The lead time distribution when lifetime is subject to competing risks in cancer screening.

This paper extends the previous probability model for the distribution of lead time in periodic cancer screening exams, namely, in that the lifetime T is treated as a random variable, instead of a fixed value. Hence the number of screens for a given individual is a random variable as well. We use the actuarial life table from the Social Security Administration to obtain the lifetime distribution, and then use this information to project the lead time distribution for someone with a future screening schedule. Simulation studies using the HIP study group data provide estimates of the lead time under different screening frequencies. The projected lead time has two components: a point mass at zero (corresponding to interval cases detected between screening exams) and a continuous probability density. We present estimates of the projected lead time for participants in a breast cancer screening program. The model is more realistic and can inform optimal screening frequency. This study focuses on breast cancer screening, but is applicable to other kinds of cancer screening also.

Bayesian Methods for Medical Test Accuracy.

Bayesian methods for medical test accuracy are presented, beginning with the basic measures for tests with binary scores: true positive fraction, false positive fraction, positive predictive values, and negative predictive value. The Bayesian approach is taken because of its efficient use of prior information, and the analysis is executed with a Bayesian software package WinBUGS®. The ROC (receiver operating characteristic) curve gives the intrinsic accuracy of medical tests that have ordinal or continuous scores, and the Bayesian approach is illustrated with many examples from cancer and other diseases. Medical tests include X-ray, mammography, ultrasound, computed tomography, magnetic resonance imaging, nuclear medicine and tests based on biomarkers, such as blood glucose values for diabetes. The presentation continues with more specialized methods suitable for measuring the accuracies of clinical studies that have verification bias, and medical tests without a gold standard. Lastly, the review is concluded with Bayesian methods for measuring the accuracy of the combination of two or more tests.

Bayesian Estimation of Combined Accuracy for Tests with Verification Bias.

This presentation will emphasize the estimation of the combined accuracy of two or more tests when verification bias is present. Verification bias occurs when some of the subjects are not subject to the gold standard. The approach is Bayesian where the estimation of test accuracy is based on the posterior distribution of the relevant parameter. Accuracy of two combined binary tests is estimated employing either "believe the positive" or "believe the negative" rule, then the true and false positive fractions for each rule are computed for two tests. In order to perform the analysis, the missing at random assumption is imposed, and an interesting example is provided by estimating the combined accuracy of CT and MRI to diagnose lung cancer. The Bayesian approach is extended to two ordinal tests when verification bias is present, and the accuracy of the combined tests is based on the ROC area of the risk function. An example involving mammography with two readers with extreme verification bias illustrates the estimation of the combined test accuracy for ordinal tests.

Bayesian inference for the lead time in periodic cancer screening.

This article develops a probability distribution for the lead time in periodic cancer screening examinations. The general aim is to allow statistical inference for a screening program's lead time, the length of time the diagnosis is advanced by screening. The program's lead time is distributed as a mixture of a point mass and a piecewise continuous distribution. Simulation studies using the HIP (Health Insurance Plan for Greater New York) study's data provide estimates of different characteristics of a screening program under different screening frequencies. The components of this mixture represent two aspects of screening's benefit, namely, a reduction in the number of interval cases and the extent by which screening advanced the age of diagnosis. We present estimates of these two measures for participants in a breast cancer screening program. We also provide the mean, mode, variance, and density curve of the program's lead time. The model can provide policy makers with important information regarding the screening period, frequency, and the endpoints that may serve as surrogates for the benefit to women who take part in a periodic screening program. Though the study focuses on breast cancer screening, it is also applicable to other kinds of chronic disease.

Interobserver and intraobserver variability of standardized uptake value measurements in non-small-cell lung cancer.

