Treatment of chronic hepatitis C virus infection with recombinant consensus interferon.

To assess the safety and efficacy of consensus interferon (IFN-Con-1), 55 patients with chronic hepatitis C infection were treated with either 3, 6, 9, 12, or 15 microg IFN-Con-1 s.c. three times a week for 24 weeks, followed by 24 weeks of observation. There was a dose-response relationship with respect to the number of patients with normalized ALT concentrations or undetectable HCV RNA. At the end of the 24-week treatment period, the serum ALT had normalized in 18% of patients given the 3 microg dose and 42% of patients given the 12 microg or 15 microg doses of IFN-Con-1. At the end of the posttreatment observation period, the serum ALT was still normal in 10% of patients given the 3 microg, 6 microg, or 9 microg doses and in 50% of patients given the 15 microg dose. Also, at the end of the 24-week treatment period, 27% of patients given the 3 microg dose and 75% given the 15 microg dose had undetectable serum HCV RNA. At the end of the posttreatment observation period, the proportion of patients with undetectable HCV RNA ranged from 9% of those given the 3 microg dose to 50% of those given the 15 microg dose. Our study indicates that treatment with IFN-Con-1 appears to be safe and effective. In addition, use of 15 microg of IFN-Con-1 resulted in significantly more patients with sustained ALT normalization and absence of HCV RNA 6 months after cessation of therapy compared with treatment with lower doses of IFN-Con-1. Additional trials are underway to confirm these findings.

The frequency of late reversibility in SPECT thallium-201 stress-redistribution studies.

The frequency of thallium-201 late reversibility was prospectively assessed in 118 patients who had stress-redistribution thallium-201 studies by single photon emission computed tomography (SPECT). These patients demonstrated two or more segments with nonreversible defects at 4 h imaging and underwent late (18 to 72 h) redistribution imaging. When the criterion of late reversibility was defined as greater than or equal to 1 segment with 4 h nonreversible defects demonstrating late reversibility, it was present in 62 (53%) of the 118 patients and 164 (22%) of 762 segments. When the criterion of greater than or equal to 2 segments was used, late reversibility was found in 41 (35%) of 118 patients and 143 (19%) of 762 segments. The frequency of detected reversible defects increased from 27% at 4 h imaging to 43% at combined 4 h and late imaging (p less than 0.0001) and was significantly increased in all myocardial regions. In comparing the efficacy of initial and late imaging alone versus performing initial, 4 h and late imaging for the identification of reversible defects, 421 (94%) of 449 segments classified as reversible by the latter protocol were also correctly identified by the early and late imaging only approach, with the remaining 6% (28 segments) comprising those segments demonstrating the reversible pattern at 4 h and the nonreversible pattern at late imaging. No major differences were noted with respect to clinical, stress electrocardiographic and scintigraphic variables between the 118 patients undergoing late imaging and 98 additional randomly selected patients with two or more nonreversible defects at 4 h, who did not have late imaging.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise thallium-201 scintigraphy and prognosis in typical angina pectoris and negative exercise electrocardiography.

Patients with a history of typical angina but negative exercise electrocardiography represent a subgroup with an intermediate likelihood of having coronary artery disease and future cardiac events. A retrospective study of the prognostic utility of stress-redistribution thallium-201 scintigraphy was performed in 190 such patients. A second group of 203 patients with typical angina and a positive exercise electrocardiogram were analyzed for comparative scintigraphic purposes. The cardiac event rate for the 144 negative exercise electrocardiogram patients with normal thallium results was 5 vs 15% in the 46 patients with abnormal thallium results (p = 0.01). These patients were further stratified into high (14 to 18%), intermediate (9%) and low (less than 2%) risk groups for future cardiac events based on combining the thallium results with the percentage of maximal predicted heart rate achieved. A multivariate analysis revealed that an abnormal thallium result was the only significant correlate of future cardiac events. Mechanisms responsible for the discordant finding of a negative exercise electrocardiogram in patients with typical angina include (1) false-positive angina symptomatology in low prevalence coronary artery disease groups in whom the thallium test is negative, and (2) "electrocardiographically silent" ischemia in patients in whom the thallium test is positive. These findings reveal that thallium stress-redistribution scintigraphy can be used to stratify 1-year prognosis in this subgroup of patients with typical angina and negative exercise electrocardiograms.

Quantification of left ventricular myocardial mass in humans by nuclear magnetic resonance imaging.

