John W. Henson

Phase II Trial of Lapatinib for Brain Metastases in Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

PURPOSE One third of women with advanced human epidermal growth factor receptor 2 (HER-2)-positive breast cancer develop brain metastases; a subset progress in the CNS despite standard approaches. Medical therapies for refractory brain metastases are neither well-studied nor established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth factor receptor (EGFR) and HER-2, in patients with HER-2-positive brain metastases. PATIENTS AND METHODS Patients had HER-2-positive breast cancer, progressive brain metastases, prior trastuzumab treatment, and at least one measurable metastatic brain lesion. Patients received lapatinib 750 mg orally twice a day. Tumor response was assessed by magnetic resonance imaging every 8 weeks. The primary end point was objective response (complete response [CR] plus partial response [PR]) in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included objective response in non-CNS sites, time to progression, overall survival, and toxicity. RESULTS Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%) were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified additional patients with some degree of volumetric reduction in brain tumor burden. The most common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%). CONCLUSION The study did not meet the predefined criteria for antitumor activity in highly refractory patients with HER-2-positive brain metastases. Because of the volumetric changes observed in our exploratory analysis, further studies are underway utilizing volumetric changes as a primary end point.

Brain Tumor Imaging in Clinical Trials

SUMMARY: There are substantial challenges in the radiologic evaluation of tumor size during clinical trials, and it is important for neuroradiologists to have a firm understanding of these issues. This review will examine measurement approaches, response criteria, selection of lesions for measurement, technical imaging considerations, interval between tumor measurements and response confirmation, and validity of imaging as a measure of efficacy.

Clinical and radiographic features of peritumoral infarction following resection of glioblastoma

Focal areas of restricted diffusion adjacent to high-grade glioma resection cavities were detected in 70% of patients on immediate postoperative MRI studies. Follow-up studies demonstrated cystic encephalomalacia in 91% of these foci, suggesting the presence of infarction, and the infarcted tissue demonstrated enhancement in 43% of cases. New postoperative deficits correlated well with the anatomic region of infarction in six patients. Enhancement in perioperative infarcts can mimic tumor progression on follow-up imaging studies.

MRI in treatment of adult gliomas

Diffuse astrocytomas of the adult cerebral hemispheres are unique among tumours in human beings in the extent to which their imaging features are related to histopathological characteristics and clinical behaviour. However, understanding is still restricted about the value of imaging features in the measurement of response and of progression in these tumours. The present approach used in clinical trials, which consists of an anatomical measurement of the enhancing tumour on MRI, has many problems, and might not be acceptable as a surrogate endpoint for survival in patients with glioblastoma who are enrolled in clinical trials. Dynamic imaging techniques, such as capillary permeability mapping, are being used in studies of new drugs that target specific molecular features of gliomas; however, the validity of these techniques has not been elucidated. Diffusion imaging can be valuable for fibre-tract mapping to assist surgical planning and might become useful in measuring early response to treatment in densely cellular tumours. Functional imaging techniques can be used to localise motor, sensory, and language-control areas before surgery. Intraoperative MRI has produced improvements in the extent of tumour resection, and molecular imaging is another technique on the horizon, which could come to have a role in clinical trials in the near future. Thus, as a rapidly expanding sphere of investigation, brain-tumour imaging is producing great excitement. The aim of these new techniques is to aid the identification of more effective treatments.

Cynomolgus Polyoma Virus Infection : A New Member of the Polyoma Virus Family Causes Interstitial Nephritis, Ureteritis, and Enteritis in Immunosuppressed Cynomolgus Monkeys

Polyoma virus infection causes acute interstitial nephritis and ureteral stenosis in humans but has rarely been noted in other species. In the present study, a hitherto unknown polyoma virus was detected in 12 of 57 cynomolgus monkeys after 3 to 11 weeks of immunosuppression given to promote acceptance of renal allografts or xenografts. This virus, termed cynomolgus polyoma virus (CPV), is antigenically and genomically related to simian virus 40 (SV40). The tubular epithelial nuclei of the collecting ducts in the medulla and cortex reacted with an antibody for the SV40 large T antigen and by electron microscopy contained densely packed paracrystalline arrays of 30- to 32-nm diameter viral particles. A polymerase chain reaction analysis of DNA extracted from affected kidneys detected polyoma virus sequences using primers for a highly conserved region of the large T antigen of polyoma virus. Sequence analysis showed 7 base substitutions and 3 to 5 deletions in the 129-nucleotide segment of amplified products, compared with the corresponding portion of SV40, yielding 84% homology at the amino acid level. CPV caused interstitial nephritis in six renal allografts, a xenograft kidney, and six native kidneys. Infected animals showed renal dysfunction and had tubulointerstitial nephritis with nuclear inclusions, apoptosis, and progressive destruction of collecting ducts. CPV was detected in the urothelium of graft ureters, associated with ureteritis and renal infection. Viral infection was demonstrable in smooth muscle cells of the ureteric wall, which showed apoptosis. One animal had diarrhea and polyoma virus infection in the smooth muscle cells of the muscularis propria of the intestine. Spontaneous resolution occurred in one case; no animal had virus detected in tissues more than 3 months after transplantation. Thus, immunosuppression predisposes cynomolgus monkeys to a polyoma virus infection with clinical consequences quite similar to BK virus infection in humans, including renal dysfunction. We also suggest that this may be the pathogenetic basis for the significant incidence of late onset, isolated ureteral stenosis observed in these recipients.

Magnetic resonance imaging characteristics predict epidermal growth factor receptor amplification status in glioblastoma.