OBJECTIVES: To assess interobserver and intraobserver variabilities in measuring the maximal standardized uptake value (SUV) of non-small-cell lung cancer. METHODS: Positron emission tomography-computed tomography examinations of 20 consecutive patients referred for initial evaluation of newly diagnosed non-small-cell lung cancer were retrospectively reviewed by 5 experienced positron emission tomography-computed tomography readers, who independently measured the maximal SUV/body weight of the primary tumors. Interobserver and intraobserver variabilities were assessed by using 4 statistical methods: correlation, regression analysis, Bland-Altman analysis, and analysis of variance. The SUV measurements derived in the study were compared with the SUV measurements documented in the original reports using correlation and regression analysis. The percentages of tumors whose retrospective SUV measurements were more than 20% different and more than 25% different from those in the original report were assessed. RESULTS: Both interobserver and intraobserver SUV measurements were highly reproducible. Pearson correlation coefficients were greater than 0.95 and 0.94, respectively. Good interobserver and intraobserver agreement was shown with regression analysis (F test P value >0.05), the Bland-Altman analysis, and analysis of variance (F test P value >0.95). The mean original SUV was much less than the mean study SUV (P<0.05). The study SUV differed from the SUV of the original report by more than 20% in 50% of the tumors, and by more than 25% in 45% of the tumors. CONCLUSIONS: There was excellent interobserver and intraobserver agreement in SUVs measured in the study environment but poor agreement between study SUVs and those documented in original reports, which can affect treatment decisions substantially.

Effect of transcatheter hepatic arterial embolization on angiogenesis in an animal model.

OBJECTIVES: Transcatheter arterial embolization (TAE) is used for the treatment of patients with malignant liver tumors. However, the proangiogenesis effect of TAE-associated hypoxia has not been adequately studied. The goal of this study was to determine angiogenic activity in tumors subjected to TAE by evaluating the tumor microvessel density (MVD). MATERIALS AND METHODS: Mammary cancer 13762 NF tumor cells were inoculated into the livers of male Sprague-Dawley rats. TAE was performed 12-14 days after tumor inoculation. Rats were divided into 4 groups on the basis of treatment type. Control group animals (n = 16) were subjected to sham TAE without polyvinyl alcohol (PVA) particles. Animals in the other 3 groups were subjected to TAE with 1 (n = 11), 2 (n = 8), or 3 (n = 10) mg of PVA particles. Rats were killed 3-6 hours or 2 or 3 days after embolization, and the liver tumor tissues were dissected and frozen in liquid nitrogen. Tumor tissue slides were prepared, stained with CD-31, and evaluated for MVD. Blood samples collected just before sacrificing the animals were used to measure serum vascular endothelial growth factor (VEGF) levels. RESULTS: Tumors treated with TAE showed varying degrees of central necrosis with residual viable tumor cells in the periphery. Tumor MVD in animals treated with TAE was significantly higher than that in the control group (23.6 versus 17.5; P = 0.001). Although the MVD in animals treated with TAE using 1 mg of PVA was higher than that in the control group, this difference was not statistically significant. TAE using 2 mg of PVA resulted in a significant increase in tumor MVD (25.9 versus 17.5; P = 0.007). Use of 3 mg of PVA did not result in any further increase in MVD. There was a significant increase in tumor MVD in the animals killed 2 or 3 days after TAE compared with the control group (24.5 versus 17.5; P = 0.002). The animals treated with TAE showed a statistically significant increase in VEGF levels compared with the control group. CONCLUSIONS: TAE of hepatic tumors results in the stimulation of angiogenesis in the residual viable tumor, which could have an adverse effect on the therapeutic efficacy of TAE.

Incidental pulmonary emboli in oncology patients: prevalence, CT evaluation, and natural history.

PURPOSE: To retrospectively determine the prevalence and natural history of incidental pulmonary emboli in oncology patients, the number of such cases reported at initial thoracic computed tomographic (CT) image interpretation, and the factors that contribute to underdiagnosis. MATERIALS AND METHODS: Institutional review board approval, which included HIPAA-compliant access to protected health information and waived patient consent requirements, was obtained for this retrospective study. Four hundred three consecutive oncology patients (199 male, 204 female; age range, 14-87 years; mean age, 55 years) in whom adequate-quality multidetector thoracic CT was performed within a 10-day period for indications other than pulmonary emboli assessment were identified. There were 31 (7.7%) inpatients at the time of imaging. Each imaging case was reviewed by two independent radiologists, and all pulmonary emboli were confirmed by a panel of three thoracic radiologists. Clinical charts were reviewed for demographic data, embolus detection, and outcomes up to 2 years after the initial examination. Patient groups were compared by using chi2 and one-sided binomial tests. RESULTS: Sixteen (4.0%) of the 403 patients had pulmonary emboli. The highest prevalences were in patients with gynecologic malignancies (two of 13, 15%) and in those with melanoma (four of 41, 10%). Four (25%) of the 16 patients with emboli were identified at initial clinical CT image interpretation, and all had multiple emboli involving at least the lobar arteries. Missed emboli typically were solitary and involved smaller arteries; no other confounding factors were identified. Six (60%) of 10 patients with emboli who underwent any lower extremity imaging had deep vein thrombosis. With the exception of one patient, who was transferred back to the referring physician and lost to follow-up, all patients with reported pulmonary emboli were treated. Two patients had subsequent embolic events: one death despite treatment and one recurrent embolus in a nontreated patient. CONCLUSION: Incidental pulmonary emboli were seen in 16 (4%) oncology patients but were initially reported in only four of them. The small size of involved arteries contributes to the failed detection at initial CT image interpretation, and patients with emboli in these small vessels may have deep vein thrombosis or recurrent emboli.

