regression of log(CA125II) on time since first sample. The slope versus the intercept for the training set and the ovarian cancer cases formed a bivariate scatter plot. A curve was drawn on the scatter plot that separated most of the women with ovarian cancer from all other women; it delineated a screening test. The specificity of this test was examined on the validation set with a specificity of 99.8%. Bayes' theorem was used to calculate the risk of ovarian cancer (ROC) based on the intercept, slope, and assay variability. It is important to account for assay variability because it can produce large slopes over short periods of time. The maximum risk, which identified 83% (5 of 6) of the ovarian cancers detected within a year of last assay, was applied as a test to the training set and confirmed a high specificity of 99.7%. With this specificity and sensitivity, the ROC algorithm using the CA125II assay has an estimated positive predictive value of 16%, substantially greater than the positive predictive value based on a single assay. Further study is planned to confirm the sensitivity of this approach.

Screening for ovarian cancer.

PURPOSE: To critically review the available evidence for screening asymptomatic women for ovarian cancer with ultrasonography or the CA 125 radioimmunoassay (CA 125) or both. DATA SOURCES: A MEDLINE search of the English-language literature and bibliographies of published studies providing estimates of ovarian cancer risk and test operating characteristics (based on observational studies and meta-analyses) and effectiveness of treatment according to stage of disease (based on randomized trials). Published mathematical models simulating screening for ovarian cancer in specific populations were also included. Death from ovarian cancer and morbidity from surgical procedures were the principal outcomes considered. RESULTS: Age and family history are the most important risk factors for ovarian cancer. Annual screening with CA 125 or ultrasound in women older than 50 years without a family history of ovarian cancer would result in more than 30 false-positive results for every ovarian cancer detected. False-positive tests are likely to require invasive testing, often including laparotomy. There is currently no direct evidence that mortality from ovarian cancer would be decreased by screening. CONCLUSIONS: Available evidence does not support either screening of pre- or postmenopausal women without a family history of ovarian cancer or routine screening in women with a family history of ovarian cancer in one or more relatives (without evidence of a hereditary cancer syndrome). Women from a family with the rare hereditary ovarian cancer syndrome are at high risk for the disease and should be referred to a gynecologic oncologist.

Changing blood use in the AIDS era: the case of elective hip surgery.

BACKGROUND: Concern about the transmission of human immunodeficiency virus via blood has substantially increased the public's anxiety about the safety of the blood supply and has encouraged practices to minimize risks deriving from transfusions. STUDY DESIGN AND METHODS: To assess changes in transfusion practices in elective surgery as awareness of transfusion-transmitted human immunodeficiency virus emerged, 80 randomly selected patients per year undergoing elective total hip replacement in five calendar years between 1977 and 1989 at a large university teaching hospital were studied. RESULTS: Total blood use decreased significantly from an average of 3.3 units per patient in 1977 to 2.1 units per patient in 1989 (p = 0.0003). Autologous blood use increased from essentially zero in 1977 to 82 percent of total blood use in 1989 (p < 0.0001). The threshold hematocrit for postoperative transfusion of allogeneic blood (defined by use of logistic regression models) decreased from 30.1 percent (0.30) in 1977 to 26.7 percent (0.27) in 1989 (p = 0.01). As a result of these changes, the proportion of patients exposed to allogeneic blood decreased from 90 to 16 percent across the study period (p < 0.0001). The dramatic decrease in the use of allogeneic blood in elective total hip replacement surgery during the study period was due to decreased demand for blood during and after the operation and to a striking shift in the blood supply from allogeneic to autologous sources. CONCLUSION: These findings demonstrate that physicians can appropriately alter practices when there are perceived health risks.

Quantifying the potential benefit of CA 125 screening for ovarian cancer.

We develop a stochastic model of screening for ovarian cancer with serum levels of the CA 125 radioimmunoassay, a tumor-specific marker. The natural history of the disease is constructed using a four stage model characterized by a multivariate distribution for duration in each stage. Preserving its important features, we simplify the model to a function of two parameters; the average duration in stage I and the coefficient of variation of duration in each stage. A yearly screening program is superimposed using exponential CA 125 growth curves which result in stage-specific sensitivities corresponding to values reported in the literature. By implementing a computer simulation of the stochastic model, we estimate the benefit due to screening. This benefit is expressed as expected years of life saved per case of ovarian cancer. The model incorporates the stochastic nature of the disease process, allows easy analysis of repeated screens, and automatically accounts for correlation between subsequent tests. It provides the basis for planning optimal screening strategies with CA 125 testing.

Analysis of c-erbB-2 expression in breast carcinomas with clinical follow-up.

