The treatment planning of segmental, conformal stereotactic radiosurgery utilizing a standard multileaf collimator.

Over a period of approximately 3 years, our institution has implemented and refined a system of Stereotactic Radiosurgery (SRS) which utilizes the standard multi leaf collimator (MLC) of the Scanditronix MM50 Racetrack Microtron and treats in an arrangement of segmental "pseudo-arcs." This system employs a commercial BRW based stereotactic frame which is mounted to the treatment table. With the exception of the table-mounted frame hardware there have been no modifications to the treatment machine to accommodate these treatments. By use of standard evaluation parameters (e.g., treatment time, planning time, dose conformance and dose heterogeneity ratios) this system compares quite favorably with reported data from institutions treating SRS with either a GammaKnife or a standard linear accelerator with tertiary collimators.

Diagnosis of fatty infiltration of the liver on contrast enhanced CT: limitations of liver-minus-spleen attenuation difference measurements.

BACKGROUND: We investigated whether liver-minus-spleen (L-S) attenuation differences can accurately diagnose fatty infiltration of the liver on contrast-enhanced computed tomography (CT). METHODS: A group of 78 patients administered a fast injection (90-s duration) of 150 mL 60% ionic contrast was compared with 81 patients given a slow injection (152.5 s). The presence or absence of fatty infiltration of the liver was diagnosed by noncontrast CT. RESULTS: The L-S attenuation differences varied significantly, depending on both injection rate and timing of measurements. For the fast-injection group, the optimal L-S threshold for diagnosing fatty infiltration ranged from -43 to -33 Hounsfield units (HU) for early (79 s) and late measurements (106 s), respectively. For the slow-injection group, the optimal threshold ranged from -31 to -25 HU (80 and 112 s, respectively). In addition, sensitivity was not very high (range = 0.54-0.71) for either injection protocol at any measurement time because of significant overlap of L-S values between normal and fatty infiltration patients. Moderate and severe fatty infiltration were more reliably diagnosed than mild fatty infiltration by this method. CONCLUSIONS: Contrast injection rate and timing of measurements significantly influence the optimal L-S threshold for diagnosing fatty liver. This limits the clinical usefulness of such measurements.

Cytopathological analysis of sputum in patients with airflow obstruction and significant smoking histories.

Advances in the understanding of lung cancer biology have led to observations that specific genetic changes occur in premalignant dysplasia. These observations have occurred predominantly in molecular studies of resected lung tumors and consequently, they may not be fully representative of those biological abnormalities characterizing premalignant lesions in individuals without overt lung cancer. Studies of premalignant epithelial cell biology and chemoprevention are needed in this patient subgroup. Such an initiative is now underway through the lung cancer Specialized Program of Research Excellence (SPORE) grant awarded to the University of Colorado Cancer Center (and affiliated institutions) by the National Cancer Institute. To identify participants for the early detection and chemoprevention trials of the Colorado SPORE, we initiated a sputum cytology screening program targeting persons with chronic obstructive pulmonary disease and smoking histories of 40 or more pack-years. During the first 26 months after activation of the screening program, sputum samples from 632 participants were evaluated. Of these, 533 (84%) of the subjects submitted specimens deemed adequate for cytopathological interpretation; 99 (16%) provided sputum samples unsuitable for cytodiagnosis. Of those participants who submitted adequate samples, 48% had cytodiagnoses of mild dysplasia, 26 % had moderate to severe dysplasia, and 2% presented with carcinoma in situ or invasive carcinoma. Logistic regression modeling was pursued to determine whether selected demographic and/or clinical status variables could be identified as statistically significant predictors of the specific cytological outcome to be expected (mild dysplasia, moderate dysplasia, and so forth). The only apparent associations found from both univariate and multivariate analyses were that the total number of pack-years of smoking history decreased with severity of cytodiagnosis and that those individuals with mild or moderate dysplasia were more likely to be ex-smokers than those with grades of regular metaplasia or lower. Based on the initial results of the Colorado SPORE sputum cytology screening program, we conclude that persons with chronic obstructive pulmonary disease and 40 or more pack-years of smoking history have a high prevalence of premalignant dysplasia detectable through sputum cytology and should be targeted for research programs focusing on lung cancer prevention, early detection, and exploratory biomarker studies.