The ability of NMRI to assess LV mass was studied in 20 normal males. By means of a 1.5 Tesla GE superconducting magnet and a standard spin-echo pulse sequence, multiple gated short-axis and axial slices of the entire left ventricle were obtained. LV mass was determined by Simpson's rule with the use of a previous experimentally validated method. The weight of the LV apex (subject to partial volume effect in the short-axis images) was derived from axial slices and that of the remaining left ventricle from short-axis slices. The weight of each slice was calculated by multiplying the planimetered surface area of the LV myocardium by slice thickness and by myocardial specific gravity (1.05). Mean +/- standard deviation of LV mass and LV mass index were 146 +/- 23.1 gm (range 92.3 to 190.4 gm) and 78.4 +/- 7.8 gm/m2 (range 57.7 to 89.4 gm/m2), respectively. Interobserver agreement as assessed by ICC was high for determining 161 individual slice masses (ICC = 0.99) and for total LV mass (ICC = 0.97). Intraobserver agreement for total LV mass was also high (ICC = 0.96). NMRI-determined LV mass correlated with body surface area: LV mass = 55 + 108 body surface area, r = 0.83; with body weight: LV mass = 26 + 0.77 body weight, r = 0.82; and with body height: LV mass = 262 +/- 5.9 body height, r = 0.75. Normal limits were developed for these relationships. NMRI-determined LV mass as related to body weight was in agreement with normal limits derived from autopsy literature data.(ABSTRACT TRUNCATED AT 250 WORDS)

Computer analysis of Doppler color flow mapping images for quantitative assessment of in vitro fluid jets.

To determine the ability of Doppler color flow mapping to accurately and reproducibly assess the flow volume and kinetic energy of in vitro fluid jets, a Doppler color flow mapping system was interfaced with an image processing computer. An aliasing correction algorithm was used to extend the upper limit of measurable velocity to 184 cm/s. Images were analyzed for jet area (equal to the total number of image pixels) and jet energy (equal to the sum of all pixel velocities squared), both integrated over all frames of the injection and in single maximal frames. The Doppler flow mapping area and energy measurements were compared with known flow volume and delivered kinetic energy, and the effects of four experimental variables (orifice area, gain setting, chamber compliance and chamber size) were evaluated. Jet area correlated nonlinearly with flow volume and was markedly affected by each of these experimental variables, increasing by 40 to 150% from the smallest to the largest orifice size, 15 to 94% with the highest versus the lowest gain setting, 1 to 54% with greater chamber compliance and 7 to 70% in the large versus the small chamber. In contrast, jet energy correlated linearly with delivered kinetic energy up to 350,000 ergs, at which point velocities started to exceed the extended velocity range and second wrap aliasing occurred. The relation was not affected by orifice area, gain or compliance, and was only minimally affected by chamber size.(ABSTRACT TRUNCATED AT 250 WORDS)

Mental stress and the induction of silent myocardial ischemia in patients with coronary artery disease.

To assess the causal relation between acute mental stress and myocardial ischemia, we evaluated cardiac function in selected patients during a series of mental tasks (arithmetic, the Stroop color--word task, simulated public speaking, and reading) and compared the responses with those induced by exercise. Thirty-nine patients with coronary artery disease and 12 controls were studied by radionuclide ventriculography. Of the patients with coronary artery disease, 23 (59 percent) had wall-motion abnormalities during periods of mental stress and 14 (36 percent) had a fall in ejection fraction of more than 5 percentage points. Ischemia induced by mental stress was symptomatically "silent" in 19 of the 23 patients with wall-motion abnormalities (83 percent) and occurred at lower heart rates than exercise-induced ischemia (P less than 0.05). In contrast, we observed comparable elevations in arterial pressure during ischemia induced by mental stress and ischemia induced by exercise. A personally relevant, emotionally arousing speaking task induced more frequent and greater regional wall-motion abnormalities than did less specific cognitive tasks causing mental stress (P less than 0.05). The magnitude of cardiac dysfunction induced by the speaking task was similar to that induced by exercise. Personally relevant mental stress may be an important precipitant of myocardial ischemia--often silent--in patients with coronary artery disease. Further examination of the pathophysiologic mechanisms responsible for myocardial ischemia induced by mental stress could have important implications for the treatment of transient myocardial ischemia.

Intraoperative evaluation of mitral regurgitation by Doppler color flow mapping.

