In vivo monitoring of pH, redox status, and glutathione using L-band EPR for assessment of therapeutic effectiveness in solid tumors

Approach for in vivo real-time assessment of tumor tissue extracellular pH (pH(e)), redox, and intracellular glutathione based on L-band EPR spectroscopy using dual function pH and redox nitroxide probe and disulfide nitroxide biradical, is described. These parameters were monitored in PyMT mice bearing breast cancer tumors during treatment with granulocyte macrophage colony-stimulating factor. It was observed that tumor pH(e) is about 0.4 pH units lower than that in normal mammary gland tissue. Treatment with granulocyte macrophage colony-stimulating factor decreased the value of pH(e) by 0.3 units compared with PBS control treatment. Tumor tissue reducing capacity and intracellular glutathione were elevated compared with normal mammary gland tissue. Granulocyte macrophage colony-stimulating factor treatment resulted in a decrease of the tumor tissue reducing capacity and intracellular glutathione content. In addition to spectroscopic studies, pH(e) mapping was performed using recently proposed variable frequency proton-electron double-resonance imaging. The pH mapping superimposed with MRI image supports probe localization in mammary gland/tumor tissue, shows high heterogeneity of tumor tissue pH(e) and a difference of about 0.4 pH units between average pH(e) values in tumor and normal mammary gland. In summary, the developed multifunctional approach allows for in vivo, noninvasive pH(e), extracellular redox, and intracellular glutathione content monitoring during investigation of various therapeutic strategies for solid tumors.     

Biliary malignancy: value of arterial, pancreatic, and hepatic phase imaging with multidetector-row computed tomography

OBJECTIVE: To assess the diagnostic value of arterial, pancreatic, and hepatic phase imaging with multidetector-row computed tomography of a bile duct malignancy. METHODS: Our institutional review board approved this retrospective study and waived the requirement for informed consent. Forty-two patients with surgically proven hilar or extrahepatic cholangiocarcinoma, who underwent preoperative imaging with triple-phasic multidetector-row computed tomography, were included in this study. Images obtained during each phase were reviewed by 2 independent observers who assessed the tumor conspicuity and the biliary extent of the tumor and vascular invasion by the tumor. For quantitative analysis, another radiologist measured the tumor attenuation, the normal liver parenchyma, the aorta, and the main portal vein on each phase image. RESULTS: The degree of tumor conspicuity was higher in the pancreatic and hepatic phases than in the arterial phase (P < 0.01); however, there was no statistical difference in tumor conspicuity between the pancreatic and hepatic phases (P > 0.05). The mean tumor attenuation was greater in the hepatic phase at 114.2 +/- 24.6 Hounsfield units versus 72.9 +/- 18.3 Hounsfield units in the arterial phase (P < 0.001). The images obtained in the hepatic phases were significantly superior to those obtained in the arterial phase for predicting the tumor involvement into the secondary biliary confluence (P < 0.05). In predicting for the vascular involvement by the tumors, there was no significant difference among the 3 enhancement phases (P > 0.05). CONCLUSIONS: Routine acquisition of arterial phase images is not necessary for successful detection and evaluation of the extent of hilar or extrahepatic bile duct carcinoma.     

Early metabolic changes following chemotherapy of human gliomas in vivo demonstrated by phosphorus magnetic resonance spectroscopy

The authors have used phosphorus magnetic resonance spectroscopy to monitor pH changes in malignant gliomas following treatment with intravenous and intra-arterial 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU). Image-guided, localized phosphorus spectra of human gliomas in situ were obtained using a 1.5-T whole body combined imaging and spectroscopy system. Initial intravenous BCNU treatment was followed by a transient decrease of tumor intracellular pH by 0.15 +/- 0.03 pH units (mean +/- SD). Superselective intra-arterial administration of the same drug was followed by an increase of tumor intracellular pH by 0.15 +/- 0.6 pH units (mean +/- SD). These changes occurred prior to any changes on x-ray, computed tomography (CT), or magnetic resonance imaging (MRI). In addition to enhancing our understanding of the metabolic effects of BCNU, such changes may correlate with drug efficacy or toxicity and may be useful in guiding therapy in the future.     