Renal function in high dose chemotherapy and autologous hematopoietic cell support treatment for breast cancer.

Autologous and allogeneic bone marrow grafting both require cytoreductive therapy but only the allogeneic procedure requires immunosuppressive agents. Allogeneic bone marrow transplantation has been reported to be associated with a high incidence of both renal failure and veno-occlusive disease (VOD) of the liver, the combination of which is associated with a high morbidity and mortality. There is less known about the frequency and severity of these complications in patients undergoing autologous bone marrow transplantation. In the present study renal, hepatic and other complications were examined in 232 patients with Stages II/III and IV breast cancer who were treated with high-dose chemotherapy and autologous hematopoietic cell support with either marrow or peripheral blood progenitor cells. The post-treatment severity of the renal dysfunction was classified as follows: Grade 0, normal renal function [< 25% decrement in glomerular filtration rate (GFR)]; Grade 1. mild renal dysfunction (> 25% decrement in GFR but < a twofold increase in serum creatinine); Grade 2, > twofold rise in serum creatinine but no need for dialysis; Grade 3 > than twofold rise in serum creatinine and need for dialysis. There were 102 patients (44%) who were classified as Grade 0 and 81 patients (35%) who were classified as Grade 1 renal dysfunction. Severe renal dysfunction (Grades 2 and 3) was observed in 49 of the 232 patients (21%). This severe renal dysfunction of 21% compares with a previously reported 53% incidence of severe renal dysfunction for allogeneic bone marrow transplantation. Similarly, the frequency of hepatic VOD was less (4.7% or 11 of 232 patients) in this autologous bone marrow transplant study as compared to a reported incidence of hepatic VOD ranging from 22 to 53% in large series of allogeneic bone marrow transplant patients. The severe renal dysfunction (Grades 2 and 3) in the present autologous hematopoietic cell support study correlated most significantly with sepsis, liver and pulmonary dysfunction. The major fall in GFR occurred during chemotherapy but before hematopoietic cell support, thus primarily incriminating the cytoreductive therapy rather than the hematopoietic cell support. The only significant effect of different chemotherapy protocols was, at four weeks, the Taxol-treated group had a significantly lower creatinine clearance as compared to the BCNU treated group.

Correlation of tumor markers p53, bcl-2, CD34, CD44H, CD44v6, and Ki-67 with survival and metastasis in laryngeal squamous cell carcinoma.

BACKGROUND: Recent basic discoveries about the biological significance of nuclear and cell-surface marker proteins have opened new areas of research into head and neck cancer. However, the clinical significance of these markers is not yet understood. OBJECTIVE: To perform a historical prospective study of 70 patients with squamous cell carcinoma of the larynx who were treated at our institution between 1979 and 1989 to correlate tumor marker expression with survival and metastasis. DESIGN: Archival tissue was immunohistochemically stained for the p53 tumor suppressor gene product, the inhibitor of apoptosis (bcl-2), the stem cell marker CD34, the cell adhesion molecules CD44H and CD44v6, and a marker of cellular proliferation (Ki-67). The slides were examined using a light microscope and scored according to intensity and percentage of cells labeled. The patients were stratified by tumor stage, and survival and metastatic data were correlated with staining scores. RESULTS: For the stage IV group, increased expression of p53 and decreased expression of CD44H and CD44v6 correlated with a decreased survival (P = .03, P = .03, and P = .02, respectively), and decreased expression of CD44H correlated with an increase in metastasis (P = .01). For all stages, excluding metastatic cases, increased p53 expression was consistent with a shorter survival (P < .03), while increased CD44v6 expression was consistent with a longer survival (P < .02). CONCLUSIONS: The present study suggests that a loss of cell proliferation control implied by overexpression of p53 and loss of cell adhesion implied by decreased expression of CD44 may be determinants of survival in patients with carcinoma of the larynx. The tumor markers bcl-2 and Ki-67 were not prognostic discriminators in this limited series. This study also indicates that the stem cell marker CD34 is rarely expressed by laryngeal carcinoma cells.

