[Show abstract][Hide abstract] ABSTRACT: Purpose:
To use clinically measured reproducibility of volumetric CT (vCT) of lung nodules to estimate error in nodule growth rate in order to determine optimal scan interval for patient follow-up.
We performed quantitative vCT on 89 stable non-calcified nodules and 49 calcified nodules measuring 3-13 mm diameter in 71 patients who underwent 3-9 repeat vCT studies for clinical evaluation of pulmonary nodules. Calculated volume standard deviation as a function of mean nodule volume was used to compute error in estimated growth rate. This error was then used to determine the optimal patient follow-up scan interval while fixing the false positive rate at 5%.
Linear regression of nodule volume standard deviation versus the mean nodule volume for stable non-calcified nodules yielded a slope of 0.057±0.002 (r2 = 0.79, p<0.001). For calcified stable nodules, the regression slope was 0.052±0.005 (r2 = 0.65, p = 0.03). Using this with the error propagation formula, the optimal patient follow-up scan interval was calculated to be 81 days, independent of initial nodule volume.
Reproducibility of vCT is excellent, and the standard error is proportional to the mean calculated nodule volume for the range of nodules examined. This relationship constrains statistical certainty of vCT calculated doubling times and results in an optimal scan interval that is independent of the initial nodule volume.
PLoS ONE 09/2015; 10(9):e0138144. DOI:10.1371/journal.pone.0138144 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This perspective discusses the report by Pinsky and colleagues, which addresses whether non-calcified pulmonary nodules identified on CT screening carry short- and long-term risk for lung cancer. We are facing challenges related to distinguishing a large majority of benign nodules from malignant ones and among those a majority of aggressive from indolent cancers. Key questions in determining individual probabilities of disease, given their history, findings on CT, and upcoming biomarkers of risk, remain most challenging. Reducing the false positives associated with current low-dose computed tomography (LDCT) practices and identification of individuals who need therapy and at what time during tumor surveillance could reduce costs and morbidities associated with unnecessary interventions.
Cancer Prevention Research 10/2014; 7(12). DOI:10.1158/1940-6207.CAPR-14-0364 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Importance
Positron emission tomography (PET) combined with fludeoxyglucose F 18 (FDG) is recommended for the noninvasive diagnosis of pulmonary nodules suspicious for lung cancer. In populations with endemic infectious lung disease, FDG-PET may not accurately identify malignant lesions.Objectives
To estimate the diagnostic accuracy of FDG-PET for pulmonary nodules suspicious for lung cancer in regions where infectious lung disease is endemic and compare the test accuracy in regions where infectious lung disease is rare.Data Sources and Study Selection
Databases of MEDLINE, EMBASE, and the Web of Science were searched from October 1, 2000, through April 28, 2014. Articles reporting information sufficient to calculate sensitivity and specificity of FDG-PET to diagnose lung cancer were included. Only studies that enrolled more than 10 participants with benign and malignant lesions were included. Database searches yielded 1923 articles, of which 257 were assessed for eligibility. Seventy studies were included in the analysis. Studies reported on a total of 8511 nodules; 5105 (60%) were malignant.Data Extraction and Synthesis
Abstracts meeting eligibility criteria were collected by a research librarian and reviewed by 2 independent reviewers. Hierarchical summary receiver operating characteristic curves were constructed. A random-effects logistic regression model was used to summarize and assess the effect of endemic infectious lung disease on test performance.Main Outcome and Measures
The sensitivity and specificity for FDG-PET test performance.Results
Heterogeneity for sensitivity (I2 = 87%) and specificity (I2 = 82%) was observed across studies. The pooled (unadjusted) sensitivity was 89% (95% CI, 86%-91%) and specificity was 75% (95% CI, 71%-79%). There was a 16 percentage point–lower average adjusted specificity in regions with endemic infectious lung disease (61% [95% CI, 49%-72%]) compared with nonendemic regions (77% [95% CI, 73%-80%]). Lower specificity was observed when the analysis was limited to rigorously conducted and well-controlled studies. In general, sensitivity did not change appreciably by endemic infection status, even after adjusting for relevant factors.Conclusions and Relevance
The accuracy of FDG-PET for diagnosing lung nodules was extremely heterogeneous. Use of FDG-PET combined with computed tomography was less specific in diagnosing malignancy in populations with endemic infectious lung disease compared with nonendemic regions. These data do not support the use of FDG-PET to diagnose lung cancer in endemic regions unless an institution achieves test performance accuracy similar to that found in nonendemic regions.
