Biomedical subjects
Publications and source records attributed to P T Lavin.
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A new method, based on a continuous time autoregressive [CAR(1)] model of time series data, is provided for detecting departures of tumour markers from steady states in breast cancer patients following surgery. A Kalman filter recursive algorithm is used to calculate the likelihood function arising from the CAR(1) model and to calculate recursive residuals, which are monitored by a Shewhart-Cusum scheme. This approach can be used to monitor the serial marker data of large numbers of patients even when the series are short and the data are serially correlated and unequally spaced. Further, the methodology can be used to recommend appropriate testing intervals.
Careful patient selection for hepatic resection of colorectal cancer metastases is essential to improve current poor results. Carcinoembryonic antigen level and number of metastases were significant preoperative prognostic indicators of 5-year disease-free survival in patients selected clinically for hepatic surgery. Surgical margin, weight of hepatic tissue resected, carcinoembryonic antigen level, and flow cytometry were significant postoperative prognostic indicators. Patients with a carcinoembryonic antigen level less than 200 ng/mL, 1-cm surgical margins, and less than 1,000 g of liver tissue removed had a greater than 50% estimated 5-year disease-free survival rate. If the metastases were diploid on flow cytometry, an additional survival advantage may have been gained. Inadequate surgical margins led to high rates of liver-only recurrence. Nonhepatic recurrence was unrelated to surgical margins. Intraoperative liver examination by ultrasound during primary colon cancer resection and adjuvant chemotherapy may offer earlier selection of biologically appropriate patients and improved outcome; both recommendations require clinical trials.
BACKGROUND: The ability to predict prolonged length of stay (LOS) is essential to control escalating hospital costs. Operative mortality is a poor predictor of LOS; morbidity as defined by hospitalization for > 14 days after coronary artery bypass graft surgery (CABG), appears to be responsible for increasing costs. The purpose of this study was to measure preoperative predictive indicators of increased LOS with an eventual plan to offer alternative cost-benefit therapeutic options. METHODS AND RESULTS: Nine hundred twenty-four consecutive patients (age, 60-86 years) undergoing CABG were retrospectively studied by means of the Cox proportional hazards model. Seventeen variables, excluding death, were analyzed and quantified as to importance, and point totals were calculated for each patient. Scores were 12 for congestive heart failure and intra-aortic balloon assist device; 10, creatinine > 2; 6, intra-aortic balloon assist device only; 5, congestive heart failure only; 3, obesity; 6, age > 75 years; 3, age 70-75 years; and 2, 65-69 years. CONCLUSIONS: Increasing index score directly correlated with an exponential increase in LOS. These data substantiate the hypothesis that a mathematical model can predict LOS in CABG patients and may offer rational alternative strategies in delivering cost-effective health care.
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The hemodynamic and metabolic consequences of microvascular occlusion, often present in the runoff bed of distal arterial reconstructions, have been difficult to quantitate clinically. To investigate these pathophysiologic relationships, a porcine hindlimb model was developed in which arteriolar patency, which we term outflow capacity, may be quantitatively defined and reduced by serial distal microembolization with 70 microns flow-directed glass bubbles. In 10 anesthetized adult pigs, hindlimb perfusion was limited to femoral artery flow (FAF) by collateral ligation. Serial measurements of outflow resistance (OR), femoral artery flow, and resting muscle pH (mpH), a metabolic index of tissue perfusion, were made as relative outflow capacity (ROC) underwent graded reduction from 1.0 (baseline) to 0 (complete occlusion). Femoral artery flow decreased linearly (FAF = 87 ROC - 3), and outflow resistance increased in hyperbolic fashion (OR = 1.66/ROC) in response to graded peripheral microembolization, whereas resting muscle pH followed a more complex relationship (In mpH = 0.055 ROC + 1.95). An integrated analysis of these results suggests that a 50% to 60% reduction in arteriolar patency represents a critical point beyond which outflow resistance rises rapidly and hindlimb flow decreases to levels that are inadequate to support the metabolic demands of resting tissues.
