Successful frameless radiosurgery for glossopharyngeal neuralgia - Case report.

Idiopathic glossopharyngeal neuralgia (GPN) is a rare disorder of the ninth cranial nerve characterized by severe paroxysmal pain affecting the ear, tongue and throat. Frame-based radiosurgery (SRS) has been shown to be an effective option. We report the first successful pain alleviation by frameless SRS in a GPN patient that failed both medical and surgical interventions.

Successful stereotactic body radiation therapy for stage I non-small cell lung cancer with malignant hypercalcemia - Case report.

In patients with lung malignancy, the development of malignant hypercalcemia (MH) carries a dismal prognosis and represents a major therapeutic challenge given that conventional medical treatments have limited durability. Robust and lasting hypercalcemic reversal and symptomatic relief have been documented following surgical tumor resection. Stereotactic body radiation therapy (SBRT) has emerged as an effective treatment modality in medically inoperable patients with Stage I non-small cell lung cancer (NSCLC). In the current report, SBRT achieved durable tumor control and calcemic correction in a medically inoperable 79 year-old man with Stage I NSCLC patient with parathyroid hormone-related peptide (PTHrP)-induced MH.

Frame and frameless linear accelerator-based radiosurgery for idiopathic trigeminal neuralgia.

PURPOSE: We report outcome of linear accelerator (Linac)-based stereotactic radiosurgery (SRS) for trigeminal neuralgia (TGN) utilizing rigid head frame (RF) and facemask (FM) immobilization.Method: From November 2008 to October 2012, 48 patients with idiopathic TGN underwent primary SRS by a dedicated Linac. RF immobilization was utilized for 34 patients, and frameless image-guided radiosurgery (IGRS) with FM immobilization was performed in 14 patients. Treatment outcome was assessed by patient interviews with a 7-item questionnaire. RESULTS: Sub-millimeter targeting accuracy (0.71±0.31 mm) was recorded for frameless IGRS by a novel hidden-target phantom method. With a follow-up of 26 months, significant pain relief was recorded in 43 (89%) patients, including 26 (54%) complete and 17 (35%) partial responses; with a significant reduction of 2.4±1.3 points (p < 0.01) on the 5-point Barrow Neurological Institute pain scale. No significant pain relief difference (p = 0.23) was detected between patients immobilized by RF and FM. Notable pin site problems were reported in 9 (26%) of 34 patients immobilized by RF. CONCLUSION: Frameless IGRS with FM immobilization is more patient friendly and can achieve as excellent treatment outcome as with RF immobilization for idiopathic TGN.

DNA topoisomerase I drugs and radiotherapy for lung cancer.

Lung cancer represents the most common cause of cancer-related mortality in the United States and around the world. DNA topoisomerase I (TOP1) drugs such as irinotecan and topotecan represent a unique class of chemotherapeutic agents that exhibit not only potent cytotoxic effect, but also tumor-selective radiation-sensitizing effect. The mechanism of cytotoxicity and radiation sensitization by TOP1 drugs has been intensely investigated. Modern radiotherapy, aided by improved imaging and treatment delivery technology, is capable of targeting tumors more precisely, while sparing surrounding critical structures. Clinical trials with camptothecin derivatives and radiotherapy have been conducted in lung cancers. Combined modality therapy with TOP1 drugs and radiotherapy offers a new frontier for lung cancer therapy. We review the present state of TOP1-targeted chemotherapy and modern radiotherapy for lung cancer.

The option of Linac-based radiosurgery in a Gamma Knife radiosurgery center.

OBJECTIVE: Due to the fundamental differences in treatment delivery, linear-accelerator-based radiosurgery can be complementary to Gamma Knife (GK) for intracranial lesions. We reviewed the effect of adding GK to an existing linear accelerator (Linac)-based radiosurgery practice and analyzed case selections for the two modalities. PATIENTS AND METHODS: UC Davis Medical Center installed a Leksell Gamma Knife Model C in October 2003 to supplement an established Linac-based radiosurgery program. Radiosurgery indications for the 15 months before and after installation were compared. RESULTS: Radiosurgery cases expanded by twofold from 68 patients before GK installation to 139 after, with 106 treated by GK and 33 by Linac. Besides a major increase for trigeminal neuralgia and a general growth for acoustic neuroma, meningioma and brain metastases, case numbers for glioma and arteriovenous malformation (AVM) remained stable. Considering case selections for Linac, glioma decreased from 28 to 18%, while meningioma and metastases increased from 9 to 21% and 38-46%, respectively. The Linac patients receiving fractionated treatment also increased from 37 to 61%. CONCLUSIONS: While the majority of patients were treated with GK, a significant proportion was judged to be suited for Linac treatment. This latter group included particularly patients who benefit from fractionated therapy.

Clinical impact of magnetic resonance imaging on Gamma Knife surgery for brain metastases.