Bone marrow involvement by lobular carcinoma of the breast cannot be identified reliably by routine histological examination alone.

The aims of this study were twofold: (1) to evaluate the ability of pathologists to recognize infiltration of bone marrow core biopsy specimens by breast carcinoma, particularly lobular carcinoma, using routine hematoxylin-eosin (HE) sections; and (2) if indicated, to determine the reasons for difficulties in diagnosis. Thirty-six bone cores obtained before bone marrow harvest were involved by breast carcinoma and were confirmed by pancytokeratin immunostains. Thirty of the 36 were ductal carcinomas and six were lobular carcinomas. Fourteen negative bone core biopsy specimens (from patients with breast cancer or lymphoma) were included as controls. These 50 bone cores were reviewed by three surgical pathologists. Lobular carcinoma was correctly identified in only 39% of positive specimens as compared with 88% for ductal carcinoma. After instruction, sensitivity for the detection of lobular carcinoma improved to 61% but at the expense of an unacceptably high rate of false-positive diagnoses (18%). None of the three pathologists was able to achieve both high sensitivity and high specificity in recognizing lobular carcinoma in the bone marrow. Lobular carcinoma was difficult to detect because of tumor cell size similar to hematopoietic cells, infiltration as single cells, presence of bland cytological features, and paucity of tissue reaction to the tumor. Although the number of cases of bone marrow involved by lobular carcinoma is small, these findings suggest that pancytokeratin stains should be performed routinely in the evaluation of bone core biopsy specimens from patients with lobular carcinoma, and probably from patients with ductal carcinoma whose HE-stained bone core biopsy specimens are considered negative for tumor.

Transplantation of enriched CD34-positive autologous marrow into breast cancer patients following high-dose chemotherapy: influence of CD34-positive peripheral-blood progenitors and growth factors on engraftment.

PURPOSE: To evaluate the capacity of enriched CD34-positive (CD34+) progenitor cells to reconstitute hematopoiesis in poor-prognosis breast cancer patients following administration of a high-dose alkylating agent chemotherapy regimen. PATIENTS AND METHODS: Forty-four breast cancer patients received high-dose chemotherapy followed by autologous bone marrow support (ABMS) with CD34+ hematopoietic progenitor cells in five sequentially treated cohorts. Following infusion of CD34+ marrow, cohort no. 1 received no growth factor, cohort no. 2 received granulocyte colony-stimulating factor (G-CSF), and cohort no. 3 received granulocyte-macrophage colony-stimulating factor (GM-CSF). Cohort no. 4 received the CD34+ fractions of both marrow and peripheral-blood progenitor cells (PBPCs) plus G-CSF. Cohort no. 5 received only the CD34+ PBPCs plus G-CSF. Immunohistochemical staining for breast cancer was performed on all hematopoietic cell products before and after the positive selection procedure, to assess quantitatively the level of tumor-cell contamination. RESULTS: Cohorts no. 1, 2, 3, 4, and 5 achieved a granulocyte count > or = 500 x 10(9)/L in a median of 23, 10, 16, 11, and 11 days, with a platelet count greater than 20,000 x 10(9)/L documented in a median of 22, 23, 32, 12, and 10 days, respectively. The time to granulocyte reconstitution was significantly shorter for patients who received CD34+ PBPCs alone (cohort no. 5), or in combination with CD34+ marrow (cohort no. 4), when compared with those who received only the CD34+ marrow fraction (P < .01). From 1 to greater than 4 logs of breast cancer cell depletion were documented after CD34-selection, for patients in whom tumor was initially detected. CONCLUSION: CD34+ marrow and/or PBPCs provide reliable and timely hematopoietic reconstitution in breast cancer patients receiving high-dose chemotherapy. Contamination of both marrow and PBPCs with breast cancer cells was reduced using this positive selection technique.