To assess the value of autolymphocyte therapy (ALT) in the treatment of metastatic renal-cell carcinoma, 90 patients were randomised to receive every month for six months oral cimetidine plus an infusion of autologous peripheral blood lymphocytes activated in vitro by a previously generated autologous lymphokine mixture, or cimetidine alone. The median follow-up was 15 months. Survival time for the autolymphocyte group was approximately 2.5 times that for the cimetidine group (p = 0.008). Patients who had greater than 500 pg interleukin-1 (IL-1) per ml autologous lymphokine mixture had a six-fold survival advantage over those with less than 500 pg/ml (p less than 0.00005). Men treated with ALT had a four-fold survival advantage (p = 0.001) over men who received cimetidine only. Infusion of the cultured autolymphocytes was accompanied by mild, self-limited fever in 11 of the 45 ALT patients, and by only one instance in which fever was accompanied by tachypnoea and hypotension.
Thirty-six patients with Stage IV renal cell carcinoma were treated with autolymphocyte therapy (ALT). This new form of adoptive immunotherapy is based on the infusion of relatively small numbers of autologous lymphocytes that are depleted of suppressor cells and immunized in vitro by a method designed for antigen-specific activation using a 3M KCl extract of autologous tumor and an autologous lymphokine mixture. Patients received six monthly infusions of immunized lymphocytes, all on an outpatient basis. The majority of patients experienced no toxicity. The few reactions that occurred were minor and self-limiting; none required any medical intervention or subsequent delay in therapy. Patients also received oral cimetidine to reduce in vivo suppressor cell function. Survival at twenty-four months is 36 percent. Median survival is fifteen months, a significant improvement over the natural history of this disease. A multi-site, randomized, controlled trial of ALT in renal cell carcinoma has been initiated to confirm that this treatment causes a significant prolongation of survival with virtually no toxicity in these patients.
A pilot study was designed to estimate the variance components in the determination of the MIC of cefoxitin for isolates of the Bacteroides fragilis group. Twenty different organisms were tested, and replicate, trial, and reader variabilities were examined. When the total-variance component was used, if the true MIC was 16 micrograms/ml, then the chance that the observed MIC was between 8 and 32 micrograms/ml, inclusive, was 95%. For all analyses, the isolate (P = 0.0001) and reader (P less than 0.03) effects were significant. The probability of specific MIC observations for various true MICs (over the range of 16 to 32 micrograms/ml at 4-micrograms/ml increments) was calculated. For true MICs of 20, 24, and 28 micrograms/ml, the probabilities of observing an MIC of 16 or 32 micrograms/ml (inclusive) were 86, 75, and 62%, respectively. An upward bias was shown to exist in addition to sources of sizeable variation. The recommendation stemming from recognition of this inherent variability is that ranges of percent susceptibility at various concentrations be included in reports of in vitro susceptibility studies.
Phenylpropanolamine (PPA) is frequently used in over-the-counter diet aids and cold medicines, In view of concern about the safety of this sympathomimetic agent, we undertook a double-blind, multicenter clinical trial to determine the factors that influence the pressor effect of short-term oral administration of PPA in healthy individuals. Eight hundred eighty-one healthy individuals in four categories of body weight were randomized to receive placebo capsules three times per day (n = 286), a 75-mg sustained-release PPA hydrochloride preparation once per day (n = 296) followed by two doses of placebo capsules, or a 25-mg immediate-release PPA hydrochloride preparation three times per day (n = 299). The median age of the study population was 28 years, 56% were men, 73% were white, and 47% were in excess of 30% above their ideal body weight. Measurements of pulse rate and supine and standing blood pressure were made 11 times during the day of PPA administration. A statistically significant but clinically unimportant pressor effect for the short-term administration of PPA was observed. The effect occurred in the first 6 hours after administration and was greater in the sustained-release group. Significant independent determinants of the pressor effect of PPA were baseline diastolic blood pressure, baseline body weight, and treatment.