JAMA The Journal of the American Medical Association 09/2014; 312(12):1227-1236. DOI:10.1001/jama.2014.11488 · 35.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Existing predictive models for lung cancer focus on improving screening or referral for biopsy in general medical populations. A predictive model calibrated for use during preoperative evaluation of suspicious lung lesions is needed to reduce unnecessary operations for a benign disease. A clinical prediction model (Thoracic Research Evaluation And Treatment [TREAT]) is proposed for this purpose.
We developed and internally validated a clinical prediction model for lung cancer in a prospective cohort evaluated at our institution. Best statistical practices were used to construct, evaluate, and validate the logistic regression model in the presence of missing covariate data using bootstrap and optimism corrected techniques. The TREAT model was externally validated in a retrospectively collected Veteran Affairs population. The discrimination and calibration of the model was estimated and compared with the Mayo Clinic model in both the populations.
The TREAT model was developed in 492 patients from Vanderbilt whose lung cancer prevalence was 72% and validated among 226 Veteran Affairs patients with a lung cancer prevalence of 93%. In the development cohort, the area under the receiver operating curve (AUC) and Brier score were 0.87 (95% confidence interval [CI], 0.83-0.92) and 0.12, respectively compared with the AUC 0.89 (95% CI, 0.79-0.98) and Brier score 0.13 in the validation dataset. The TREAT model had significantly higher accuracy (p < 0.001) and better calibration than the Mayo Clinic model (AUC = 0.80; 95% CI, 75-85; Brier score = 0.17).
The validated TREAT model had better diagnostic accuracy than the Mayo Clinic model in preoperative assessment of suspicious lung lesions in a population being evaluated for lung resection.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2014; 9(10). DOI:10.1097/JTO.0000000000000287 · 5.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The results of the National Lung Screening Trial strongly support early detection and definitive treatment to reduce lung cancer mortality. Once lung cancer is discovered, accurate staging at baseline is imperative to maximize patient benefit and cost-effective use of health care resources. Although computed tomography (CT) remains a powerful tool for staging of lung cancer, advances in other imaging modalities, specifically positron emission tomography/CT and magnetic resonance imaging, can improve baseline staging over CT alone and can allow a more rapid and accurate assessment of response to treatment. Although noninvasive imaging is extremely useful, tissue diagnosis remains the criterion standard for staging lung cancer and monitoring treatment response. Accordingly, tissue sampling using advanced bronchoscopic imaging guidance, such as ultrasound or electromagnetic navigation, allows precise tissue location and sampling of mediastinal nodes or lung nodules in the least invasive manner. In the future, bronchoscopy may allow real-time microscopic analysis.
The Cancer Journal 05/2013; 19(3):208-216. DOI:10.1097/PPO.0b013e318295185f · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
Measured human dosimetry of the (68)Ga-labeled synthetic somatostatin analog (68)Ga-DOTATATE has not been reported in the peer-reviewed literature. (68)Ga-DOTATATE is an investigational PET/CT imaging agent that binds with high affinity to somatostatin receptor subtype 2, found on many human cancers, most classically neuroendocrine tumors but also others. Reporting of measured dosimetry of (68)Ga-DOTATATE could be useful for investigations for diagnosis, staging, and restaging of somatostatin receptor-expressing tumors.
We performed measured dosimetry with (68)Ga-DOTATATE PET/CT scanning in 6 volunteer human subjects as part of an Institutional Review Board-approved biodistribution investigation of the use of this radiopharmaceutical for possible future use in the diagnosis of indeterminate lung nodules or lung cancer. Five subjects were imaged at 3 time points, and 1 subject was imaged at 2 time points. Dosimetry was then measured for the whole body and for specific organs.