Various monoclonal antibodies reactive with protooncogene products or tumor-associated antigens have been utilized to investigate breast carcinoma biology or antigen expression with potential prognostic relevance. Murine monoclonal antibody TA1, generated by immunization of BALB/c mice with whole c-erbB-2 (neu) transformed NIH/3T3 cells, recognizes the extracellular domain of the c-erbB-2 protein and binds a Mr 185,000 protein by immunoprecipitation. Using avidin-biotin-peroxidase techniques and monoclonal antibody TA1, 313 archival primary adenocarcinomas of the breast were evaluated for c-erbB-2 overexpression; 290 of these were used for multiparametric statistical analysis. Historical, clinical (age, laterality), histological (nuclear grade, tumor size, lymph node status, lymphatic or blood invasion), and hormone receptor data as well as clinical outcome (minimal follow-up, 6 years; median follow-up, 8.5 years) were compared to TA1 staining. For these 290 patients Cox regression multivariate analysis showed the strongest correlation between lymph node status or estrogen receptor status and overall survival (P = 0.0001 and 0.049, respectively). TA1 staining did not significantly correlate with survival (P = 0.395). However, univariate analysis of certain patient subpopulations showed a significant correlation if the examined tumors were subdivided into negative or focally reactive and those with greater than or equal to 40% cellular reactivity. For T3, T4 patients, strong TA1 immunoreactivity correlated with a shortened disease-free survival (log rank P = 0.0018; Wilcoxon p = 0.0078) and overall survival (log rank P = 0.0002; Wilcoxon P = 0.0013). For these patients the overall survival at 6 years was markedly different between the strongly reactive tumors (0%) and the negative to weakly reactive tumors (55%). In lymph node-positive patients a trend between high TA1 reactivity and a worse overall survival was also noted (log rank P = 0.128; Wilcoxon P = 0.054), with a 6-year survival of 42% in the strongly reactive tumors (n = 16) and 65% in the negative to weakly reactive carcinomas (n = 105). No correlation between TA1 immunoreactivity and other historical, clinical, and histological features were noted. c-erbB-2 overexpression as measured by immunohistochemical techniques, therefore, may have clinical significance in certain patient subpopulations.

Three-dimensional volumetric assessment of response to treatment: stage I and II diffuse large cell lymphoma of the mediastinum.

From 1981 to 1986, 12 patients with Stage I and II diffuse large cell lymphoma of the mediastinum were treated with 4 or more cycles of multiagent chemotherapy and for nine patients this was followed by mediastinal irradiation. The response to treatment was assessed by three-dimensional volumetric analysis utilizing thoracic CT scans. The initial mean tumor volume of the five patients relapsing was 540 ml in contrast to an initial mean tumor volume of 360 ml for the seven patients remaining in remission. Of the eight patients in whom mediastinal lymphoma volumes could be assessed 1-2 months after chemotherapy prior to mediastinal irradiation, the three patients who have relapsed had volumes of 292, 92, and 50 ml (mean volume 145 ml) in contrast to five patients who have remained in remission with residual volume abnormalities of 4-87 ml (mean volume 32 ml). Four patients in prolonged remission with CT scans taken one year after treatment have been noted to have mediastinal tumor volumes of 0-28 ml with a mean value of 10 ml. This volumetric technique to assess the extent of mediastinal large cell lymphoma from thoracic CT scans appears to be a useful method to quantitate the amount of disease at presentation as well as objectively monitor response to treatment.

Stage IA to IIB mediastinal Hodgkin's disease: three-dimensional volumetric assessment of response to treatment.

From 1979 to 1986, the response to treatment of 53 patients with stage IA to IIB mediastinal Hodgkin's disease was evaluated by three-dimensional volumetric analysis using thoracic computed tomographic (CT) scans. The mean initial volume of mediastinal disease in 34 patients treated with mantle and para-aortic irradiation was 166 mL, whereas for 19 patients treated with two to six cycles of multiagent chemotherapy and mantle and para-aortic irradiation the mean initial volume was 446 mL. Preliminary data suggested that patients with mediastinal volumes of less than 200 mL had a lower mediastinal relapse rate (13%) than patients with volumes greater than 200 mL (32%). For 12 patients receiving six cycles of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP), those with a greater than 85% reduction in volume 1 to 2 months after chemotherapy had a lower incidence of mediastinal relapse (zero of six, 0%) compared with patients having 85% or less reduction in volume (four of six, 67%). The primary value of this technique is that it provides a sensitive assessment of response to treatment and may aid in monitoring the effectiveness of a given treatment.

Adjuvant postoperative radiation therapy for colonic carcinoma.

One hundred thirty-three patients with Stage B2, B3, and C colonic carcinoma had resection for curative intent followed by adjuvant postoperative radiotherapy to the tumor bed. The 5-year actuarial local control and disease-free survival rates for these 133 patients were 82% and 61%, respectively. Stage for stage, the development of local regional failure was reduced for patients receiving postoperative radiotherapy compared with a historic control series. Local recurrence occurred in 8%, 21%, and 31% of patients with Stage B3, C2, and C3 tumors who had radiation therapy, respectively, whereas the local failure rates were 31%, 36%, and 53% in patients treated with surgery alone. There was a 13% and 12% improvement in the 5-year disease-free survival rate in the patients with Stage B3 and C3 lesions who had radiotherapy compared with the historic controls. For patients with Stage C disease, local control and disease-free survival rates decreased progressively with increasing nodal involvement; however, local control and disease-free survival rates were higher in the patients who had radiotherapy than in those who had surgery alone. Failure patterns in the patients who had radiotherapy did not show any notable changes compared with those for patients who had surgery alone. Postoperative radiation therapy for Stage B3, C2, and C3 colonic carcinoma is a promising treatment approach that deserves further investigation.