Uptake of radiolabeled anti-CEA antibodies in human colorectal primary tumors as a function of tumor mass

An inverse correlation has been demonstrated between tumor uptake (u, in units of % injected dose/kg) of monoclonal antibody (Mab) and tumor mass (m, in units of g) for colorectal carcinoma in a series of 19 consecutive patients. The correlation (=–0.510), developed using surgical samples was of the form u=am ^b and was significant at the 2% level of confidence. All tumors were positive for carcinoembryonic antigen (CEA) and the radiopharmaceutical was an iodine-131 labeled anti-CEA Mab. Such correlations have been predicted earlier from murine and rat tumor uptake data. The slope parameter (b) was –0.362, a number consistent with the previous value (–0.382) found in anti-CEA experiments in mice bearing human xenograft LS 174T tumors.Correspondence to: L.E. Williams     

Administration of gadopentetate dimeglumine in MR imaging of intracranial tumors: dosage and field strength.

PURPOSE: To investigate the efficacy of 0.025, 0.05 and 0.1 mmol/kg gadopentetate dimeglumine in MR imaging of patients with intracranial tumors at mid and high field strength. METHODS: In 88 patients, an open-label phase III multicenter dose-finding study was performed at 0.5, 1.0, and 1.5 T MR units. Before and after (5, 15, 25 minutes) intravenous administration of gadopentetate dimeglumine, imaging was performed with T1-weighted spin-echo sequences. RESULTS: With 0.1 mmol/kg yielding the highest values, tumor enhancement and numerical tumor/brain contrast showed dose-dependent 5-minute postcontrast values (P less than 0.05). Compared to 5-minute postcontrast values, there was no significant change at 15 and 25 minutes. Although the lowest values of enhancement were found at 0.5 T, differences in enhancement among the field strengths were not statistically significant. The numerical data were confirmed by visual assessment of tumor/brain contrast. Eighty to 90% of cases had diagnostically valuable enhancement at 0.1 mmol/kg, 50% at 0.05 mmol/kg, and 10% at 0.025 mmol/kg (P less than 0.05). There were no adverse events. CONCLUSION: Our results confirm that 0.1 mmol/kg gadopentetate dimeglumine is more effective at enhancing intracranial tumors than lower doses at mid and high field MR units.     

Imaging of differential protease expression in breast cancers for detection of aggressive tumor phenotypes

PURPOSE: To determine if different expression levels of tumor cathepsin-B activity in well differentiated and undifferentiated breast cancers could be revealed in vivo with optical imaging. MATERIALS AND METHODS: A well differentiated human breast cancer (BT20, n = 8) and a highly invasive metastatic human breast cancer (DU4475, n = 8) were implanted orthotopically in athymic nude mice. Tumor-bearing animals were examined in vivo with near-infrared fluorescence (NIRF) imaging 24 hours after intravenous injection of an enzyme-sensing imaging probe. Immunohistochemistry, Western blotting (on cells and whole tumor samples), and correlative fluorescence microscopy were performed. RESULTS: Both types of breast cancers activated the NIRF probe so that tumors became readily detectable. However, in tumors of equal size, there was a 1.5-fold higher fluorescence signal in the highly invasive breast cancer (861 arbitrary units +/- 88) compared with the well differentiated lesion (566 arbitrary units +/- 36, P <.01). Western blotting confirmed a higher cathepsin-B protein content in the highly invasive breast cancer (DU4475) of about 1.4-fold (whole tumor samples) to 1.7-fold (cells). Immunohistochemistry and fluorescence microscopy findings confirmed the imaging findings. CONCLUSION: Cathepsin-B enzyme activity can be determined in vivo with NIRF optical imaging, while differences in tumoral expression may correlate with tumor aggressiveness.     

Does contrast enhancement on CT suggest tumor response for chemotherapy in small cell carcinoma of the lung?