There were no observed adverse events to the radiopharmaceutical in the immediate or delayed time frames, with a follow-up of 1 y. One patient had stage IV non-small cell lung cancer and remains alive but with disease progressing on treatment. For the other 5 patients, it was ultimately proven that they had benign nodules. The measured dosimetry shows that the critical organ with (68)Ga-DOTATATE is the spleen, followed by the uroepithelium of the bladder, the kidneys, and the liver, in that order. Organ-specific and whole-body dosimetries for (68)Ga-DOTATATE were similar to but often slightly greater than those for (68)Ga-DOTATOC or (68)Ga-DOTANOC but less than those for (111)In-diethylenetriaminepentaacetic acid-octreotide.
No toxicity was observed in our 6 patients, and no adverse events occurred. The measured human dosimetry of (68)Ga-DOTATATE is similar to that of other (68)Ga-labeled somatostatin receptor analogs.
Journal of Nuclear Medicine 03/2013; 54(6). DOI:10.2967/jnumed.112.114165 · 6.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) is an incurable plasma cell malignancy of the bone marrow. MM has 3 components: diffuse marrow infiltration, focal bone lesions, and soft-tissue (extramedullary) disease. The hallmark biomarker in blood or urine is a monoclonal immunoglobulin, the monoclonal protein. Waldenstrom macroglobulinemia is a similar disease with secretion of IgM. Staging is classically performed with the 1975 Durie-Salmon system, which includes conventional radiographs. Recently updated, the Durie-Salmon Plus staging system includes CT, MRI, and (18)F-FDG PET/CT. The hallmark radiographic lesion of symptomatic MM is a well-demarcated, focal osteolytic bone lesion. The number of focal bone lesions correlates inversely with outcome. Extramedullary disease is typically an aggressive, poorly differentiated form of MM that confers inferior outcome, with median survival of less than 1 y if present at diagnosis. Achievement of a complete response on (18)F-FDG PET before stem-cell transplantation correlates with a superior outcome.
Journal of Nuclear Medicine 06/2012; 53(7):1091-101. DOI:10.2967/jnumed.111.098830 · 6.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary nodules often require operative resection to obtain a diagnosis. However, 10 to 30% of operations result in a benign diagnosis. Our purpose was to determine whether negative thoracic operations are futile by describing the pathological diagnoses; determining new diagnoses and treatment changes initiated based on operative findings; and assessing morbidity, mortality, and cost of the procedure.
At our academic medical center, 278 thoracic operations were performed for known or suspected cancer between January 1, 2005, and April 1, 2009. We collected and summarized data pertaining to preoperative patient and nodule characteristics, pathologic diagnosis, postoperative treatment changes resulting from surgical resection, perioperative morbidity and mortality, and hospital charges for patients with benign pathology.
Twenty-three percent (65/278) of patients who underwent surgical resection for a suspicious nodule had benign pathology. We report granulomatous disease in 57%, benign tumors in 15%, fibrosis in 12%, and autoimmune and vascular diseases in 9%. Definitive diagnosis or treatment changes occurred in 85% of cases. Surgical intervention led to a new diagnosis in 69%, treatment course changes in 68% of benign cases, medication changes in 38%, new consultation in 31%, definitive treatment in 9%, and underlying disease management in 34%. There was no intraoperative, in-hospital, or 30-day mortality. Postoperative in-hospital events occurred in seven patients. The mean total cost was $25,515 with a mean cost per day of $7618.
