A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors.

BACKGROUND: Axitinib and bevacizumab are targeted therapies against the vascular endothelial growth factor pathway. METHODS: Patients with previously treated solid tumors received axitinib (starting dose 5 mg twice daily) combined with FOLFOX plus bevacizumab (1, 2, or 5 mg/kg, cohorts 1-3, respectively), FOLFIRI (cohort 4), or FOLFOX (cohort 5). Safety and pharmacokinetics were assessed. RESULTS: Thirty patients were enrolled (n = 16, 8, and 6 for cohorts 1-3, 4, and 5, respectively). Plasma concentrations and pharmacokinetic (PK) parameters were similar when drugs were administered alone and in various combinations. Most treatment-emergent adverse events (AEs) were mild to moderate and clinically manageable (most common: nausea, fatigue, diarrhea, anorexia, hypertension). Two of the four patients receiving axitinib with FOLFOX plus 5 mg/kg bevacizumab experienced dose-limiting toxicity (DLT) of inability to resume treatment for 14 days following treatment interruption (associated AE: hypertension); the maximum tolerated dose of bevacizumab in this combination was 2 mg/kg. No DLTs occurred with axitinib plus FOLFIRI or FOLFOX. Ten patients had RECIST-confirmed partial tumor responses (objective response rate: 33.3%). CONCLUSION: Axitinib is well tolerated in combination with FOLFOX, FOLFIRI, or FOLFOX plus 2 mg/kg bevacizumab. PK interactions appear to be absent.

Racial differences in microbleed prevalence in primary intracerebral hemorrhage.

BACKGROUND: Primary intracerebral hemorrhage is two to three times more common in many racial populations, including black patients. Previous studies have shown that microbleeds, identified on gradient echo MRI (GRE), are present in 50-80% of patients with primary ICH. The objective of this study was to compare, by race, the rates, risk factors, and topography of microbleeds in patients hospitalized for primary ICH. METHODS: Patients diagnosed with primary ICH at two metropolitan stroke centers were included. Clinical and neuroimaging data were recorded for each patient. Analyses were performed to compare baseline characteristics as well as imaging findings by race. RESULTS: A total of 87 patients met inclusion criteria (42 black subjects, 45 white subjects). The black cohort was younger (p < 0.001), and had a greater rate of hypertension (p = 0.001), but not other vascular risk factors. Microbleeds were more prevalent in the black population, with 74% of blacks having one or more microbleeds compared to 42% of whites (p = 0.005). The black population also tended to have a greater frequency of microbleeds in multiple territories than the white population (38% vs 22%, p = 0.106). When adjusting for age, hypertension, and alcohol use, race was an independent predictor of microbleeds (OR 3.308, 95% CI 1.144-9.571, p = 0.027). CONCLUSIONS: These pilot data suggest that significant racial differences exist in the frequency and topography of microbleeds in patients with primary ICH. Microbleeds may be an important emerging imaging biomarker with the potential to provide insights into ICH pathophysiology, prognosis, and disease progression, as well as possible therapeutic strategies, particularly in medically underserved populations.

Adult T-cell leukemia/lymphoma: a rare case in the USA and review of the literature.

Adult T-cell leukemia/lymphoma (ATLL), in its acute stage, is a uniformly fatal disease. ATLL is caused by the human T-cell lymphotropic virus I (HTLV-1), a retrovirus endemic in numerous areas throughout the world including Japan, the Caribbean, Central and South America and certain areas of the United States. Although the progression from HTLV-1 carrier status to ATLL occurs only rarely, ATLL is incurable and thus prevention of HTLV-1 transmission should be a primary goal. With the development of new anti-retroviral and monoclonal therapies, there exist potential cures or at least prolonged remissions for patients diagnosed with ATLL. We present a case of ATLL that, to our knowledge, is only the third reported case in Georgia. In addition, we present a brief review of the literature, including potential new treatment regimens that appear to have promise in the treatment of ATLL.

Leukemic leptomeningeal involvement in stage 0 and stage 1 chronic lymphocytic leukemia.

Central nervous system (CNS) involvement in early (Rai Stage 0 and Stage 1) chronic lymphocytic leukemia (CLL) is rare, with only five cases reported. We present the sixth reported case, a 77-year-old male with a 4 year history of Stage 0 CLL who presented with sudden onset of diplopia and headache. Workup revealed a leukemic involvement of his CNS and he responded well to treatment with intrathecal (IT) methotrexate. After his third IT treatment, he developed a change in his mental status, consistent with a chemotherapy induced encephalopathy, which was effectively treated with IT hydrocortisone. In addition to the case presentation, we review the previously reported cases in an effort to determine any characteristics common among the Stage 0/1 CLL patients with reported CNS involvement.

Design and assembly of an 8 tesla whole-body MR scanner.

PURPOSE: The purpose of this report is to describe the design and construction of an 8 T/80 cm whole-body MRI system operating at 340 MHz. METHOD: The 8 T/80 cm magnet was constructed from 414 km of niobium titanium superconducting wire. The winding of this wire on four aluminum formers resulted in a total inductance of 4,155 H. Gradient subsystems included either a body gradient or a head gradient along with a removable shim insert. The magnet and gradient subsystems were interfaced to two spectrometers. These provided the control of the gradient amplifiers and the two sets of four RF power amplifiers. The latter provide in excess of 8 kW of RF power from 10 to 140 MHz and 10 kW of RF power from 245 to 345 MHz. A dedicated computer-controlled patient table was designed and assembled. The entire system is located in a clinical setting, facilitating patient-based studies. RESULTS: The 8 T/80 cm magnet was energized without complication and achieved persistent operation using 198.9 A of current, thereby storing 81.5 MJ of magnetic energy. Exceptional performance was observed for nearly all components both in isolation and when combined within the complete system. CONCLUSION: An 8 T/80 cm MRI system has been assembled. The magnet subsystem is extremely stable and is characterized by good homogeneity and acceptable boil-off rates.

