Preoperative risk stratification using gated myocardial perfusion studies in patients with cancer.

UNLABELLED: Cancer patients frequently have anemia or an altered coagulation state that may affect their risk stratification for perioperative cardiac events. We performed this study to investigate the incidence of perioperative cardiac events in cancer patients who had abnormal stress myocardial perfusion imaging (MPI) results versus cancer patients with normal MPI results. METHODS: We included 394 consecutive cancer patients with normal (n = 201) or abnormal (n = 193) results on MPI studies performed for preoperative risk stratification. MPI was performed within 6 mo before each patient's scheduled operation. All the patients had surgical procedures requiring general anesthesia, except for 18 who had endoscopic or colonoscopic procedures. We retrospectively reviewed their data for the incidence of major cardiac events intraoperatively and for 1 mo postoperatively. We collected data on their cancer type, risk factors for coronary artery disease, MPI findings, risk of operation, and intraoperative or postoperative major cardiac events, which included death, myocardial infarction (MI), and congestive heart failure (CHF). RESULTS: The patients with abnormal MPI results included 97 with ischemia, 80 with scarring, and 16 with mixed scarring and ischemia. The mean left ventricular ejection fraction and end-diastolic volume were 63.8% +/- 9.8% and 82.0 +/- 53.5 mL in the normal MPI group versus 52.1% +/- 13.1% and 118.1 +/- 53.4 mL in the abnormal-MPI group (P < 0.001). There were 9 major intraoperative or postoperative cardiac events (4.7%) in the patients with abnormal MPI results and none in the patients with normal MPI results (P = 0.001). These major events consisted of 3 deaths, 2 acute MIs, 1 non-Q-wave MI, and 3 cases of CHF. Four of these patients had only scarring on their MPI studies, 3 had ischemia, and 2 had scarring and ischemia. CONCLUSION: Normal MPI results have a high negative predictive value for perioperative cardiac events in cancer patients. Abnormal MPI results, whether demonstrating scarring or ischemia, should prompt appropriate perioperative management in patients with cancer to minimize major cardiac events.

Novel in vivo imaging shows up-regulation of death receptors by paclitaxel and correlates with enhanced antitumor effects of receptor agonist antibodies.

Susceptibility to apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is mediated through cognate death receptor signaling. We hypothesized that auto-amplification of this apparatus would enhance antitumor effects in vivo and could be optimized using the results obtained from novel imaging techniques. We therefore imaged mice bearing human colorectal cancer (Colo205) tumor xenografts with HGS-ETR1 and HGS-ETR2 agonist antibodies to TRAIL receptor-1 (TRAIL-R1) and TRAIL-R2, respectively, after radiolabeling the antibodies. Paclitaxel significantly increased in vivo expression of TRAIL-R1 and TRAIL-R2 in a time-dependent manner. The imaging results were confirmed by immunoblots for steady-state protein levels (>20-fold increase in TRAIL-R1 and TRAIL-R2 levels in tumor xenografts by 48 h after paclitaxel administration). TRAIL-R1 and TRAIL-R2 mRNA expression did not change, suggesting that these effects were posttranscriptional. Sequential treatment with paclitaxel followed by HGS-ETR1 or HGS-ETR2 after 48 h resulted in markedly enhanced antitumor activity against Colo205 mouse xenografts. Our experiments suggest that sequential taxane treatment followed by TRAIL-R agonist antibodies could be applied in the clinic, and that novel imaging techniques using radiolabeled receptor antibodies may be exploitable to optimize sequence timing and patient selection.

The prevalence of myocardial ischemia after concurrent chemoradiation therapy as detected by gated myocardial perfusion imaging in patients with esophageal cancer.

UNLABELLED: The detection of myocardial perfusion abnormalities after radiation therapy (RT) has been investigated previously in patients with lymphoma and breast cancer. However, the prevalence and association of such abnormalities with RT in esophageal cancer patients have not been investigated previously. METHODS: The prevalence of myocardial perfusion abnormalities detected using gated myocardial perfusion imaging (GMPI) in patients with esophageal cancer after RT (RT group) was compared with that in patients with esophageal cancer who did not undergo RT (NRT group). The patients' data were extracted from a prospectively collected database. The results of GMPI that were read by multiple readers were tested further by an expert reader who was unaware of the patients' clinical information. This reader's findings were correlated with the different RT isodose lines as seen in the CT for RT planning. Isodose lines containing the affected segments in GMPI as well as the rest of the left ventricle were recorded. Additionally, information with regard to the mean radiation dose to the heart for each patient was collected. An overall, mean radiation dose to the heart in patients with abnormal GMPI studies was compared with that in patients with normal GMPI studies. RESULTS: Fifty-one patients were included, 26 in the RT group and 25 in the NRT group. The mean and median interval between RT and GMPI was 7.5 and 3.0 mo, respectively. We identified myocardial perfusion defects in 14 patients (54%) in the RT group and in 4 patients (16%) in the NRT group. Eleven patients (42%) in the RT group had mild inferior wall ischemia versus only 1 patient (4%) in the NRT group (P = 0.001). All of the patients with inferior wall ischemia had distal esophageal cancer. The remaining 12 patients in the RT group and 21 patients in the NRT group had normal GMPI results. The mean left ventricular ejection fraction was 59.0% +/- 10.7% in the RT group and 59.3% +/- 9.8% in the NRT group (P = not significant). Good agreement was found between the GMPI results interpreted by multiple readers and those of the single expert reader (kappa = 0.84). In 7 of 10 patients (70%) who had abnormal GMPI results in the RT group, the myocardial perfusion defect was encompassed in RT isodose lines >/= 45 Gy, whereas in only 5 of 20 patients (25%) the normal left ventricle was included in the RT isodose line >/= 45 Gy. CONCLUSION: RT is associated with a high prevalence of inferior left ventricular ischemia, as detected using GMPI in patients with distal esophageal cancer. Most perfusion defects are encompassed within an isodose line >/= 45 Gy in the RT plan.