Patients with a benign diagnosis after surgical resection for a pulmonary nodule received a new diagnosis or had a treatment course change in 85% of the cases.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 07/2011; 6(10):1720-5. DOI:10.1097/JTO.0b013e318226b48a · 5.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is a deadly disease that is difficult to diagnose and even more difficult to treat effectively. Many pathways are known to affect tumor growth, and targeting these pathways provides the cornerstone by which cancer is treated. Somatostatin receptors (SSTR) are a family of G protein coupled receptors that signal to alter hormonal secretion, increase apoptosis, and decrease cellular proliferation. These receptors are expressed in many normal and malignant cells, including both small cell and non-small cell lung cancer. Synthetic analogs of SSTRs are commercially available, but their effects in lung cancer are still largely uncertain. Signaling pathway studies have shown that SSTRs signal through phosphotyrosine phosphatases to induce apoptosis as well as to decrease cell proliferation. Radiolabeled SSTR2 analogs are utilized for radiographic imaging of tumors, which, when combined with positron emission tomography-computed tomography (PET-CT) may improve detection of lung cancer. These radiolabeled SSTR2 analogs also hold promise for targeted chemotherapy as well as radiotherapy. In this review, we summarize what is known about SSTRs and focus our discussion on the knowledge as it relates to lung cancer biology, as well as discuss current and future uses of these receptors for imaging and therapy of lung cancer.
[Show abstract][Hide abstract] ABSTRACT: The significance of medical imaging in multiple myeloma was established in 1975 with the classic description of the Durie–Salmon
staging system which incorporated the presence and number of focal osteolytic lesions in the staging scheme. A third of a
century later, this staging system remains in use, though augmented by advances in medical imaging. By the early 1980s, CT
imaging demonstrated more focal bone lesions than were seen with standard radiographs as well as extramedullary disease. By
the 1980s, MRI imaging revealed skeletal disease that was not apparent by either standard x-rays or CT, focal plasmacytomas
in bone that had not yet produced focal osteolysis, and diffuse marrow infiltration. Subsequent work throughout the 1990s
developed and established MRI as a very powerful tool to demonstrate the full extent of skeletal disease with resolution approaching
a few millimeters. MRI was also used to direct biopsies of focal lesions which increased the detection rate of clinically
relevant information compared to random marrow biopsies. However, standard MRI lacked the wide field of view of CT and was
both considerably more expensive and less widely available than CT. An additional weakness of standard x-rays, CT, and MRI
was their limited utility in the demonstration of response to treatment. By the mid- to late 1990s, the utility of 18F-FDG PET and (after 2000) PET/CT was apparent. PET/CT was particularly powerful since it provided a “whole-body” examination
combining the utility of CT (“anatomy”) with a “metabolic” image that was linked to the Warburg physiology of tumors, at a
fraction of the cost of an extensive MRI. Thus, PET and PET/CT can demonstrate both active disease and, very importantly,
response to treatment. The PET image fused to the CT portion of the PET/CT also provides a “free” whole-body metastatic bone
survey that can reveal not only focal bone lesions but also additional clinically relevant findings (fractures or impending
fractures, additional malignancies, occult infections, unsuspected regions of tumor involvement such as extramedullary tumor).
Recent work has established the fundamental importance of 18F-FDG PET and PET/CT for the baseline evaluation of patients with multiple myeloma and related plasma cell dyscrasias, as
well as for subsequent evaluations related to patient management. Future directions for imaging research in multiple myeloma
will include PET imaging with isotopes other than 18F-FDG and whole-body MRI.
KeywordsImaging-MRI-PET-PET/CT-Skeletal survey-Focal lesion-Osteolytic lesion-Occult infection-DKK1-Extramedullary disease (EMD)
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer (CRC) is the third most common cause of malignancy in both men and women. The incidence rate has decreased over the last two decades partially due to an increase in screening. The American Cancer Society estimates that there are approximately 149,000 new cases of CRC per year and approximately 50,000 patients per year die from this disease in the USA, representing 10% of new cases and 8% of all cancer deaths. Approximately 70–80% of patients are treated with curative intent, mostly by surgery. Chemotherapy alone, or in combination with radiation (for rectal cancer), is given before or after surgery to most patients whose tumor has penetrated the bowel wall or spread to lymph nodes. The overall survival at 1 and 5 years is 82 and 64%, respectively. The 5-year survival is 90% for localized stage, 68% when there is regional spread, and 10% when there are distant metastases.