Purpose: Two clinical-molecular glioblastoma subtypes have been described: “primary” glioblastomas arise de novo in older patients and often overexpress epidermal growth factor receptor (EGFR); “secondary” glioblastomas progress from lower-grade tumors in younger patients and commonly have TP53 mutations. EGFR overexpression correlates in experimental gliomas with increased angiogenesis, edema, and invasion. No radiographic predictors of molecular glioblastoma subtype are known. Experimental Design: We retrospectively reviewed 75 glioblastomas, classified as TP53-mutated (n = 11), EGFR-amplified (n = 31), or neither (non-TP53/non-EGFR; n = 33). Four variables were derived from preoperative magnetic resonance imaging: (a) T2/T1, the ratio of T2-bright volume to enclosed T1-enhancing volume; (b) percentage of tumor volume that was necrosis; and (c and d) T1 and T2 border sharpness coefficients (BSC), the rates of change in grayscale intensity of adjacent 0.02-cm2 voxels traversing the anterior, posterior, and lateral borders on T1-enhanced and T2 images. Results and Conclusions: Mean T2/T1 was 4.7 for EGFR-amplified glioblastomas, greater than that of TP53-mutated glioblastomas (2.3) or non-TP53/non-EGFR glioblastomas (2.6; P < 0.00005). All four tumors with T2/T1 > 7.2 were EGFR-amplified; 0 of 15 with T2/T1 < 4.7 underwent gross total resection. The mean T2 BSC of EGFR-amplified glioblastomas was 33.7, less sharp (P < 0.0000005) than TP53-mutated (72.2) and non-TP53/non-EGFR glioblastomas (81.2). All 15 glioblastomas with T2 BSC < 30.8 were EGFR-amplified. Percentage necrosis and T1 BSC did not differ between glioblastoma subtypes. The increased T2/T1 ratio and decreased T2 BSC in EGFR-overexpressing tumors are the first radiographic distinctions described between glioblastoma molecular subtypes. These findings may reflect increased angiogenesis, edema, and/or invasion in EGFR-overexpressing tumors.

Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults

We conducted a phase II study of the combination of temozolomide and angiogenesis inhibitors for treating adult patients with newly diagnosed glioblastoma. Patients who had stable disease following standard radiation therapy received temozolomide for 5 days in 28-day cycles, in combination with daily thalidomide and celecoxib. Patients were treated until tumor progression or development of unacceptable toxicity. Four-month progression-free survival (PFS) from study enrollment was the primary end point, and overall survival (OS) was the secondary end point. In addition, we sought to correlate response with O(6)-methylguanine-DNA methyltransferase promoter methylation status and serum levels of angiogenic peptides. Fifty patients with glioblastoma were enrolled (18 women, 32 men). Median age was 54 years (range, 29-78) and median KPS score was 90 (range, 70-100). From study enrollment, median PFS was 5.9 months (95% confidence interval [CI]: 4.2-8.0) and 4-month PFS was 63% (95% CI: 46%-75%). Median OS was 12.6 months (95% CI: 8.5-16.4) and 1-year OS was 47%. Of the 47 patients evaluable for best response, none had a complete response, five (11%) had partial response, four (9%) had minor response, 22 (47%) had stable disease, and 16 (34%) had progressive disease. Analysis of serial serum samples obtained from 47 patients for four angiogenic peptides failed to show a significant correlation with response or survival for three of the peptides; higher vascular endothelial growth factor levels showed a trend toward correlation with decreased OS (p=0.07) and PFS (p=0.09). The addition of celecoxib and thalidomide to adjuvant temozolomide was well tolerated but did not meet the primary end point of improvement of 4-month PFS from study enrollment.

Age-dependent rate of anaplastic transformation in low-grade astrocytoma

Article abstract Age and histologic grade are interrelated characteristics of diffuse fibrillary astrocytomas, because the peak age incidence rises with increasing grade. The relationship between age and grade may be explained if age determines the rate of anaplastic progression in astrocytomas. The authors tested this hypothesis by determining the interval between diagnosis of low-grade astrocytoma and progression to high-grade astrocytoma in patients of various ages. A two-way scatterplot of age at initial diagnosis versus interval to anaplastic progression demonstrated a strong negative correlation (n = 24; Pearson correlation coefficient = −0.83; Spearman correlation coefficient = −0.79; p < 0.001 for both values). It was concluded that the rate of anaplastic progression in low-grade astrocytoma is directly correlated with patient age.

Treatment-related myelodysplasia/AML in a patient with a history of breast cancer and an oligodendroglioma treated with temozolomide: Case study and review of the literature

The emergence of temozolomide as an effective alkylating agent with little acute toxicity or cumulative myelosuppression has led to protracted courses of chemotherapy for many patients with gliomas. Secondary, or treatment-related, myelodysplasia (t-MDS) and acute myelogenous leukemia (t-AML) are life-threatening complications of alkylating chemotherapy and have been reported in patients with primary brain tumors. We describe a case of temozolomide-related t-MDS/AML and discuss the clinical features of this condition. Administration of an alkylating agent in patient populations with long median survivals must be undertaken with an understanding of the potential for this treatment complication.

Amplification of JC virus DNA from brain and cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy

We have established an assay to detect JC viral DNA in brain tissue and CSF of patients with progressive multifocal leukoencephalopathy (PML) and amplified a 106-base pair segment of the gene encoding JC viral large T antigen by polymerase chain reaction (PCR) from the brains of eight patients with PML and from one of six CSF samples. Brain and C SF of patients without PML did not yield JC virus-specific DNA amplification products. Southern analysis documented that the sequences of the 106-base pair PCR product and JC viral DNA are identical. This assay can be used in the diagnosis of PML and to investigate the biology of JC virus.