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.

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.

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.

HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production.

The retinoid N-(4-hydroxyphenyl)retinamide (4-HPR also known as fenretinide) is a potent inducer of apoptosis in breast cancer cells. We observed a 4.5-fold reduction in 4-HPR-mediated apoptosis in MCF-7 breast cancer cells transfected with HER2/neu (MCF-7/HER2) as compared with the parental MCF-7 (MCF-7/WT) cells. Blocking HER2/neu with trastuzumab (Herceptin) led to a six-fold increase in 4-HPR-induced apoptosis in HER2/neu-overexpressing cells. These data indicate that HER2/neu reduces the sensitivity of breast cancer cells to 4-HPR. We showed previously that nitric oxide (NO) is essential for 4-HPR to induce apoptosis in breast cancer cells. The inhibitory effects of the 4-HPR and trastuzumab combination correlated with the amount of NO produced in HER2/neu-overexpressing cells. When a NO synthase (NOS) inhibitor was used to block NO production, decreased apoptosis by the 4-HPR and trastuzumab combination was observed. Furthermore, 4-HPR-mediated NOSII expression was lower in MCF-7/HER2 than MCF-7/WT cells, but was increased by trastuzumab in HER2/neu-overexpressing cells. Here we report the novel findings that HER2/neu reduces the ability of 4-HPR to induce apoptosis in breast cancer cells, and that one mechanism by which HER2/neu increases the resistance of breast cancer cells to 4-HPR is by decreasing NOSII-mediated NO production.

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.

Loss of MDA-7 expression with progression of melanoma.

PURPOSE: Ectopic transfer of the melanoma differentiation-associated gene-7 (mda-7) has been shown in vitro to suppress growth and induce apoptosis in a variety of human tumor cell lines; similar effects are not elicited in normal cells. Thus, the mda-7 gene seems to function as a novel tumor suppressor, and there is interest in the potential of mda-7 gene transfer as cancer therapy. The objective of this study was to determine if MDA-7 protein is lost during primary melanoma progression from superficial to invasive stages and from localized to metastatic tumor. As a secondary objective, we analyzed MDA-7 protein expression in primary melanomas for correlation with predictors of outcome and with survival. MATERIALS AND METHODS: MDA-7 protein expression was evaluated by immunohistochemistry in 41 primary melanomas and 41 metastases, including 24 paired samples. Each sample was scored for the percentage of positive cells and the overall intensity of immunolabeling. RESULTS: Significant decreases in MDA-7 immunostaining, reflected in both number and intensity scores, were observed when comparing the intraepidermal and superficially invasive portions with the deeply invasive portions of primary tumors. Significant differences were also observed when comparing primary tumors to paired metastases. CONCLUSION: Downregulation of MDA-7 expression in primary melanomas facilitates progression to invasive and metastatic stages. These data support the development of Ad-mda7 as gene therapy for advanced melanoma.

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.

Interobserver and intraobserver variability in measurement of non-small-cell carcinoma lung lesions: implications for assessment of tumor response.

PURPOSE: Response of solid malignancies to therapy is usually determined by serial measurements of tumor size. The purpose of our study was to assess the consistency of measurements performed by readers evaluating lung tumors. MATERIALS AND METHODS: The study group was composed of 33 patients with lung tumors more than 1.5 cm. Bidimensional (BD) and unidimensional (UD) measurements were performed on computed tomography (CT) scans according to the World Health Organization (WHO) criteria and the Response Evaluation Criteria in Solid Tumors (RECIST), respectively. Measurements were performed independently by five thoracic radiologists using printed film and were repeated after 5 to 7 days. Inter- and intraobserver measurement variations were estimated through statistical modeling. RESULTS: There were 40 tumors with an average size of 1.8 to 8.0 cm (mean, 4.1 cm). Analysis of variance showed a significant difference (P <.05) among readers and among the measured nodules for UD and BD measurements. Interobserver misclassification rates were more than intraobserver misclassification rates using either progressive disease or response criteria. The probability of misclassifying a tumor with the WHO criteria or RECIST was greatest with interobserver measurements when criteria for progression (43% BD, 30% UD) were used and lowest with intraobserver measurements when criteria for response (2.5% BD, 3.0% UD) were used. In addition, interobserver misclassification rates were more than intraobserver misclassification rates for both regular and irregular tumors. CONCLUSION: Measurements of lung tumor size on CT scans are often inconsistent and can lead to an incorrect interpretation of tumor response. Consistency can be improved if the same reader performs serial measurements for any one patient.