Diagnosis of bowel obstruction on plain abdominal radiographs: significance of air-fluid levels at different heights in the same loop of bowel.

OBJECTIVE: Differential air-fluid levels are two distinct air-fluid interfaces on horizontal-beam abdominal radiographs that are at different heights but within the same loop of bowel. Differential air-fluid levels have been considered by many to be strong evidence of mechanical bowel obstruction, but others have found this sign unreliable for differentiating mechanical from adynamic obstructions. Neither opinion is supported by evidence from large series of patients. Accordingly, we determined the efficacy of differential air-fluid levels for distinguishing mechanical from adynamic bowel obstruction. MATERIALS AND METHODS: We identified patients who had a total of 62 episodes of proved mechanical bowel obstruction and 38 episodes of adynamic obstruction through a computer search of medical records and radiographic files. On horizontal-beam abdominal radiographs of these patients, the presence and height of intestinal differential air-fluid levels were determined by the consensus of two experienced radiologists. These data were then statistically analyzed to determine the usefulness of differential air-fluid levels for distinguishing between mechanical and adynamic bowel obstructions. RESULTS: Plain films showed differential air-fluid levels in 32 (52%) of the 62 episodes of mechanical obstructions compared with 11 (29%) of the 38 adynamic obstructions, giving a sensitivity for mechanical obstruction of 0.52 and a specificity of 0.71. As the minimum significant height of differential air-fluid levels increased, specificity increased and sensitivity decreased. The positive predictive value also increased as differential air-fluid level heights increased, reaching a level of 0.86 or greater at 20 mm. CONCLUSION: The presence of differential air-fluid levels is an insensitive method of determining if a bowel obstruction is mechanical, because only a small proportion of mechanical obstructions have differential air-fluid levels. In our population of patients, however, a differential air-fluid level of 20 mm or greater was moderately suggestive that a bowel obstruction was mechanical in nature.

A model for the objective assessment of clinical training programs: the initial application to two pulmonary medicine fellowship programs.

A model is presented for the objective assessment of clinical training programs. The model documents the clinical trainee's experience by the diagnoses seen and procedures performed during a full year of experience. It also surveys faculty impressions of the trainee's experience and their judgment of what is necessary to constitute an adequate experience. In the pilot study applying this model to two pulmonary medicine fellowship programs, several important observations were made: (1) faculty members may not have an accurate perception of the fellow's actual clinical experience, (2) faculty impressions of the fellow's experience often do not correspond to their own conception of an adequate clinical experience, (3) interprogram variability exists, (4) pulmonary fellows may have inadequate experience with certain invasive procedures. These observations suggest that wilder application of such a model could provide valuable information to program directors and subspecialty boards. In addition, directors of pulmonary disease training programs have been asked by the American Board of Internal Medicine to establish systems to evaluate, document, and substantiate those components of overall clinical competence considered essential for certification in the subspecialty. The model presented here provides an accurate and efficient means for such evaluation and documentation.

Acute acetaminophen overdose during pregnancy.

During a nationwide acetaminophen overdose study conducted at the Rocky Mountain Poison and Drug Center from 1976-1985, 113 patients entered into the study were reported to be pregnant at the time of the overdose. Follow-up, including appropriate laboratory and pregnancy outcome data, was available in 60 cases. Of these, 19 women overdosed during the first trimester, 22 during the second trimester, and 19 during the third trimester of pregnancy. Of the 24 patients with acetaminophen levels above the acetaminophen overdose nomogram line, ten were treated with N-acetylcysteine within 10 hours post-ingestion; eight delivered normal infants and two had elective abortions. Of ten patients treated with N-acetylcysteine 10-16 hours post-ingestion, five delivered viable infants, two had elective abortions, and three had spontaneous abortions. Of four women treated with N-acetylcysteine 16-24 hours post-ingestion, one mother died, and there was one spontaneous abortion, one stillbirth, one elective abortion, and one delivery. Multiple logistic regression demonstrated a statistically significant correlation between the time to loading dose of N-acetylcysteine and pregnancy outcome, with an increase in the incidence of spontaneous abortion or fetal death when treatment was begun late. We recommend that pregnant women who take an acetaminophen overdose and have a potentially toxic serum level be treated with N-acetylcysteine as early as possible.