Human leptomeningeal and cortical vascular anatomy of the cerebral cortex at 8 Tesla.

PURPOSE: The purpose of this work was to describe the human leptomeningeal and cortical vascular anatomy as seen at high resolution on an 8 T UHFMRI system. METHOD: With a 1024 x 1024 matrix, axial gradient echo images of the cerebral cortex were acquired on a human volunteer at 8 T with TR 500 ms, TE 16 ms, flip angle 22.5 degrees, bandwidth 53 kHz, and slice thickness 2.84 mm. The same subject was evaluated at 1.5 T using similar parameters. The images were then reviewed in detail and compared with known cortical and leptomeningeal vascular anatomy. RESULTS: Two hundred forty micron in-plane resolution images of the human brain were acquired at 8 T without evident artifact from susceptibility distortions, RF penetration, or dielectric resonances. The CSF, gray matter, and white matter structures were well discerned. The microscopic leptomeningeal vascular anatomy was well visualized, and the course of small perforating cortical vessels could be followed from the cortical surface to the white matter junction. CONCLUSION: Initial 8 T images of the brain demonstrate detailed leptomeningeal and cortical vascular anatomy.

Cognitive, cardiac, and physiological safety studies in ultra high field magnetic resonance imaging.

A systematic analysis of the effect of an 8.0 tesla static magnetic field on physiological and/or cognitive function is presented in the normal volunteer and in the swine. A study of ten human subjects revealed no evidence of detectable changes in body temperature, heart rate, respiratory rate, systolic pressure, and diastolic blood pressure after 1 hour of exposure. In addition, no cognitive changes were detected. Important ECG changes were noted which were related both to the position of the subject in the magnet and to the absolute strength of the magnetic field. As such, the ECG tracing at 8 tesla was not diagnostically useful. Nonetheless, all subjects exhibited normal ECG readings both before and following exposure to the 8 tesla field. Cardiac function was also examined in detail in the swine. No significant changes in body temperature, heart rate, left ventricular pressure, left ventricular end diastollic pressure, time rate of change of left ventricular pressure, myocardial stiffness index, cardiac output, systolic volume, troponin, and potassium levels could be detected following 3 h of exposure to a field strength of 8.0 tesla. It is concluded that no short term cardiac or cognitive effects are observed following significant exposure to a magnetic field of up to 8.0 tesla.

High signal-to-noise FLASH imaging at 8 Tesla.

A radio frequency (RF) and gradient spoiled fast low angle shot technique was used to acquire images from the human brain at 8 Tesla. The resulting FLASH images, obtained with a 17 degrees nutation, a 70 ms repetition time, and a 17 ms echo time, displayed an average signal-to-noise ratio (SNR) of 220:1 (slice thickness 2.2 mm, field-of-view 24 cm, matrix 256 x 128). These images were compared with images obtained at 1.5 Tesla using identical parameters yielding a signal-to-noise of less than 10:1. As such, the 8 Tesla images display a remarkable improvement in SNR with increasing field strength. The images also show little evidence of susceptibility distortion, chemical shift, or RF penetration limitations.

Acquisition of human multislice MR images at 8 Tesla.

PURPOSE: The purpose of this work was to acquire high quality multislice MR images from the human brain at 8 Tesla (T). METHOD: Initial images were acquired with an 8 T/80 cm magnet designed and manufactured by Magnex Scientific (Abingdon, England). Images were acquired using volume RF coils operating at 340 MHz. A torque-free head gradient insert was utilized to spatially encode the spins. Images were acquired from the human head using gradient-recalled echo pulse sequences. RESULTS: Ultra high frequency (UHF) MR images have been obtained from the human head that display both excellent signal/noise ratio and image quality. The power required to obtain the 8 T images was much less than expected based on the trend obtained at lower fields. CONCLUSION: In this work, we have demonstrated that it is possible to obtain high quality multislice images from the human brain at 8 T. These images display the phenomenal potential for imaging at UHF and reveal that none of the stumbling blocks advanced by the MR community for an 8 T project (RF penetration, dielectric effects, specific absorption rate problems, RF power requirements) proved to be a limitation.

Brain metastases in small cell carcinoma of the lung.

The records of 177 patients with small cell carcinoma of the lung were reviewed to determine parameters associated with brain metastases. Complete autopsy, including examination of the brain, was done in each case. Of the 70 cases of brain metastases, only two patients (3%) were aged 70 years or more as compared with 19 (18%) aged 70 years or more who did not have brain metastases. Patients with brain metastases had a longer median survival as compared with those without brain metastases. Patients with brain metastases had involvement of the thyroid and kidney more frequently (23% and 34%, respectively) compared with patients without brain metastases (8% and 13%). Thus, patients who have brain metastases tend to (1) be less than 70 years of age; (2) have a longer survival; and (3) have a higher incidence of metastases to the thyroid and kidney.