Tumor iNOS predicts poor survival for stage III melanoma patients.

Inducible nitric oxide synthase (iNOS) produces nitric oxide, which has growth promoting activity in melanoma. A preliminary study of tumors from patients with Stage III melanoma who had received neo-adjuvant therapy revealed an association of tumor iNOS expression with shortened survival. The objective of the present study was to determine whether iNOS expression in tumors of newly diagnosed, untreated Stage III patients is predictive of survival. iNOS expression was examined by immunohistochemistry in tumors from 132 patients. The staining was evaluated for percentage of positive cells (Number score) and the intensity of staining (Intensity score). The association of iNOS expression with overall and disease-specific survival was tested in univariate and multivariate Cox proportional hazards regression models that included other known prognostic factors. Results of the univariate analysis demonstrated that the presence of iNOS in a patient's tumor, whether graded on the basis of Number or Intensity score, was associated with a significant increase in the hazard ratio of death from melanoma. These findings were corroborated by median survival data estimated from Kaplan Meier analysis. In the multivariate model including iNOS number or intensity, gender, age, number of lymph nodes, macroscopic disease and in-transit disease, only iNOS expression predicted survival. We conclude that a significant association exists between tumor iNOS expression and shortened survival in untreated Stage III melanoma patients. The ability of iNOS to predict outcomes for these patients may be independent of other known prognostic factors, providing a new molecular marker with significant potential for clinical utility.

Integrated computed tomography-positron emission tomography in patients with potentially resectable malignant pleural mesothelioma: Staging implications.

BACKGROUND: Integrated computed tomography-positron emission tomography imaging with coregistration of anatomic and functional imaging data may improve the accuracy of malignant pleural mesothelioma staging. We evaluate the use of integrated computed tomography-positron emission tomography in patients with malignant pleural mesothelioma who are being considered for extrapleural pneumonectomy. METHODS: Twenty-nine patients with malignant pleural mesothelioma who were judged to be candidates for extrapleural pneumonectomy after clinical and conventional radiologic evaluation underwent whole-body integrated computed tomography-positron emission tomography and pathologic staging. Two reviewers blinded to the results of clinical and pathologic staging retrospectively evaluated computed tomography, positron emission tomography, and coregistered computed tomography-positron emission tomography images. Staging was performed according to the International Mesothelioma Interest Group TNM staging system. Histopathology and/or results of further radiologic evaluation or follow-up served as the reference standard. RESULTS: Integrated computed tomography-positron emission tomography provided additional information in 11 of 29 patients that precluded extrapleural pneumonectomy. The overall tumor stage was correctly classified in 21 of 29 patients. The tumor stage was correctly determined in 15 of 24 patients, 6 of whom had T4 (nonresectable) disease. The node stage was accurately determined in 6 of 17 patients. Extrathoracic metastases not identified by routine clinical and conventional radiologic evaluation were detected in 7 of 29 patients and were found to be diffuse (n = 2) or solitary (n = 5). CONCLUSIONS: Integrated computed tomography-positron emission tomography increases the accuracy of malignant pleural mesothelioma staging and is important in determining the appropriate therapy in patients being considered for extrapleural pneumonectomy.

The value of 99mTc-sestamibi SPECT/CT over conventional SPECT in the evaluation of parathyroid adenomas or hyperplasia.