Forty-four patients with clear cell adenocarcinoma of the ovary diagnosed between 1944 and 1981 were compared with a matched cohort of 55 patients with the most common epithelial malignant lesion, serous adenocarcinoma, in terms of their presentation and clinical course. None were lost to follow-up. Median follow-up was 9 years. Fifty percent of clear cell patients presented in Stage I versus 31% of serous patients. Patients with clear cell carcinoma presented more often with pelvic masses (84% vs 65%) and had larger (diameter greater than 10 cm) primary tumors (73% vs 29%). Forty-nine percent of clear cell patients were nulligravid compared with 24% of serous patients and endometriosis was strikingly more common in clear cell patients (58% vs 12%). When compared stage for stage, clear cell tumors were uniformly associated with poorer 5-year survival rates with an overall rate of 34%. In patients with recurrent disease, lymph node involvement was much more common in patients with clear cell carcinoma (40% vs 7%). Parenchymal organ involvement was also more common in the clear cell group (40% vs 13%). Ovarian clear cell adenocarcinoma has distinctly different clinical behavior compared to serous carcinoma and should be regarded as an aggressive epithelial histologic type.
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The clinical aspects and pathologic findings in 44 cases of pure clear cell carcinoma of the ovary are presented. The patients ranged in age from 28 to 78 years (mean, 50.6 years); 54% were nulliparous. Thirty-three percent of the patients had endometriosis in the involved ovary, and an additional 25% had endometriosis only in sites distant from the tumor. Microscopically, three architectural patterns (papillary, tubulocystic, and solid) and four cell types (clear, hobnail, eosinophilic, and flattened) were seen. A predominant tubulocystic architectural pattern was a good prognostic factor (p less than 0.01); however, no significant difference in survival by cell type was found. Grading of the tumors by conventional architectural and cytologic criteria had no predictive value for survival. Stage at presentation was the most important prognostic factor (p less than 0.001), with a 5-year overall survival of 34% and stage I survival of 55%. The poor stage I survival reflects the 15 patients (34%) in the study with stage Iaii lesions. In the 25 patients who developed recurrence, both distant organ involvement (40%) and lymph node involvement (40%) were frequent. Ovarian clear cell carcinoma has unusual pathologic and clinical features, and it represents a distinct histologic type of ovarian carcinoma.
Previous studies have revealed that the regional accumulation of ischemic metabolites including hydrogen ion (H+) and PCO2 diminish after repeated occlusions. We postulated that this diminution reflects a blunted metabolic response that is related to the severity of ischemic injury and, hence, may be most pronounced in subendocardial (ENDO) regions. To investigate this hypothesis, the left anterior descending coronary artery was serially occluded three times in 51 dogs for a period of either 3 minutes (n = 15), 5 minutes (n = 18), or 15 minutes (n = 18). Each occlusion was separated by 45 minutes of reperfusion. Myocardial [H+] was measured in the endomyocardium and in the epimyocardium of the ischemic anterior wall by use of miniature pH glass electrodes. Accumulation of H+ during occlusion (delta [H+]) in the ENDO region was significantly less during the second occlusion when compared with the first occlusion (3-minute occlusions: 28.2 +/- 3.7 nM/l vs. 39.4 +/- 5.4 nM/l, p less than 0.002; 5-minute occlusions: 49.8 +/- 5.0 nM/l vs. 72.1 +/- 6.5 nM/l, p less than 0.0002; 15-minute occlusions: 132.3 +/- 14.6 nM/l vs. 225.6 +/- 27.7 nM/l, p less than 0.0003). A similar trend was noted for delta [H+] in the subepicardial (EPI) regions. During occlusion, the rise in [H+] occurred sooner, and delta [H+] was consistently greater in the ENDO when compared with the EPI regions (p less than 0.05). Regional myocardial blood flow did not change during the three occlusions, indicating that the diminution in H+ accumulation stemmed from a decrease in H+ production and not from an increase in collateral flow. The decrement in H+ accumulation between the first and second occlusions (delta [H+]1-delta [H+]2) 1) was greater in the ENDO than in the EPI regions (p less than 0.05); 2) correlated with the duration of occlusion (ENDO: r = 0.66, p less than 0.001; EPI: r = 0.82, p less than 0.0001); and 3) was related to the impairment of anterior wall systolic shortening after the first reperfusion period. These findings suggest that the diminution in H+ production that follows serial coronary occlusions reflects a blunted metabolic response that is related to both the duration of ischemia and the degree of systolic dysfunction. Moreover, though attenuation of ischemic metabolite production occurs transmurally, it is most pronounced in the deep ENDO regions.