Glucose control and the renal and retinal complications of insulin-dependent diabetes.

Two hundred thirty subjects with insulin-dependent diabetes were followed up longitudinally by measuring glycohemoglobin values to relate glucose control with renal and retinal complications. Subjects with long-term poor control (glycohemoglobin values greater than 1.5 times the upper limit of normal) had 3.6 times the prevalence of microalbuminuria and 2.5 times the prevalence of level 3 to 6 retinopathy than that found in subjects with long-term good control (glycohemoglobin values within 1.33 times the upper limit of normal). Variables related to kidney damage were glucose control and, to a lesser degree, duration of diabetes. Variables related to eye disease were, in descending order of significance, duration of diabetes, glucose control, and age. No subject whose mean glycohemoglobin value was consistently within 1.1 times the upper limit of normal had retinopathy or microalbuminuria. In contrast, when the mean glycohemoglobin value was more than 1.5 times the upper limit of normal, 24 (29%) of 82 subjects had microalbuminuria and 30 (37%) of 82 had level 3 to 6 retinopathy.

Tissue factor activity in HeLa cells measured with a continuous chromogenic assay and ELISA reader.

Tissue factor activity expressed by Hela cells cultured in 96-well plates has been quantitated in situ using a continuous spectrophotometric assay. Following the assay, cells assayed without physical disruption remained as viable as cells not subjected to the assay. Very little (or no) tissue factor was expressed in nondisrupted cells relative to that available in cells disrupted by freeze-thawing and sonication. Total tissue factor activity (that available in disrupted cells) decreased not as a simple function of time after subculturing, but was inversely related to cell density.

Distribution of the T4D bacteriophage binding sites on the Escherichia coli B surface.

A study of the distribution of the T4D bacteriophage binding sites on the Escherichia coli B bacterial surface has shown that: (1) the number of binding sites per unit surface area is larger during growth period than during the division period, (2) the density of the binding sites on one-half of the bacterial cell is larger than the density of binding sites on the other half; (3) in newly-divided bacteria, the maximal binding site density is situated at one pole; (4) as bacteria grow, this maximum shifts to the middle of the cell; (5) when the septum is established, the middle of the cell becomes very poor in phage binding sites activity, and (6) phage adsorbs in clusters or in groups following curved lines around the bacterial cell.

Techniques for improving glucose control in type I diabetes.

Intervention for poor glucose control was attempted in 38 children and adolescents with a mean follow-up time of 3 years. Changing the quantity of insulin or changing the number of injections per day resulted in improvement in 10 of the 21 patients who responded to intervention. Six others responded to a family conference and four responded to a parent temporarily taking over the diabetes management. The presence of a supportive family member living in the home was a major factor in the likelihood of intervention being successful.

On comparing regression lines with unequal slopes.

For the situation in which the slopes of two regression lines may differ, procedures are discussed for the comparison of the lines at a single X, simultaneous comparison at several values of X, and determination of the range of X for which the difference between the lines is large enough to be statistically significant. These useful procedures have previously been discussed but do not seem to be well known. Their usefulness in the analysis of physiological data is demonstrated with data arising from a study of pulmonary response to hypoxia.

The predictive value of clinical laboratory test results.

Bayes' formula is being used with increasing frequency to calculate predictive values for positive and negative clinical laboratory test results. Because of its nonlinear form, however, it is difficult to visualize how changes in the test characteristics or disease prevalence will effect predictive values. This paper shows that Bayes' formula is transformed to a linear function through the use of odds, rather than probabilities, thus facilitating conceptualization, understanding, and memory.

Optimizing the enzyme--labeling of antibody.

Recently developed immunohistochemical techniques allow the biologist to monitor the migration and activity of immunoglobulins via enzymatic labels. This paper proposes a model for the description of this labeling process and investigates the optimum mixture of immunoglobin and label for this model.