Excessive residual mitral regurgitation after mitral valve reconstruction or coronary artery bypass graft surgery may necessitate reoperation. We evaluated a new intraoperative technique for assessment of mitral regurgitation, real-time two-dimensional Doppler color flow mapping, in 96 patients undergoing cardiac surgery. In comparison with technically adequate preoperative left ventriculography (n = 68) obtained at a similar level of afterload (systolic arterial pressure), Doppler color flow mapping demonstrated a sensitivity of 94% (50/53) and specificity of 93% (14/15) for detection of the presence and absence of mitral regurgitation, respectively. Semiquantitative comparison of color Doppler with angiography demonstrated excellent agreement (kappa = .80, p less than .001), differing by more than one grade in two patients (3%). The pulmonary capillary wedge "V" wave pressure (absolute magnitude, and height above mean) correlated poorly with the simultaneously obtained mitral regurgitation grade by color Doppler, both before (r = .37 and .45) and after (r = .04 and -.15, p = NS) cardiopulmonary bypass. No value of the V wave clearly distinguished 3 + or 4 + regurgitation from lesser degrees of regurgitation. In 15 patients who underwent mitral valve repair, fluid filling of the ventricle was falsely positive (leak, with no regurgitation) in 40% (2/5), and falsely negative (no leak, with 2 + to 3 + regurgitation) in 30% (3/10). Regurgitation grade by color Doppler demonstrated a highly significant (p less than .01) dependence on systolic pressure, suggesting that intraoperative changes in afterload conditions importantly influence mitral regurgitation severity. Thus, Doppler color flow mapping provides accurate intraoperative evaluation of mitral regurgitation and may aid surgical decision making.(ABSTRACT TRUNCATED AT 250 WORDS)

Northern California Oncology Group protocol 6G91: response to treatment with radiation therapy and seven-drug chemotherapy in patients with glioblastoma multiforme.

The Northern California Oncology Group (NCOG) conducted a nonrandomized phase II study to evaluate the benefit of a seven-drug chemotherapy protocol (NCOG 6G91) in patients with glioblastoma multiforme (GM). Time to tumor progression was the primary end point of the study. The treatment consisted of 5-FU and lomustine administered after surgery and before radiation therapy, hydroxyurea and misonidazole during radiation therapy, and procarbazine and vincristine alternated with carmustine and 5-FU after radiation therapy. Ninety patients entered the study; data from the 64 patients with GM who completed radiation therapy and at least started the postradiation chemotherapy regimen and returned for follow-up examination are analyzed in this report. The median time to tumor progression in the 64 adequately treated patients was 42 weeks; the 25th percentile value was 60 weeks. A Cox multivariate analysis showed that age and extent of surgical resection were important prognostic variables in patients with GM. The results of this treatment regimen were similar to those of a previous NCOG protocol (6G61), which consisted of hydroxyurea during radiation therapy followed by chemotherapy with carmustine or a combination of lomustine, procarbazine, and vincristine.

Gynecomastia in testicular cancer patients. Prognostic and therapeutic implications.

Eighty-one patients with advanced testicular cancer were evaluated for gynecomastia or severe breast tenderness at diagnosis and after platinum-based chemotherapy. The prognostic significance of gynecomastia in these two settings was explored. At presentation, 10% (8 patients) had gynecomastia or breast tenderness and elevated HCG levels. The likelihood of gynecomastia was greater with increasing HCG level (P = 0.002). However, gynecomastia at presentation was a more powerful independent discriminant of poor survival than the initial HCG level by multivariate analysis (P = 0.004). Fifteen percent (12 patients) developed transient gynecomastia after chemotherapy not attributable to other known causes. HCG levels were normal. Endocrine evaluation typically revealed elevated FSH, LH, and estradiol/testosterone ratios. This may have reflected damage to testicular germinal epithelium. All 12 patients are alive without disease in contrast to the 8 patients who had gynecomastia at diagnosis. Therapy decisions should therefore be based on the time of onset of gynecomastia and in the context of appropriate clinical markers and evaluation.

Digital quantification eliminates intraobserver and interobserver variability in the evaluation of coronary artery stenosis.