Immunohistologic studies were performed to evaluate the expression and regional distribution of 20 colorectal carcinoma-associated antigens in the colonic mucosa of 12 normal adults. A distinct regional variation was seen in the expression of blood group A, B, Lewis(b), and extended Lewis(y) antigens, which were expressed predominantly in the right colon, whereas Lewis(a), Lewis(y), and H-type 2 were prevalent throughout. Lewis(x) and X-like antigens were only occasionally expressed. Two antibodies against sialylated Lewis(a) showed different staining patterns, with CA19.9 positive in only two biopsies and CO29.11 intensely positive in most. Two of the three antibodies detecting carcinoembryonic antigen epitopes (3d6 and COL-4) stained many biopsies, whereas COL-12 was rarely detected. No regional gradient was found in the expression of the other antigens studied (B72.3, ME491; GA73.3, ND1, and ND4). This mapping data will provide an important baseline for future studies of epitope distribution in the colon in premalignant and neoplastic conditions.
CA 125 levels were measured in 158 patients with palpable pelvic masses who were about to undergo diagnostic laparotomy. When the 68 patients found to have cancer were compared with the 90 patients with benign disease, those with malignancies were significantly older, were more frequently postmenopausal, and had significantly higher values of serum CA 125. Patients with benign pelvic masses had CA 125 levels greater than 65 U/ml in 8% of cases, whereas those with malignancies had CA 125 levels greater than 65 U/ml in 75% of cases. If only those patients who had frankly malignant, primary, nonmucinous epithelial ovarian carcinomas were considered, CA 125 levels greater than 65 U/ml predicted malignancy with a sensitivity of 91% for all patients. Greater sensitivity and specificity were observed in the postmenopausal subgroup than in the premenopausal subgroup. In the postmenopausal group with a 63% prevalence of ovarian cancer the predictive positive value was 98% and the predictive value negative was 72%. In a premenopausal population with a 15% prevalence of ovarian cancer the predictive value for a positive test was 49%, while the predictive value for a negative test was 93%.
An open, randomized, parallel clinical study comparing the antihypertensive efficacy and tolerability of the angiotensin converting enzyme inhibitor enalapril and the diuretic hydrochlorothiazide was carried out in 40 patients with mild uncomplicated essential hypertension. Changes in plasma lipid profiles were also studied. The results show that the two treatments were equally efficacious in controlling blood pressure and were generally well tolerated. Favorable changes in the plasma lipid profile were observed during the 12-week treatment period with enalapril. However, adverse alterations in the plasma lipid profile were observed during treatment with hydrochlorothiazide. These included a significant increase in the total cholesterol/high density lipoprotein cholesterol ratio and the low density lipoprotein cholesterol/high density lipoprotein cholesterol ratio. Further studies are needed to confirm these plasma lipid findings and to determine their clinical significance.
The ability to differentiate a malignant from a benign ovarian mass was assessed for four diagnostic procedures: serum CA 125, clinical examination, original ultrasound, and reviewer ultrasound interpretation. When these tests were used individually, the sensitivity and specificity of CA 125 levels were equal to those of a review ultrasound. Overall, the sensitivity of clinical impression and original ultrasound was poor. Sensitivity and specificity were highest for CA 125 assays in postmenopausal patients, especially when these were used as the second diagnostic test. Positive and negative predictive values significantly increased among postmenopausal patients when CA 125 was added to any of the other diagnostic tests examined. In conjunction with such tests, measurement of serum CA 125 significantly increased diagnostic accuracy and may thus have an important role in the preoperative evaluation of women with ovarian masses.