A novel retinoic acid-response element requires an enhancer element mediator for transcriptional activation.

The Col11a2 gene codes for alpha2(XI), a subunit of type XI collagen that is a critical component of the cartilage extracellular matrix. The 5' regulatory region of Col11a2 was subjected to deletional analysis to detect any regulatory element in addition to the two known chondrocyte-specific enhancer elements B/C and D/E. Deletion of the region from -342 to -242 bp reduced transcriptional activity to less than 50% of wild-type, but the sequence showed no independent ability to increase transcription from a minimal promoter. When cloned downstream of the D/E enhancer, however, a subsection of the sequence nearly doubled transcriptional activity and produced an additional 3-fold activation in response to RA (retinoic acid). A 6-bp direct repeat, separated by 4 bp (a DR-4 element) near the 5'-end of this region, was found to be essential for its activity, and was further shown to bind the RA X receptor beta in electrophoretic mobility-shift assays. The present study has revealed a novel RA-response element in Col11a2 that does not interact directly with the promoter, but instead requires the D/E enhancer to mediate transcriptional activation. Proteins bound at the enhancer, therefore, would be expected to affect the transcriptional response to RA. Such a system of regulation, particularly if found to be operating in other cartilage genes, could explain the conflicting responses RA produces in chondrocytes under different experimental conditions.

Stereotactic radiosurgery alone for patients with 1-4 radioresistant brain metastases.

Brain metastases from radioresistant histologies are perceived to be less responsive to WBRT compared to other histologies, and stereotactic radiosurgery (SRS) may provide better local control. The aim of this study was to examine the outcomes of patients with 1-4 brain metastasis from radioresistant histologies (renal cell carcinoma and melanoma) treated with SRS alone. Thirty-eight patients with 1-4 radioresistant brain metastases (66 lesions) were treated with SRS alone. The median age was 55 years. Fourteen and 24 patients had renal cell carcinoma (RCC) and melanoma brain metastases, respectively. Distribution of number of lesions was as follows: one lesion, 22 patients; 2 lesions, 8 patients; 3 lesions, 5 patients; and 4 lesions, 3 patients. Distribution of RTOG recursive partitioning analysis (RPA) classes was as follows: II, 37 patients and III, 1 patient. The median marginal dose was 20 Gy. The median follow-up was 6.1 months. The 3-, 6-, 9-, 12-, and 18-month local control (LC) rates were 87.9, 81.4, 67.9, 67.9, and 60.3%, respectively. The corresponding free-from-distant-brain failure (FFDBF) rates were 71.3, 58.1, 49.8, 40.2, and 27.6%. The corresponding progression-free survival (PFS) rates were 55.3, 41.9, 33, 23.3, and 13.3%. RCC histology was associated with better LC (P = 0.0055). Although SRS alone could yield reasonable LC in patients with 1-4 radioresistant brain metastases, the risk of distant brain failure was substantial. The approach of routine omission of WBRT outside of a trial setting should be used judiciously.

Pathologic complete response of a solitary melanoma brain metastasis after local ablative radiation therapy: case report.

A 73-year-old female with malignant melanoma metastatic to her left frontal lobe status post-gross total resection of the metastasis, whole brain radiotherapy, and Gamma Knife-based stereotactic radiosurgery for local recurrence presented with an area of increasing enhancement on follow-up magnetic resonance imaging (MRI) and hypermetabolic lesions on 18-fluorodeoxyglucose positron emission tomography/computerized tomography (18FDG PET/CT) of the brain suspicious for tumor recurrence. Surgical resection of the lesion was performed showing radiation necrosis with no evidence of tumor. The patient was alive 1 year after her second craniotomy. This case illustrates that despite being perceived as a radioresistant histology, complete local eradication of melanoma is possible with ablative dose regimens. Prolonged survival is possible in patients with limited metastatic melanoma if local tumor control is achieved.

Stereotactic radiosurgery with or without whole brain radiotherapy for patients with a single radioresistant brain metastasis.