Clinical factors associated with cancer-related fatigue in patients being treated for leukemia and non-Hodgkin's lymphoma.

PURPOSE: To describe fatigue severity, fatigue interference, and associated factors in hematologic malignancies. PATIENTS AND METHODS: Patients being treated for leukemia and non-Hodgkin's lymphoma (n = 228) completed the Brief Fatigue Inventory to rate fatigue severity and functional interference caused by fatigue. Data on patient demographics, Eastern Cooperative Oncology Group performance status, other physical symptoms, current treatments, and laboratory values were also collected. Descriptive statistics, bivariate correlation, and logistic regression were used for data analysis. RESULTS: Fifty percent of the sample reported severe fatigue, which was defined as a "fatigue worst" rating of 7 or greater. More patients with acute leukemia (61%) reported severe fatigue compared with those with chronic leukemia (47%) and non-Hodgkin's lymphoma (46%). Increased fatigue severity significantly compromised patients' general activity, work, enjoyment of life, mood, walking, and relationships with others. Fatigue severity was strongly associated with performance status, use of opioids, blood transfusions, gastrointestinal symptoms, and sleep disturbance items, as well as with low serum hemoglobin and albumin levels. Regression analysis indicated that nausea was the significant clinical predictor of severe fatigue (odds ratio, 13), and low serum albumin was the significant laboratory value predictor (odds ratio, 3.8). CONCLUSION: Disabling fatigue occurs with high frequency in hematologic malignancy, supporting a need to develop better methods of fatigue management. Better control of gastrointestinal and other symptoms may be of benefit. The mechanism and relationship between low albumin and severe fatigue needs to be investigated further, and longitudinal studies of the effects of treatment, host factors, and other symptoms are needed.

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.

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.

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.

Negative association of melanoma differentiation-associated gene (mda-7) and inducible nitric oxide synthase (iNOS) in human melanoma: MDA-7 regulates iNOS expression in melanoma cells.

The melanoma differentiation association gene-7 (mda-7) is a novel tumor suppressor gene of which the protein expression decreases to nearly undetectable levels in metastatic melanoma. In contrast, expression of inducible nitric oxide synthase (iNOS) is increased in advanced stages of melanoma, and iNOS expression has been proposed as a potential prognostic marker in this disease. Thus, expression of these molecules in the same tumor appears to exhibit reciprocal characteristics. We hypothesize that the relative ratios of these melanoma progression molecules may define either tumor progression or tumor suppression in human melanoma. The first goal of this study was to determine whether MDA-7 expression in melanoma negatively correlates with iNOS expression. The second goal was to determine whether iNOS expression could be regulated by MDA-7 expression in melanoma cells. Expression of MDA-7 and iNOS proteins were evaluated by immunohistochemistry in a total of 81 tumor samples: 38 primary melanomas and 43 metastatic melanomas. Evaluation of these melanoma patient samples showed that expression of MDA-7 and iNOS exhibits a significant negative correlation (P = 0.03). In vitro studies revealed that iNOS expression in melanoma cell lines is lost in a dose-dependent fashion after treatment with an adenoviral vector encoding the mda-7 gene (Ad-mda7) or with rhMDA-7 protein, demonstrating that MDA-7 down-regulates iNOS expression. Furthermore, we demonstrate that the STAT-3-modulated expression of IFN regulatory factors 1 and 2 is regulated by MDA-7, which may alter iNOS gene expression. These studies demonstrate that expression of the MDA-7 tumor suppressor can negatively regulate iNOS expression in malignant melanoma cell lines.

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.

High prevalence of hypothyroidism among patients with cutaneous melanoma.

We have previously reported a high prevalence of hypothyroidism among patients with uveal melanoma. The objectives of the present study were to determine if a similar pattern of thyroid pathology exists among patients with cutaneous melanoma as well. To address this question, the medical records of all patients registered at the University of Texas M.D. Anderson Cancer Center with a diagnosis of cutaneous melanoma during the years 1997 and 1998 were examined for a history of overt hypothyroidism, defined as a requirement for thyroid hormone replacement. Data regarding stage and site of the primary tumor were obtained for these patients and for age/gender matched euthyroid controls from the same melanoma study population. Among 1,580 cutaneous melanoma patients (948 M/632 F), 111 (7.0%) gave a history of hypothyroidism [23/948 M (2.4%) and 88/632 F (13.9%)]. The prevalences of hypothyroidism for both males and females were significantly higher than those reported for the general population. Characteristics of the primary tumor did not differ between cases and controls, although there was a trend for a lower rate of primary tumor ulceration among the hypothyroid case subjects. We conclude that hypothyroidism of varied etiologies is common among patients with cutaneous melanoma. These data suggest that melanoma may be responsive to hormones of the thyroid hormone control loop, raising many questions of clinical and biologic importance.

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.