UNLABELLED: As SPECT/CT technology evolves, its applications and indications need to be evaluated clinically for more efficient and cost-effective use. This retrospective study evaluated the clinical value of simultaneously acquired (99m)Tc-sestamibi SPECT/CT versus conventional SPECT in diagnosing and locating parathyroid adenomas or hyperplasia in patients with primary hyperparathyroidism. METHODS: Immediately and 60 minutes after intravenous administration of 740-925 MBq of (99m)Tc-sestamibi, static planar images of the neck and chest were obtained. SPECT/CT images were acquired 30 minutes after injection. Two experienced masked readers independently evaluated whether conventional SPECT images provided information beyond what was available from the planar images either by changing the diagnosis or by better locating the glands and whether the SPECT/CT images provided information beyond what was available from the planar plus conventional SPECT images. Forty-eight consecutive patients with a clinical diagnosis of primary hyperparathyroidism were included in the study. The 32 whose scans showed positive results underwent surgical resection and were examined histopathologically. RESULTS: Planar and SPECT imaging, with or without CT fusion, identified 89% of the surgically confirmed diseased parathyroid glands. Use of SPECT/CT changed the diagnosis in only 1 patient (2%) from positive to negative and better located the glands in only 4 patients (8%). SPECT/CT was particularly helpful in locating the 2 ectopic parathyroid adenomas diagnosed in this cohort. Tracer retention in diseased glands did not correlate with histologic characteristics. Also, biochemical markers did not correlate with the scan findings. CONCLUSION: SPECT/CT has no significant clinical value additional to that of conventional SPECT for parathyroid imaging except in locating ectopic parathyroid glands. Eliminating the CT acquisition will spare patients the additional time, radiation exposure, and expense.

Small (

PURPOSE: To retrospectively compare the diagnostic yield and complications associated with the use of short versus long needle paths for computed tomography (CT)-guided biopsy of small subpleural lung lesions. MATERIALS AND METHODS: The study was approved by the institutional review board, and the requirement for informed patient consent was waived. The medical and imaging records of patients who underwent CT-guided biopsy of subpleural pulmonary nodules measuring up to 2 cm in diameter were reviewed. The study included 176 patients (79 men, 97 women; age range, 18-84 years) who were divided into two groups: In group A, a direct approach in which the needle traversed a short lung segment was used. In group B, an indirect approach involving the use of a longer needle path was used. Diagnostic yield, accuracy, and pneumothorax and chest tube placement rates were compared between the two groups. Two-tailed t tests and Pearson chi(2) tests were used to analyze continuous and categorized variables, respectively. RESULTS: Group A comprised 48 patients; and group B, 128 patients. The mean needle path length was 0.4 cm in group A and 5.6 cm in group B. The short-path approach necessitated more needle punctures (mean, 2.9 vs 1.8 with long-path approach, P < .001) through the pleura. The diagnostic yield in group A was significantly lower than that in group B (71% vs 94%, P < .001), particularly in patients with small (0-1-cm) nodules (40% in group A vs 94% in group B, P < .001). The frequency of postbiopsy pneumothorax was identical (69%) in the two groups. However, more group B than group A patients required chest tube placement for treatment of pneumothorax (38% vs 17%, P = .006). CONCLUSION: Use of long-needle-path biopsy of subpleural lesions resulted in a higher diagnostic yield, especially for small nodules. However, compared with the short-needle-path technique, this approach was associated with a higher frequency of chest tube placement for pneumothorax.

Radiation dosimetry of 99mTc-labeled C225 in patients with squamous cell carcinoma of the head and neck.

UNLABELLED: This study assessed the radiation dosimetry of 99mTc-labeled ethylene dicysteine (EC) C225 (EC-C225), a promising radioligand for functional tumor imaging. METHODS: Whole-body scanning was performed on 6 patients with head and neck squamous cell carcinoma up to 24 h after administration of 99mTc-EC-C225. Alternate patients who had been randomized to receive C225 in a phase III trial received 99mTc-EC-C225 before their 20-mg test dose or after their 400 mg/m2 loading dose of unlabeled C225 (patients 1/3/5 and 2/4/6, respectively). Radiation dosimetry was assessed using the MIRD method. RESULTS: The critical organ was the kidney, with an average radiation-absorbed dose for all 6 patients of 0.0274 mGy/MBq. The average total-body absorbed dose was 0.0022 mGy/MBq (0.243 cGy/1,110 MBq). CONCLUSION: The new radiopharmaceutical 99mTc-EC-C225 appears to have reasonable dosimetric properties for a diagnostic nuclear medicine agent. Correlation of the imaging results with clinical findings is the next step.

NHERF (Na+/H+ exchanger regulatory factor) gene mutations in human breast cancer.