PURPOSE: To examine the outcomes of patients with a single brain metastasis from radioresistant histologies (renal cell carcinoma and melanoma) treated with stereotactic radiosurgery (SRS) with or without whole brain radiotherapy (WBRT). METHODS AND MATERIALS: We reviewed the medical records of 27 patients treated at our institution between 2000 and 2007 with a single radioresistant brain metastasis. Patients were treated with Gamma Knife based SRS. Tumor histologies included renal cell carcinoma and melanoma. RESULTS: Patients were treated to a median marginal dose was 20 Gy (range, 15-22 Gy). At follow-up intervals ranging from 1.8 to 23.2 months, the radiographic responses were as follows: progression in 7 patients; stable in 5 patients; and shrinkage in 15 patients. Fifteen patients (56%) developed distant brain failure. Seven of the 27 patients were alive at last follow-up. The 3-, 6-, 9-, 12-, and 18-months after SRS local control rates were 82.8%, 77.9%, 69.3%, 69.3%, and 55.4%, respectively. None of the 5 patients who received WBRT developed distant brain failure although the follow-up intervals were short (range, 3.5-13.7 months; median, 5.1 months). WBRT did not appear to affect local control, progression free survival, and overall survival (P = 0.32, 0.87, 0.69). One patient developed worsening of symptoms attributable to SRS. CONCLUSIONS: Gamma Knife SRS is a safe and feasible strategy for treatment of patients with a single radioresistant brain metastasis. Radiosurgery alone is a reasonable treatment option, but may carry a greater likelihood of distant brain recurrence.

Palliative treatment of poor prognosis patients with malignant gliomas.

High-grade gliomas are the most commonly diagnosed malignant brain tumor in adults. Prognosis can be estimated by examining risk factors, including histology, age and performance status. Postoperative radiation therapy is associated with improved survival and standard treatment includes external beam radiotherapy to a dose of 60 Gy in 30-33 fractions. Patients with poor prognostic features have a more limited benefit from radiotherapy. This article reviews the current state of knowledge on risk stratification and analyzes strategies that can be employed to better individualize treatment for poor-prognosis patients.

Optimizing radiotherapy schedules for elderly glioblastoma multiforme patients.

Glioblastoma is the most common malignant primary brain tumor. Despite recent advances, the overall prognosis remains poor with median survivals of approximately 1 year and 5-year survivals of less than 5%. Efforts at risk stratification have identified age and performance status as the most important prognostic features. It is well established that patients treated with postoperative radiation therapy have improved survival and functional capacity compared with unirradiated patients. Recent evidence suggests that the benefit of postoperative radiation persists even within the cohort aged 70 years or over. Some investigators have questioned whether the standard treatment schedule of 60 Gy delivered over a 6-week period is necessary for older patients with limited functional status. Alternative treatment schedules have been devised to reduce the inconvenience and morbidity of standard therapy. This review aims to evaluate the current state of knowledge on alternative radiotherapy schedules for elderly and poor-prognosis patients with glioblastoma.

CNS germinomas: what is the best treatment strategy?

CNS germ cell tumors are rare primary brain malignancies. Germinomas comprise approximately two-thirds of CNS germ cell tumors. Owing to their radiosensitivity, radiotherapy has been used to treat patients with CNS germinomas, with favorable treatment outcomes. Historically, craniospinal irradiation has been used. Given the concerns over long-term toxicities associated with craniospinal irradiation, reduced volume radiotherapy with or without chemotherapy has been employed. Data on the use of different strategies in the treatment of CNS germinomas are emerging but a standard strategy has not been established. This article reviews the different strategies used in the management of CNS germinomas.

What is the best adjuvant treatment for very young patients with medulloblastoma?

The standard treatment for medulloblastoma is surgery followed by adjuvant chemotherapy and external beam radiotherapy to the craniospinal axis and posterior fossa. However, in very young children, craniospinal irradiation has a more significant detrimental effect in terms of neurocognitive function and growth. This article reviews the different strategies used for very young patients with medulloblastoma.