PURPOSE: The purpose of this article is to assess the correlation between contrast enhancement on CT and the tumor reduction ratio in small cell carcinoma of the lung after first-line chemotherapy. MATERIALS AND METHODS: Twenty-eight patients with small cell carcinoma of lung underwent preenhancement and postenhancement CT scans before and after first-line chemotherapy, followed by second-line chemotherapy in 7 patients who had relapsed. The authors retrospectively analyzed the correlation between the tumor reduction ratio and the CT numbers of contrast enhancement in each case by multiple regression analysis using SPSS. RESULTS: The mean tumor-reduction ratio was 58.2 +/- 43.2% after first-line chemotherapy, and the mean CT enhancement was 33.2 +/- 11.0 Hounsfield units (HU). The correlation coefficient between the tumor reduction ratio and the CT numbers of contrast enhancement was 0.57 (r = 0.32), and p value was < 0.002. After chemotherapy, more than 90% tumor reduction was seen in 11 patients. They revealed an average 41.9 +/- 7.6 HU tumor enhancement. Less than 50% tumor reduction was seen in 10 patients. They revealed an average 26.2 +/- 7.9 HU tumor enhancement. If these criteria of 30 HU contrast enhancement and 80% tumor reduction ratio were applied as a guide for chemotherapy response, the sensitivity, specificity, positive predictive value, and negative predictive value would be calculated as 85.7%, 84.6%, 85.7%, and 84.6%, respectively. CONCLUSION: In small cell carcinoma of the lung, it is statistically proven that the more enhanced tumor on CT, the better response to chemotherapy. Tumor enhancement of 30 HU is a suggestive guide for chemotherapy response in patients with small cell carcinoma.     

Measuring in vivo tumor pHe with CEST-FISP MRI

Paramagnetic chemical exchange saturation transfer (PARACEST) MRI contrast agents have been developed that can measure pH in solution studies, but these agents have not previously been detected in vivo. To use the PARACEST agent Yb-DO3A-oAA to measure the extracellular pH (pHe) in tumor tissue, a chemical exchange saturation transfer fast imaging with steady state precession MRI protocol was developed, the saturation period was optimized for sensitive chemical exchange saturation transfer (CEST) detection, and median filtering was used to remove artifacts in CEST spectra. These improvements were used to correlate pH with a ratio of two CEST effects of Yb-DO3A-oAA at a 7 T magnetic field strength (R(2) = 0.99, standard deviation of precision = 0.011 pH units). The PARACEST agent could not be detected in tumor tissue following i.v. injection due to the low sensitivity of in vivo CEST MRI. Yb-DO3A-oAA was detected in tumor tissue and leg muscle after directly injecting the PARACEST agent into these tissues. The measured CEST effects were used to measure a tumor pH of 6.82 ± 0.21 and a leg muscle pH of 7.26 ± 0.14, and parametric pH maps were also generated from these tissue regions. These results demonstrated that tumor pHe can be measured with a PARACEST agent and a rapid CEST-MRI protocol.     

Computed tomography findings in squamous cell carcinoma of the pancreas

This case illustrates previously unreported computed tomography findings in a primary pancreatic squamous cell carcinoma, an unusual pancreatic malignancy. With bolus injection of intravenous contrast, attenuation of this tumor increased from 35 to 61 Hounsfield units, a finding not typical for pancreatic adenocarcinoma.     

Computed tomography of primary mediastinal seminomas

Two cases of primary mediastinal seminoma presented as (a) aortic aneurysm with symptoms suggestive of coarctation of the aorta and (b) nonspecific tumor mass with left diaphragmatic paralysis. By computed tomographic (CT) scans both tumors were massive with sharply demarcated borders, loss of fat planes between the tumor and surrounding organs, and homogeneous density (30 to 40 Hounsfield units) only slightly enhanced by contrast medium infusion. Such CT findings should suggest the possibility of a primary mediastinal seminoma.     

Evaluation of prototype equipment for digital subtraction angiography in diagnosing intracranial lesions

Two prototype units for digital subtraction angiography have been developed by Japanese manufacturers. Their performance in demonstrating various intracranial lesions in 121 patients was evaluated. Comparison with conventional selective catheter angiography was possible in 77 patients. Digital subtraction angiography proved useful in preoperative evaluation of pituitary tumors when transsphenoidal surgery was being considered; demonstration of faint tumor stains which might be missed on conventional angiography; demonstration of larger aneurysms, arteriovenous malformations, and tumors as a screening technique; demonstration of abnormalities involving the dural sinuses; and follow-up of patients after surgery or embolization.     

Comparison of three IMRT inverse planning techniques that allow for partial esophagus sparing in patients receiving thoracic radiation therapy for lung cancer.