OBJECT: Stereotactic radiosurgery is beneficial for patients with a limited number of small brain metastases. Increased numbers of brain metastases, not infrequently at unreachable locations, are identified using thin-section magnetic resonance (MR) imaging on the day of Gamma Knife surgery (GKS). To improve patient selection and design better treatment strategies, a retrospective study was conducted to determine factors that may contribute to detecting additional brain metastases on the day of GKS. METHODS: A total of 100 patients with brain metastases who underwent GKS between October 2003 and May 2006 at the University of California Davis Medical Center were included in the present study. Patients were categorized by age, sex, Karnofsky Performance Scale score, status of systemic disease, histological characteristics of the primary tumor, and whether they received previous whole-brain radiotherapy (WBRT). The number of lesions identified by diagnostic MR imaging at referral, by thin-section double-contrast MR imaging on the day of GKS, and the actual lesions treated by GKS were recorded. The diagnostic MR images were categorized in terms of section thickness and time interval before GKS. CONCLUSIONS: The characteristics of this patient population match well with the general GKS practice. Fifty-six had been treated with WBRT. On average, patients presented with 2.2 +/- 1.7 lesions, a number based on their original diagnostic MR imaging, had 3.6 +/- 3.4 lesions identified on the thin-section treatment MR imaging (p < 0.05), and underwent treatment of 3.1 +/- 2.6 lesions on the day of GKS. Significantly, treatment was compromised in 21 patients, in whom not all additional lesions could be treated with the initial headframe placement. Analysis shows that a significantly greater number of lesions were detected using thin-section MR imaging on the day of GKS in patients who had undergone thick-section diagnostic MR imaging, did not receive WBRT, and had progressive systemic disease. To optimize treatment planning and minimize additional treatment, the number of metastases needs to be determined accurately before frame placement, ideally by performing thin-section MR imaging, as used on the day of GKS.

Ku86 modulates DNA topoisomerase I-mediated radiosensitization, but not cytotoxicity, in mammalian cells.

Ku86 is an integral component of the nonhomologous end-joining (NHEJ) pathway of cellular double-strand break repair. In the current study, we investigated the role of Ku86 in DNA topoisomerase I-mediated radiosensitization induced by camptothecin in mammalian cells. Interestingly, as examined by clonogenic survival assay, a 30-minute camptothecin treatment induced significantly higher levels of radiosensitization in the Ku86-deficient Chinese hamster ovary xrs-6 cells than in the hamster Ku86-complemented xrs-6+hamKu86 cells, albeit exhibiting similar drug toxicity in these two cell lines. To confirm these findings, similar studies were conducted in two pairs of transfectant sublines established from the Ku86-deficient Chinese hamster lung fibroblast XR-V15B cells. Compared with the vector-alone sublines, radiation resistance was restored in the human Ku86-complemented sublines without alteration of cell cycle distributions. Again, significantly higher levels of camptothecin-induced radiosensitization were observed in the vector-alone sublines than in the Ku86-complemented XR-V15B sublines. In contrast, camptothecin treatments, ranging from 0.5 to 24 hours, induced similar cytotoxicities in both vector-alone and Ku86-complemented sublines. Because neither the DNA-damaging etoposide and cisplatin nor the tubulin-binder vinblastine induced enhanced levels of radiosensitization in the Ku86-deficient cells, Ku86 seems to uniquely affect topoisomerase I-mediated radiosensitization induced by camptothecin. Furthermore, cotreatment with DNA replication inhibitor aphidicolin abolished both camptothecin-induced cytotoxicity and radiosensitization in the vector-alone, as well as the Ku86-complemented subline cells, indicating both events are initiated by replication-dependent topoisomerase I-mediated DNA damages. Taken together, our data show a novel role of Ku86 in modulating topoisomerase I-mediated radiosensitization, but not cytotoxicity, in mammalian cells.

Silatecan DB-67 is a novel DNA topoisomerase I-targeted radiation sensitizer.

The silatecan 7-tert-butyldimethylsilyl-10-hydroxy-camptothecin (DB-67) represents a new generation of camptothecin derivatives that exhibits a potent in vitro DNA topoisomerase I (TOP1)-mediated DNA-damaging activity, improved blood stability, and holds significant promise for the treatment of human cancers. In this study, we characterize the role of TOP1 in mediating the radiosensitization activity of DB-67. As examined by clonogenic survival assay, DB-67 exhibited potent radiosensitization activity at a concentration 10-fold lower than camptothecin in the human glioma D54-MG and T-98G cells, which harbor wild-type and mutant p53, respectively. Analyzed by the single-hit multitarget model, DB-67 induced radiosensitization by obliterating the "shoulder" of the radiation survival curve in the D54-MG cells. The in vivo targeting of TOP1 by DB-67 was investigated by immunoblot analysis. In a dose-dependent manner, DB-67 specifically stimulates covalent linking of TOP1 to chromosomal DNA at concentrations 10-fold lower than camptothecin in the D54-MG cells. The potency of in vivo targeting of TOP1 by DB-67 correlates well with its cytotoxicity and radiosensitization activity. Furthermore, DB-67 exhibited substantially less cytotoxicity and radiosensitization activity in the TOP1 mutant Chinese hamster lung fibroblast DC3F/C-10 cells than in their parental DC3F cells. Together, our data show that DB-67 exhibits potent cytotoxicity and radiosensitization activity by targeting TOP1 in mammalian cells and has great potential for being developed to treat human cancers.