Yeast two-hybrid screening was used to explore novel proteins that interact with a breast tumor or metastasis suppressor, SYK (spleen tyrosine kinase). The screening yielded NHERF (Na+/H+ exchanger regulatory factor, also known as NHERF1 or EBP-50) that binds to the interdomain B of SYK. NHERF is an estrogen-responsive gene that encodes an inhibitory factor for epithelial Na+/H+ exchanger isoform 3 (NHE3). We found intragenic mutation of the NHERF gene accompanied by loss of heterzygosity (LOH) in approximately 3% (3/85) of breast cancer cell lines and primary breast tumors. Mutations occurred at the conserved PDZ domains at NHERF NH2-terminus that bound to SYK, or at its COOH-terminus motif that binds to MERLIN, the product of Neurofibromatosis 2 (NF2) tumor suppressor gene. NHERF tumorigenic mutations decreased or abolished its interaction with SYK or MERLIN, suggesting a pathway link among these three molecules that may play a critical role in mammary neoplastic progression. Primary breast tumors with LOH at the NHERF locus had clinical presentations of higher aggressiveness, indicating that deregulated NHERF signaling may be associated with disease progression. Moreover, the LOH was inversely correlated with SYK promoter methylation, suggesting that NHERF and SYK may transduce a common suppressive signal. Taken together, the results indicated NHERF to be a candidate tumor suppressor gene in human breast carcinoma that may be interconnected to the SYK and MERLIN suppressors.

Biochemotherapy in patients with metastatic anorectal mucosal melanoma.

BACKGROUND: Patients with metastatic anorectal melanoma generally have an unfavorable prognosis, but no effective systemic therapy has been reported. METHODS: The authors retrospectively evaluated the medical records of all patients with metastatic anorectal melanoma treated with biochemotherapy between January 1991 and December 2001 at the University of Texas M. D. Anderson Cancer Center (Houston, TX). RESULTS: The search yielded 18 patients. Of these patients, 14 had undergone treatment with cisplatin (CDDP), vinblastine (VB), dacarbazine (DTIC), interferon alpha-2b (IFN), and interleukin 2 (IL-2); 2 had undergone treatment with CDDP, VB, DTIC, and IFN; 1 had undergone treatment with CDDP, IFN, and IL-2; and 1 had undergone treatment with CDDP, VB, temozolomide, IFN, and IL-2. All IL-2 treatments were administered intravenously. The median follow-up time was 12.2 months (range, 3.5-43.7 months). Eight patients (44%) had major responses, including two (11%) complete responses (CRs). Three patients were lost to follow-up evaluation after the completion of treatment. The median time to progression among the 15 remaining patients was 6.2 months. Four patients, including 1 with a CR, were alive at their last documented follow-up visits (survival: 14.0, 20.7, 31.3, and 43.7 months, respectively). The median overall survival was 12.2 months. Among 13 patients who received biochemotherapy as first-line systemic therapy, 6 patients (46%) had major responses, including two (15%) CRs. The median time to progression for this group was 6.2 months, and the median overall survival was 12.9 months. CONCLUSIONS: Biochemotherapy had substantial activity against metastatic anorectal melanoma and should be considered for use in the treatment of metastatic disease from primary anorectal melanoma.

Cyclooxygenase-2 is essential for HER2/neu to suppress N- (4-hydroxyphenyl)retinamide apoptotic effects in breast cancer cells.

We reported that HER2/neu reduces the sensitivity of breast cancer cells to N-(4-hydroxyphenyl)retinamide (4-HPR) by suppressing nitric oxide production. We show that HER2/neu uses Akt to induce cyclooxygenase-2 (COX-2) expression and that inhibition of Akt or COX-2 increases 4-HPR-induced apoptosis and nitric oxide production. Apoptosis induced by the 4-HPR and COX-2 inhibitor combination, although unaffected by an anti-HER2/neu antibody, was reversed by the COX-2 product prostaglandin E(2), indicating that COX-2 is a major mechanism by which HER2/neu suppresses 4-HPR apoptosis in breast cancer cells. Combining 4-HPR with COX-2 inhibitors may be a novel chemopreventive strategy against HER2/neu-overexpressing breast tumors.

Detection of small pancreatic tumors with multiphasic helical CT.