[Show abstract][Hide abstract] ABSTRACT: A variety of benign and malignant tumors occur in the liver. The most common benign hepatic tumors are cysts followed by cavernous
hemangiomas. Focal nodular hyperplasia and adenomas more often affect women on oral contraceptives, whereas fatty infiltration
and regenerating nodules more commonly occur in patients with cirrhosis. Abscesses and angiomyolipomas are uncommon. Among
malignant tumors, metastases to the liver from various primaries, often multifocal, occur 20 times more often than primary
hepatocellular carcinoma (HCC). Although many tumors may metastasize to the liver, this occurs mainly in colorectal, gastric,
pancreatic, lung, and breast carcinoma. Ninety percent of malignant primary hepatic tumors are of epithelial origin and include
HCC and cholangiocarcinoma.
[Show abstract][Hide abstract] ABSTRACT: Malignant cerebral tumors represent a small percentage (approximately 2%) of all malignancies, but have severe prognosis due
to high morbidity and mortality. According to the American Cancer Society, in 2007 there were 23,300 new benign cerebral tumors
and 20,500 new malignant cerebral tumors diagnosed in the United States, with an estimated number of resulting deaths of 12,760.
Malignancies of the central nervous system (CNS) are the second most common malignancy in patients under the age of 20 (after
hematologic malignancies) and are the leading cause of death from solid tumors in children and the third leading cause of
death from cancer in the 15- to 34-year-old age group.
[Show abstract][Hide abstract] ABSTRACT: Infection imaging became widespread in 1971 with the release of 67Ga citrate. Multiphase skeletal scintigraphy and radiolabeled white blood cells (WBCs) have since become the most widespread clinically used agents for the imaging of infection. A wide variety of other radiolabeled probes are under investigation, based on antibodies, cytokines, assorted proteins and other molecules, alone or in various combinations. However, these latter agents, with a few exceptions, are not routinely used clinically. Radiolabeled ciprofloxacin represents the first attempt to develop an infection-specific imaging agent (most infection-imaging probes localized nonspecifically to inflammation as well), but it has not proven superior to radiolabeled WBCs or 18F-fluoro-deoxy-glucose (FDG) PET. Because of the ability to combine exquisite anatomic detail with focal uptake of 18F-FDG, PET-computed tomography has achieved great success in the detection and localization of infection, including in clinically adverse conditions. Despite these advances, at this time an infection-specific imaging agent does not exist.
[Show abstract][Hide abstract] ABSTRACT: To assess the prevalence, time of onset, risk factors, and outcome of avascular necrosis (AVN) of bone in patients with multiple myeloma undergoing antineoplastic therapy.
A total of 553 consecutive assessable patients were enrolled onto a treatment protocol consisting of dexamethasone-containing induction chemotherapy, autologous stem-cell transplantation, consolidation chemotherapy, and maintenance with interferon alfa. Patients were randomly assigned to receive thalidomide (269 patients) or no thalidomide (284 patients) throughout the study period.
With a median follow-up of 33 months (range, 5 to 114 months), AVN of the femoral head(s) developed in 49 patients (9%). Median time to onset of AVN was 12 months (range, 2 to 41 months). Three risk factors for AVN were identified by multivariate analysis: cumulative dexamethasone dose (odds ratio [OR], 1.028; 95% CI, 1.012 to 1.044; P = .0006 [per 40 mg dexamethasone]), male sex (OR, 0.390; 95% CI, 0.192 to 0.790; P = .009), and younger age (OR, 0.961; 95% CI, 0.934 to 0.991 per year; P = .0122). Thalidomide-treated patients had a prevalence of AVN similar to that of the control group (8% v 10%, respectively; P = .58). AVN-related pain and limited range of motion of the affected joint were present in only nine and four patients, respectively, and four patients underwent hip replacement because of AVN. Fluorine-18 fluorodeoxyglucose positron emission tomography failed to detect abnormal uptake in the AVN-affected bones.
AVN is a rare and usually asymptomatic complication during myeloma therapy. Cumulative dexamethasone dose, male sex, and younger age, but not thalidomide, increase the risk of AVN.