A leading problem with subjective interpretation of coronary angiography is high intraobserver and interobserver variability. Four experienced angiographers independently determined percent diameter narrowing of 36 stenoses using 3 methods: by subjective analysis of single-frame cine film images (film), by subjective analysis of digitized nonenhanced single-frame images (digital), and by using a semiautomated digital caliper quantification system (Corona). The reproducibility of interpretations was assessed by comparison of estimated intraclass correlation coefficients. Digital and Corona readings correlated well with subjective interpretation of film (r greater than 0.85 for both). In contrast to Corona, the angiographers systematically overestimated the magnitude of stenoses in the intermediate (50 to 75%) range. Corona markedly improved intraobserver (p less than 0.005) and interobserver (p less than 0.001) reproducibility. Corona less frequently misclassified individual observations than did film when categories of less than 50%, 50 to 75% and more than 75% diameter stenosis were used (3.7% vs 31.5%, p less than 0.001). Our results suggest that digitization of a coronary angiogram in a 512 X 512 matrix has no significant adverse effects on the perception and quantification of stenosis by angiographers. Additionally, automatic measurement of coronary stenosis has 2 major advantages: It is accurate compared with a group of experienced angiographers and for the practical purpose of clinical decision-making, it eliminates intraobserver and interobserver variability.

Phase III comparison of BCNU and the combination of procarbazine, CCNU, and vincristine administered after radiotherapy with hydroxyurea for malignant gliomas.

The authors report the results of a randomized study conducted to evaluate the relative benefit of treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or the combination of procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and vincristine (PCV) administered after radiation therapy with hydroxyurea to 76 evaluable patients with glioblastoma multiforme and 72 patients with other anaplastic gliomas. The primary end-point of the study was time to tumor progression. For better-risk patients with Karnofsky performance scores of 70 to 100, results suggest that PCV was of greater benefit than BCNU (p = 0.15 for glioblastoma multiforme; p = 0.13 for other anaplastic gliomas). Median times to tumor progression were 31 and 32 weeks for patients with glioblastoma multiforme; 25th percentile times to progression were 70 and 40 weeks for patients treated with PCV and BCNU, respectively. For patients with other anaplastic gliomas treated with PCV and BCNU, median times to progression were 123 and 77 weeks, respectively. Multivariate analysis showed that the prognostic variables of age and Karnofsky scores were important for patients with glioblastoma multiforme and other anaplastic gliomas, and that the extent of surgical resection was important for those with other anaplastic gliomas.

How accurate are computed tomographic scans in assessment of changes in tumor size?

The computed tomographic scan plays an integral part in the diagnosis and management of tumors; however, its potential has not yet been fully exploited. With a computer-assisted volume determination method, the reproducibility of derived volume calculations was assessed, and radiologists' standard interpretations of interval change on serial scans were compared with the investigators' calculations of tumor volume change. Interobserver reproducibility of tumor volume calculations of the mean of two repeated volume determinations was satisfactory (mean of 3 percent, median of 1 percent). There were 29 comparisons (47 scans of 19 patients with liver tumors) of computed tumor changes with the radiologists' computed tomographic reports of consecutive scans. In only 41 percent (12 of 29) of the cases did the radiologists' interpretations and the computer-assisted volume determinations agree. It is concluded that objective computer-assisted volume determination provides a potentially more sensitive assessment of tumor change and that such precise, specific, reproducible determination of tumor volume should further clinical research and improve patient care.

5-Fluorouracil + Oncovin + Adriamycin + mitomycin C (FOAM): an effective program for breast cancer, even for disease refractory to previous chemotherapy. A Northern California Oncology Group (NCOG) Study.

One hundred and thirty-one patients (118 evaluable) with disseminated breast cancer were treated with a combination of 5-fluorouracil + Oncovin + Adriamycin + mitomycin C (FOAM). The objective response rate for 82 evaluable patients whose disease was refractory to previous CMF or L-PAM chemotherapy was 35%; that for 36 evaluable patients who had not previously received chemotherapy, 56%. The hematologic toxicity of this therapy was generally mild and acceptable. It is believed that FOAM is an effective therapy for patients whose tumors are resistant to CMF.

Therapy of liver tumors metastatic from colorectal cancer with whole-liver radiation combined with 5-FU, adriamycin, and methotrexate.