OBJECTIVE: The purpose of this study was to evaluate the sensitivity and specificity of helical CT in the detection of adenocarcinomas of the pancreas measuring 2 cm or smaller at pathologic examination. MATERIALS AND METHODS: Thin-section triple phase (20, 40, and 70 sec after the start of injection) contrast-enhanced helical CT scans of the abdomen in 18 patients with a pancreatic carcinoma that was 2 cm or smaller and 18 patients with a normal pancreas were retrospectively reviewed by two senior radiologists who specialized in oncologic abdominal imaging. Discrepancies were resolved by consensus. The observers were unaware of the clinical information. CT scans were evaluated for the presence of a pancreatic mass, bile, and pancreatic duct stricture. The location and size of tumors as determined on CT were compared with pathologic findings. The CT results were also compared with the prospective CT interpretations derived from the radiology reports and with the endoscopic sonographic reports when available. RESULTS: The sensitivity of thin-section triple-phase helical CT in the detection of small pancreatic masses was 77%, and the specificity was 100% for the two experienced observers. The sensitivity and specificity were 72% and 100%, respectively, for the prospective interpretations done by 10 observers. There was no correlation between the tumor size at pathology and the CT measurements. CONCLUSION: Thin-section contrast-enhanced helical CT is sensitive and highly specific for the detection of pancreatic tumors measuring 2 cm or smaller. Improvement in the detection rate of this technique compared with previous techniques lies in the optimization of parenchymal enhancement during the pancreatic phase and the decrease in slice thickness.

Importance of predosing of recombinant human thrombopoietin to reduce chemotherapy-induced early thrombocytopenia.

PURPOSE: Recombinant human thrombopoietin (rhTPO) increases platelets, and the peak response of rhTPO is delayed and is, therefore, not uniformly effective when administered after chemotherapy. The purpose of this study was to identify an effective schedule of rhTPO to best attenuate early thrombocytopenia. PATIENTS AND METHODS: Cohorts of six patients with sarcoma (66 assessable patients) were treated sequentially with doxorubicin and ifosfamide (AI), with rhTPO by a fixed dose and varying schedules being administered before and/or after chemotherapy in cycle 2 and subsequent cycles. Cycle 1 without rhTPO served as an internal control. RESULTS: AI causes cumulative thrombocytopenia. The platelet nadir in cycle 2 was higher than in cycle 1 (mean nadir +/- SEM, 119 +/- 12 x 10(3)/microL v 80 +/- 7 x 10(3)/microL, respectively; P <.001) in 24 (80%) of the 30 patients (P <.001) in whom rhTPO (1.2 microg/kg) was administered starting from 5 days before chemotherapy (pre/postdoses, three/one or one/one) compared with only four (17%) of 24 patients given rhTPO by other schedules (pre/postdoses, two/two, one/three, zero/four, or four/zero) and none of 15 historical control patients. The need for platelet transfusions in four cycles was significantly lower (13 [11%] of 114 cycles, P <.001) in patients who received rhTPO from day -5 (pre/post doses, three/one or one/one) compared with patients who received rhTPO at later time points (28 [47%] of 60 cycles). Bone marrow megakaryocytes increased markedly (four-fold) before chemotherapy with predosing rhTPO and remained elevated (two-fold) after chemotherapy, which may explain the possible mechanism for response. One patient developed subclavian vein thrombosis, and no patients developed neutralizing antibodies to rhTPO. CONCLUSION: These results demonstrate the importance of timing of rhTPO in relation to chemotherapy and indicate that, by optimizing the timing, only two doses of rhTPO (one before and one after chemotherapy) were required to significantly reduce the severity of chemotherapy-related early thrombocytopenia.

Method for efficient fast spin echo Dixon imaging.

In order to satisfy the Carr-Purcell-Meiboom-Gill (CPMG) condition, echo shift as dictated in fast-spin-echo (FSE)-based Dixon imaging was previously achieved by applying a time shift to the readout gradient and the data acquisition window. Accordingly, interecho spacing is increased, which entails increased image blurring and, in multislice imaging, a significant reduction in the slice coverage for a given imaging time. In this work, a new method is developed by which the echo shift is induced by "sandwiching" in time the readout gradient with a pair of small gradients of equal area and of opposite polarity. While data with non-zero phase shifts between water and fat signals are collected as fractional echoes, no increase in echo spacing is necessary with the modified acquisition strategy, and increased time efficiency is therefore achieved. In order to generate separate water-only and fat-only images in data processing, a set of low-resolution images are first reconstructed from the central symmetric portion (either 128 x 128 or 64 x 64) of the acquired multipoint Dixon data. High-resolution images using all the acquired data, including some partial Fourier-reconstructed images, are then phase demodulated using the phase errors determined from the low-resolution images. The feasibility of the technique is demonstrated using a water and fat phantom as well as in clinical patient imaging.