[Show abstract][Hide abstract] ABSTRACT: Heparanase is an enzyme that cleaves heparan sulfate and through this activity promotes tumor growth, angiogenesis, invasion, and metastasis in several tumor types. In human breast cancer patients, heparanase expression is associated with sentinel lymph node metastases. However, the precise role of heparanase in the malignant progression of breast cancer is unknown. To examine this, a variant of MDA-MB-231 cells was transfected with the cDNA for human heparanase (HPSE cells) or with vector alone as a control (NEO cells). Transfection produced a 6-fold increase in heparanase activity in HPSE cells relative to NEO cells. When injected into the mammary fat pads of severe combined immunodeficient mice, the tumors formed by HPSE cells initially grow significantly faster than the tumors formed by NEO cells. The rapid growth is due in part to increased angiogenesis, as microvessel densities are substantially elevated in primary HPSE tumors compared with NEO tumors. Although metastases to bones are not detected, surprisingly vigorous bone resorption is stimulated in animals bearing tumors formed by the HPSE cells. These animals have high serum levels of the C-telopeptide derived from type I collagen as well as significant elevation of the active form of tartrate-resistant acid phosphatase (TRAP)-5b. In contrast, in animals having a high tumor burden of Neo cells, the serum levels of C-telopeptide and TRAP-5b never increase above the levels found before tumor injection. Consistent with these findings, histologic analysis for TRAP-expressing cells reveals extensive osteoclastogenesis in animals harboring HPSE tumors. In vitro osteoclastogenesis assays show that the osteoclastogenic activity of HPSE cell conditioned medium is significantly enhanced beyond that of NEO conditioned medium. This confirms that a soluble factor or factors that stimulate osteoclastogenesis are specifically produced when heparanase expression is elevated. These factors exert a distal effect resulting in resorption of bone and the accompanying enrichment of the bone microenvironment with growth-promoting factors that may nurture the growth of metastatic tumor cells. This novel role for heparanase as a promoter of osteolysis before tumor metastasis suggests that therapies designed to block heparanase function may disrupt the early progression of bone-homing tumors.
Cancer Research 08/2005; 65(13):5778-84. DOI:10.1158/0008-5472.CAN-05-0749 · 9.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to evaluate the role of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging in the diagnosis of infection of implantable vascular catheters.
We evaluated six patients with haematological cancer and infection of their implantable vascular catheter and who underwent FDG PET imaging around the time of their infection.
Six patients with multiple myeloma who developed infection of their implantable device (five port pocket infections and one tunnel infection) were identified. FDG PET revealed increased uptake at the site of the implantable catheter (SUV 2.7-4.5) in all six patients, even in the absence of signs or symptoms of infection at the site of the device (three), and the presence of severe neutropenia (four). The three patients who did not have local inflammation at the site of the device were profoundly neutropenic. The FDG PET diagnosis led to removal of the device in two patients.
FDG PET is a safe, rapid and accurate tool for diagnosing infection of an implantable catheter, including among those patients not exhibiting local signs and symptoms of infection, and in whom the diagnosis of infected device may be difficult. FDG PET may help prevent the unnecessary removal of implantable intravascular catheters and the unwarranted use of antibiotics.
Nuclear Medicine Communications 09/2004; 25(8):813-8. DOI:10.1097/01.mnm.0000130247.37315.66 · 1.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Medical imaging is migrating from anatomic imaging to functional imaging and fused anatomic/functional imaging. The technology is being adapted for biomedical research using both clinical and small animal scanners. The ability to externally image real-time physiologic processes in both normal and deranged conditions, including various models to image gene expression, apoptosis, or drug biodistribution, has powerful impact on the exploration of biomedical and fundamental biological research. Positron emission tomography (PET) has a unique ability to not only provide such images but also to do so with high resolution (typically 1-2mm resolution for small animal scanners) and to provide both relative and absolute quantitation. This technology is revolutionizing biomedical and biological research. This article reviews the underlying principles involved in this technology, gives a brief history of its development, and then introduces the interested researcher to some of the important techniques that could be of use.
[Show abstract][Hide abstract] ABSTRACT: PET is one of the most exciting advancements in medicine in many years. Its ability to image physiology rather than anatomy, combined with the wide range of organic "probes" or molecules that can be utilized, offer remarkable possibilities for medical imaging in the coming years.
The Journal of the Arkansas Medical Society 11/2002; 99(4):119-21.