The purpose of this study is to compare 3 intensity-modulated radiation therapy (IMRT) inverse treatment planning techniques as applied to locally-advanced lung cancer. This study evaluates whether sufficient radiotherapy (RT) dose is given for durable control of tumors while sparing a portion of the esophagus, and whether large number of segments and monitor units are required. We selected 5 cases of locally-advanced lung cancer with large central tumor, abutting the esophagus. To ensure that no more than half of the esophagus circumference at any level received the specified dose limit, it was divided into disk-like sections and dose limits were imposed on each. Two sets of dose objectives were specified for tumor and other critical structures for standard dose RT and for dose escalation RT. Plans were generated using an aperture-based inverse planning (ABIP) technique with the Cimmino algorithm for optimization. Beamlet-based inverse treatment planning was carried out with a commercial simulated annealing package (CORVUS) and with an in-house system that used the Cimmino projection algorithm (CIMM). For 3 of the 5 cases, results met all of the constraints from the 3 techniques for the 2 sets of dose objectives. The CORVUS system without delivery efficiency consideration required the most segments and monitor units. The CIMM system reduced the number while the ABIP techniques showed a further reduction, although for one of the cases, a solution was not readily obtained using the ABIP technique for dose escalation objectives.     

Rapid serial cranial computed tomography for tumor diagnosis

Summary Rapid serial computed tomography (RSCT) provides more information about the cerebral cortical capillary bed and leptomeningeal vessels than conventional enhanced computed tomography (CT). This increased neuroanatomical definition has potential value for separating intra- from extracerebral tumors in selected cases. RSCT offers better visualization of the angioarchitecture of highly vascular tumors than conventional enhanced CT. However, CT scans delayed several minutes after contrast administration are more useful for evaluating the extent of hypovascular tumors. Time-density curves were of limited value for tumor evaluation. However, the peak increase of Hounsfield units did correlate well with the degree of tumor vascularity assessed angiographically.     

Delayed MDCT imaging results in increased enhancement in patients with head and neck neoplasms

OBJECTIVE: Using multidetector computed tomography, we compared the utility of a spilt bolus technique and the impact of performing delayed imaging compared with immediate imaging on tumor enhancement. METHODS: Thirty-seven patients with masses of the extracranial head and neck were imaged. An initial contrast bolus (50 cm) was administered over 30 seconds (1.67 cm/s) and an initial (immediate) imaging acquisition followed. Ninety seconds after completion of the initial bolus, a second bolus of 75 cm (2.5 cm/s) was administered and a second (delayed) acquisition obtained concurrently. Mean tumor enhancement in immediate and delayed imaging was calculated and analyzed using the paired t test. RESULTS: Mean enhancement was 68.3 +/- 21.0 Hounsfield units (HU) and 91.4 +/- 27.4 HU (n = 37) for immediate and delayed imaging groups, respectively. The mean difference between the initial and delayed enhancement was 23.1 HU (P < 0.01). CONCLUSIONS: The delayed imaging technique used resulted in a statistically significant increase in enhancement relative to immediate imaging.     

Value of echography in salivary pathology

Major advances in echography techniques over the past few years include the development of simple high performance units adapted to investigating the salivary glands. This non-traumatic, painless and inexpensive technique offers a means of rapid examination and is fully complementary to X-ray and xero and sialographic imagery, particularly in tumor pathology. The author gives a review of normal images then presents different lesions of the salivary gland.     

MDR1甲基化对宫颈癌介入栓塞化疗疗效的影响

目的多重耐药（drug resistance，MDR）是肿瘤化疗失败的主要原因。本研究旨在探讨MDR1甲基化对宫颈癌经皮子宫动脉血管腔内化疗栓塞疗效的影响。 方法选择67例宫颈癌患者接受栓塞化疗，45例正常宫颈组织作为对照。免疫组化检测宫颈癌中P-糖蛋白（P-gp）水平，并与正常组织进行比较。通过使用特异性千碱基裂解法和基质辅助激光解吸电离飞行时间质谱法分析MDR1基因启动子区16个CpG岛的甲基化状态。 结果P-gp在正常宫颈组织中的阳性表达率为0％ （0/45），介入栓塞化疗前后的阳性表达率分别为61.19％（41/67）和77.61％（52/67）。宫颈癌组织与正常宫颈组织相比有明显差异（χ²=4.2523，0.0392）。化疗前P-gp的阳性表达率与化疗疗效呈负相关（r=-0.340，P=0.005）。正常组织中13个CpG岛的甲基化率显著高于宫颈组织（P<0.05）。在宫颈癌组织中，经皮子宫动脉血管腔内化疗栓塞前6个CpG岛的甲基化率高于化疗后，但1个CpG岛的甲基化率低于化疗后（P<0.05）。化疗前有效化疗的1个CpG岛甲基化率明显高于无效化疗（P<0.05），其他CpG岛相似（P<0.05）。 结论MDR1编码的P-gp表达水平，部分MDR1基因启动子区CpG岛的甲基化状态，与宫颈癌介入栓塞化疗的疗效密切相关。     