Secondary supratentorial primitive neuroectodermal tumor following irradiation in a patient with low-grade astrocytoma.

We report a case of a supratentorial primitive neuroectodermal tumor (PNET) that occurred 12 years after cranial irradiation for a grade II astrocytoma. Neuroimaging was unable to distinguish between a recurrence of the original neoplasm and the development of a new, distinct entity. Pathologic review assisted by immunohistochemical staining, however, revealed a high-grade PNET. Although rare, PNET needs to be included in the differential diagnoses for previously irradiated patients, who develop recurrent brain tumors in the presence of uncharacteristic imaging features.

Induction of radiosensitization by indolocarbazole derivatives: the role of DNA topoisomerase I.

DNA topoisomerase I (TOP1) mediates the induction of radiosensitization (RS) by camptothecin derivatives in mammalian cells. Many indolocarbazole (INDO) derivatives have been shown to induce TOP1-mediated DNA damage (T1DD). In the current study, we characterized the cytotoxic and radiosensitizing activities of six INDO derivatives in relation to their efficiencies to induce T1DD. Evaluated by clonogenic survival assay, the INDO derivatives F1, F5, and F7, but not F43, F44, or F71, were shown to induce significant levels of RS in the human breast cancer MCF-7 cells at noncytotoxic concentrations. Analyzed by the single-hit multitarget (SHMT) model, F1, F5, and F7, like camptothecin, induce RS by obliterating the "shoulder" of radiation survival curve. In contrast to the Chinese hamster DC3F cells, the TOP1 mutant DC3F/C10 cells demonstrated cross-resistance to the cytotoxicity of F7 and the induction of RS by F7 and F1. The efficiencies to induce T1DD were determined by 1) drug-stimulated TOP1 cleavage assay in vitro and 2) K(+)-SDS coprecipitation assay in vivo. These compounds exhibited varying efficiencies in inducing T1DD with the following order: F71, F7 > F44, F1 > F5 > F43. It is surprising that the individual efficiency of these compounds to induce T1DD correlates well with their individual cytotoxicity but not RS activity. Taken together, our data demonstrate that certain, but not all, INDO derivatives capable of inducing T1DD can induce RS in mammalian cells. The INDO derivatives F1, F5, and F7 have the potential to be developed as a new class of radiation sensitizers.

Enhancement of radiotherapy with DNA topoisomerase I-targeted drugs.

Since its discovery more than a century ago, ionizing radiation has become a mainstay therapy for patients suffering from cancers. Currently, radiotherapy provides cure or palliative care for approximately one half of the cancer population. The anticancer efficacy of radiotherapy is, however, largely limited by its lack of tumor specificity and, consequently, normal tissue toxicity. There is an urgent need to develop systemic adjuncts that can enhance the efficacy and the selectivity of radiotherapy toward tumor cells. DNA topoisomerase I (TOP1)-targeted drugs such as camptothecin derivatives represent a novel class of chemotherapeutic agents that have recently been shown to be excellent radiation sensitizers. Combined modality therapy with TOP1-targeted drugs and radiotherapy represents a new promising cancer therapy. The mechanism of enhancement of radiotherapy by TOP1-targeted drugs is under intense investigation. Clinical trials using combinations of radiation and camptothecin derivatives are also currently ongoing in various solid tumors including brain, head and neck, and lung cancers. A better understanding of the radiosensitization (RS) mechanism of TOP1-targeted drugs is pivotal to their clinical application, as well as in guiding the development of better radiation sensitizers.

Targeted radiosensitization with DNA topoisomerase I drugs.

Extract: Radiation has become a mainstay therapy and currently provides care for approximately one half of the cancer population since its discovery more than a century ago. However, the efficacy of radiotherapy is largely restricted by the radiation-associated side effects, which in a way reflects the lack of tumor specificity of radiation. Drugs targeting DNA topoisomerase I (TOP1) are a novel class of anticancer agents with established activity against many cancers. In addition to their ability to kill cancer cells directly, these drugs are also excellent radiation sensitizers that can enhance the cell-killing effect of radiation. Combining TOP1-targeted drugs and radiotherapy represents a new promising cancer therapy. Here, we briefly review, from basic science to clinical application, the current status of targeted radiosensitization (RS) by combining TOP1 drugs with radiation.