Twenty-seven patients with liver metastasis from colorectal cancer were treated with intrahepatic arterial chemotherapy and external radiotherapy consisting of 5-fluorouracil (5-FU) (10 mg/kg/day for 8 days), adriamycin (5 mg/m2/day for 7 days) and methotrexate (MTX) (240 mg/m2/X1), combined with 2,100 rads of whole liver irradiation. Twenty of these patients (74%) had previously received systemic chemotherapy. Of the 21 patients who could be fully evaluated, seven (33%) had an objective partial response and another 10 (48%) had stable disease following treatment. The median duration of survival for all patients after initiation of treatment was 6.5 months. Those patients responding to therapy survived longer (12.7 months) than those who had stable disease (5.5 months) or disease progression (2.5 months). The response rate was not affected by previous chemotherapy. Additionally, of the 14 patients with symptoms related to the disease, nine (64%) experienced substantial relief of these symptoms. Toxicity with the therapy used in this study was generally moderate. The median nadiR WBC was 3,500 cells/mm3; the median nadir platelet count, 121,000 cells/mm3. There was, however, one treatment-associated fatality from sepsis in a patient whose WBC was 900 cells/mm3.

Volumetric CT analysis of hepatic tumors.

Current methods of measuring hepatic volume and the percent of hepatic parenchyma replaced by tumor are crude, yet clinical decisions are often based on these imprecise measurements. We describe a new computed tomographic (CT) assisted volume calculatory program to accurately assess hepatic volume and a new computer program to discriminate tumor from normal liver and thus provide tumor volume measurements. The potential usefulness of these techniques is illustrated by an analysis of pre- and post-therapy CT scans and calculation of changes in hepatic volume and in the volume of hepatic tumor. Analysis revealed small changes in liver volume could be accompanied by substantial changes in tumor volume and vice versa. We conclude (a) quantitative CT techniques allow for rapid, reproducible measurements of liver and tumor volume, and (b) small changes in organ volume may be accompanied by substantial changes in tumor volume.

Therapy of hepatocellular cancer with combined intrahepatic arterial chemotherapy and whole liver irradiation.

Hepatocellular cancer provides an ideal model for studying combined modality chemotherapy and radiation interactions. We have treated 20 evaluable patients. All patients received intrahepatic arterial (IA) 5 FU (10 mg/kg/d continuous infusion times 5 minus 9 d) + Adriamycin (3-5 mg/m(2)/d bolus times 5 minus 7 d), and 1,500 and 2,100 rads whole liver radiation (300 rads/day). Additionally, 3 patients have received IA Mitomycin C (8 mg/m(2)). After this "induction" therapy patients usually received IV Adriamycin + 5FU +/- Mitomycin monthly. Objective regressions occurred in 9/20 (45%) and another 9/20 (45%) and stable disease. Median duration of response is 5+ months (range 1+ to 8 months). Improvement in liver function tests occurred in 11/19, and local symptomatic relief in 12/15. Median WBC nadir = 4,000; platelet nadir = 115,000. Mild anorexia, fever, and nausea were frequent, but no radiation hepatitis has been detected. This program seems to result in significant clinical benefit (subjective and objective) in this refractory neoplasm.

Therapy for hepatocellular cancer with intrahepatic arterial adriamycin and 5-fluorouracil combined with whole-liver irradiation: a Northern California Oncology Group Study.

Thirteen patients with hepatocellular cancer were treated with intrahepatic arterial Adriamycin and 5-fluorouracil combined with whole-liver irradiation. Six patients (46%) had an objective regression and five (38%) had stable disease. Symptomatic improvement was noted in 81% of the patients. The minimum median survival time was 5.0 months for those patients who responded. Toxicity was acceptable. This is an effective combination for the treatment of this especially aggressive and intractable form of cancer.

Combined modality therapy of hepatic metastasis. Northern California Oncology Group Pilot Study.

Twenty-two patients with adenocarcinoma metastatic to the liver were treated with rapid fractionation whole-liver irradiation (1350-2100 rads in 300-rad fractions) with simultaneous intrahepatic 5-fluorouracil (10-15 mg/kg/day) and intrahepatic Adriamycin 2.5-10 mg/m2/day) as part of a Phase I-II study. Of the 21 patients who completed therapy, 19 had colorectal carcinoma and 2 had metastatic adenocarcinoma of unknown origin. Objective response was judged by measurement of liver size, evaluation of liver function tests, and by liver scan or CAT scan of the liver. Ten of the 21 evaluable patients responded, yielding an overall response rate of 47.6%. The response rate in patients with colorectal carcinoma was 55% (10/19). At this time, median duration of response is 14+ weeks and median survival from onset of therapy is 15+ weeks. Hematologic and gastrointestinal toxicity were tolerable. No hepatic toxicity was documented. This combined modality therapy was found to be a safe effective method for the palliation of liver metastasis.