31P NMR spectra of extremity sarcomas: diversity of metabolic profiles and changes in response to chemotherapy

We have used 31P NMR spectroscopy to study 22 patients with suspected sarcomas prior to any treatment. The spectra are characterized by the same peaks noted in murine tumors. The mean pH was 7.14 +/- 0.08 and PCr/Pi was 1.18 +/- 0.83. Comparison of pH and PCr/Pi ratios in human and a murine tumor with a low hypoxic cell fraction revealed no significant differences. Six patients subsequently received chemotherapy and three responded to therapy (based on pathologic examination and/or tumor reduction greater than 50%). The three responding patients were noted to have significantly lower PDE/PME in their pretreatment spectra than the three nonresponding patients. The three responding patients with sarcomas also showed a rise of greater than 100% in PDE/PME during the first cycle of therapy. Two of the responding patients had an increase of 0.37 pH units during this interval, which was not detected in the nonresponding patients. These data suggest that 31P NMR spectroscopy may be a useful prognostic indicator in conjunction with other clinical parameters.     

Infantile fibromatosis of the neck with intracranial involvement: MR and CT findings.

CT and MR imaging studies were performed in a 3-year-old boy with infantile fibromatosis arising from the infratemporal fossa and extending into the middle cranial fossa. On CT scans, the lesion was hyperattenuating (44-49 Hounsfield units [HU]), enhancing significantly after application of contrast material (63-66 HU). The MR images showed a multilobulated lesion of heterogeneous signal intensity. The tumor was markedly hypointense on T2-weighted images and slightly hypointense on T1-weighted images relative to brain tissue, iso- or slightly hyperintense relative to tongue muscle on both T2- and T1-weighted images, and enhanced strongly after administration of gadopentetate dimeglumine.     

Development and experimental evaluation of a contrast medium for computed tomographic examination of the liver and spleen.

A lipoid based contrast material containing 53% of ethiodized oil in emulsion form was developed for computed tomography (CT) of the liver and spleen and tested in rabbits and monkeys. An intravenous dose of 0.2 ml/kg selectively opacified the liver and spleen, resulting in an average increase of 23 EMI units (500 scales) in the attenuation of the liver and a higher increase in the attenuation of the spleen. When injected into rhesus monkeys with carcinogen induced hepatomas there was a significant improvement in the visualization of the tumor, and small lesions, undetectable on the preliminary CT scan, became visible. Toxicity studies are in progress.     

Dynamic multislice computed tomography findings for parotid gland tumors

OBJECTIVE: Our aim was to research the enhancement features of parotid gland masses in detail and characterize if the masses were Warthin tumors, adenomas, or malignant tumors. METHODS: The prospective study included 25 parotid tumors in 21 patients. Neck computed tomography (CT) was performed using a multislice CT unit. A full-neck CT examination was done at 30 seconds after completion of contrast injection, and then tumor-level images were obtained at 90 seconds and at 5 and 25 minutes. Computed tomography number (lesion density in Hounsfield units) was determined at each phase, and differences within and among tumor groups were statistically analyzed. Diagnoses were confirmed by histopathology. RESULTS: There were 11 Warthin tumors, 8 pleomorphic adenomas, 5 malignant tumors, and 1 basal cell adenoma. Ten Warthin tumors showed rapid contrast enhancement at 30 seconds and rapid reduction of enhancement from the first to the fourth phase. The basal cell adenoma showed also a peak enhancement at 30 seconds. Seven pleomorphic adenomas showed increased enhancement through the first 3 phases. Four malignant tumors showed peak enhancement at 90 seconds. Statistically significant differences within and among tumor groups were determined. CONCLUSIONS: The data suggest that peak tumor enhancement at 30 and 90 seconds, respectively, might identify Warthin and malignant tumors. Increased enhancement through all phases might be an indicator for diagnosing pleomorphic adenomas.