CT-guided percutaneous fine-needle aspiration biopsy of small (< or =1-cm) pulmonary lesions.

PURPOSE: To determine the accuracy of percutaneous computed tomography (CT)-guided fine-needle aspiration biopsy (FNAB) of small (< or =1.0-cm in diameter) pulmonary lesions. MATERIALS AND METHODS: Sixty-one patients (34 men and 27 women) 21-89 years old (mean age, 61.3 years) with lung nodules 1.0 cm or smaller underwent CT-guided transthoracic FNAB. Fifty-seven of the 61 patients had an underlying primary malignancy. Maximum nodule diameters were 0.5-0.7 cm in 10 patients and 0.8-1.0 cm in 51 patients. Cytopathologic evaluation of FNAB samples was immediate in all patients. Sensitivity and accuracy were calculated, and each case was reviewed for complications, including pneumothorax and thoracostomy tube insertion. Four patients were not included in our statistical analysis because of a lack of follow-up information. RESULTS: FNAB samples were adequate for diagnosis in 47 (77%) of 61 patients. Diagnoses were malignancy (n = 29) or suspected malignancy (n = 3) in 52% (n = 32) and benign or atypical findings in 25% (n = 15). Findings were nondiagnostic in 23% (n = 14). Of the 29 patients without evidence of malignancy, 25 had follow-up findings available. Follow-up included chest CT in 16 patients and surgical resection in nine. Four patients were not included in statistical analysis because of a lack of follow-up information. Overall sensitivity was 82% (32 of 39); specificity, 100% (18 of 18); and diagnostic accuracy, 88% (50 of 57) on the basis of 57 patients being evaluable. Results for 47 0.8-1.0-cm lesions were considerably better (sensitivity, 88%; accuracy, 92%) than those for 10 0.5-0.7-cm lesions (sensitivity, 50%; accuracy, 70%). Sensitivity (75% vs 87%) and accuracy (87% vs 89%) also improved when comparing subpleural (< or =1.0 cm from pleural surface, n = 30) with deeper (>1 cm from pleural surface, n = 27) pulmonary lesions, but the improvement did not indicate statistical significance. Core biopsy did not reveal malignancy in any of the nine patients in whom preliminary cytologic results were inconclusive and did not improve diagnostic yield. Thirty-eight (62%) patients had pneumothorax, with 19 (31%) requiring thoracostomy tube placement. CONCLUSION: CT-guided FNAB of pulmonary lesions 1.0 cm or smaller can yield high diagnostic accuracy rates approaching those of larger lesions; FNAB of 0.8-1.0-cm lesions that are not subpleural offers the best opportunity for success.

A novel mechanism by which N-(4-hydroxyphenyl)retinamide inhibits breast cancer cell growth: the production of nitric oxide.

N-(4-Hydroxyphenyl)retinamide (4-HPR) induces apoptosis in breast cancer cells; however, the molecular basis by which 4-HPR induces apoptosis is not well understood. In breast cancer cells, nitric oxide (NO) is predominantly an apoptotic inducer. Apoptotic agents, such as phorbol ester, tumor necrosis factor-alpha, and peptide hormones, have been shown to increase NO production in breast cancer cells. Therefore, we hypothesized that the production of No is vital for 4-HPR to induce apoptosis in breast cancer cells. We found that 4-HPR induced NO production in a dose-dependent manner in all of the breast cancer cell lines tested. The degree of growth inhibition and apoptotic induction by 4-HPR was directly correlated with the amount of NO produced. To prove that NO is essential for 4-HPR to induce apoptosis, breast cancer cells were coincubated with a competitive NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA), and 4-HPR, L-NMMA prevented 4-HPR from inducing inhibitory effects, indicating that NO is crucial for 4-HPR to induce its apoptotic effects in breast cancer cells. IFNs and tamoxifen (TAM) have been shown to potentiate 4-HPR effects in breast cancer cells. Both IFN-gamma and TAM enhanced the ability of 4-HPR to induce NO production in breast cancer cells, which was correlated with increased apoptosis. Alone, 4-HPR increased expression of both inducible NOS (NOSII) and endothelial NOS (NOSIII). When combined with 4-HPR, IFN-gamma and TAM enhanced NOSII expression. Thus, we have identified a novel mechanism by which 4-HPR induces apoptosis in breast cancer cells, i.e., by increasing NOS expression to induce NO production.