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Type 2 endoleaks are the most common endoleak type following endovascular aneurysm repair. The natural history of these endoleaks can vary, with some demonstrating a self-limited or indolent course, while others can contribute to aneurysm sac enlargement and rupture. A variety of embolization techniques, including transarterial catheterization and direct sac puncture techniques, have been developed for the treatment of type 2 endoleaks. In this article, the authors review the indications, techniques, and outcomes of current treatment strategies for type 2 endoleaks.

Patients and patient advocates express a desire to speak directly with radiologists, who are ideally suited to answer imaging-related questions and recommend for further imaging or testing. While web-based patient portals have improved patient access to reports of radiology examinations, they do little to help patients understand the report, and rarely facilitate contact with their radiologists. We implemented an alias phone number that forwarded to the smartphone of each participating radiologist and embedded it in 3896 reports over 8 months. It was embedded as an invitation to the individual viewing the report to call with questions. For each call received, we logged parameters such as call duration, call reason, and required radiologist time/resources. Finally, the call was documented in the electronic medical record. Radiologists received 27 calls exclusively about cross-sectional exams: 22 from patients or caregivers, and 5 from physicians. The reasons for the calls included term definitions, correction of dictation errors, findings not specifically mentioned, and clinical impact of findings. Time spent on the phone with patients averaged 8.6 min. When including the time spent reviewing the images, patient chart, and/or literature; the total radiologist time per call was approximately 13.9 min. Averaged over all of the exams in the study, this service added 5 s to each exam. While the total call rate was low, implementation of this program required minimal effort. The aliased phone number masked the radiologist's phone number and allowed scheduled consultation hours. Even when called, the time to address questions appears to be minimal.

In the era of precision medicine, biopsies are playing an increasingly central role in cancer research and treatment paradigms; however, patient outcomes and analyses of biopsy quality, as well as impact on downstream clinical and research applications, remain underreported. Herein, we report biopsy safety and quality outcomes for percutaneous core biopsies of hepatocellular carcinoma (HCC) performed as part of a prospective clinical trial. Patients with a clinical diagnosis of HCC were enrolled in a prospective cohort study for the genetic, proteomic, and metabolomic profiling of HCC at two academic medical centers from April 2016 to July 2020. Under image guidance, 18G core biopsies were obtained using coaxial technique at the time of locoregional therapy. The primary outcome was biopsy quality, defined as tumor fraction in the core biopsy. 56 HCC lesions from 50 patients underwent 60 biopsy events with a median of 8 core biopsies per procedure (interquartile range, IQR, 7–10). Malignancy was identified in 45/56 (80.4%, 4 without pathology) biopsy events, including HCC (40/56, 71.4%) and cholangiocarcinoma (CCA) or combined HCC-CCA (5/56, 8.9%). Biopsy quality was highly variable with a median of 40% tumor in each biopsy core (IQR 10–75). Only 43/56 (76.8%) and 23/56 (41.1%) samples met quality thresholds for genomic or metabolomic/proteomic profiling, respectively, requiring expansion of the clinical trial. Overall and major complication rates were 5/60 (8.3%) and 3/60 (5.0%), respectively. Despite uniform biopsy protocol, biopsy quality varied widely with up to 59% of samples to be inadequate for intended purpose. This finding has important consequences for clinical trial design and highlights the need for quality control prior to applications in which the presence of benign cell types may substantially alter findings.

The recognition of inferior vena cava filter related complications has motivated increased attentiveness in clinical follow-up of patients with inferior vena cava filters and has led to development of multiple approaches for retrieving filters that are challenging or impossible to remove using conventional techniques. Endobronchial forceps and excimer lasers are tools for designed to aid in complex inferior vena cava filter removals. This article discusses endobronchial forceps-assisted and excimer laser-assisted inferior vena cava filter retrievals.

Introduction The aim of this study is to compare an intravenous (IV) catheter system which uses a retractable guidewire (RG-IV) designed to facilitate IV placement with a conventional IV (C-IV) catheter control. Materials and methods A prospective, randomized design was used. Patients referred to interventional radiology for outpatient procedures were offered participation. Enrollment occurred between August and November 2013. Patients were assigned to receive the RG-IV or C-IV in a 1:1 randomization scheme. After assignment, up to three attempts by a registered nurse occurred with the assigned device; if all three attempts failed, crossover to the other device occurred. The primary outcome variable was first-attempt success at IV placement. Secondary outcome variables included patient and clinician satisfaction, number of attempts, and time to successful placement. Two hundred twenty patients were enrolled (139 men, 81 women) in the study. Results Of the 220 patients, two were withdrawn prior to IV attempt leaving 218 subjects, 109 in each group. First attempt success (77% RG-IV vs. 82% C-IV, p = 0.5), number of attempts to achieve IV access (1.26 RG-IV vs. 1.29 C-IV, p = 0.98), and time to achieve IV success (2.9 minutes RG-IV vs. 2.7 C-IV, p = 0.82) did not differ between groups. Patient satisfaction with insertion was higher in the C-IV group (4.5/5 vs. 3.9/5, pConclusions In an interventional radiology outpatient population, the RG-IV and C-IV were comparable in first-attempt success, number of attempts, and time to achieve IV success. Patient satisfaction was higher with C-IV.

A 65-year-old patient with a history of DVT and contraindication to anticoagulation status post IVC filter placement 3 months ago is now tolerating anticoagulation and presents for IVC filter retrieval (Fig. 7.1).

While patient-derived xenograft (PDX) models of hepatocellular carcinoma (HCC) have been successfully generated from resected tissues, no reliable methods have been reported for the generation of PDXs from patients who are not candidates for resection and represent the vast majority of patients with HCC. Here we compare two methods for the creation of PDXs from HCC biopsies and find that implantation of whole biopsy samples without the addition of basement membrane matrix favors the formation of PDX tumors that resemble Epstein-Barr virus (EBV)-driven B-cell lymphomas rather than HCC tumors. In contrast, implantation with Matrigel supports growth of HCC cells and leads to a high rate of HCC tumor formation from these biopsies. We validate the resulting PDXs, confirm their fidelity to the patients’ disease and conclude that minimally invasive percutaneous liver biopsies can be used with relatively high efficiency to generate PDXs of HCC.

Purpose: To evaluate the technical success, clinical success, and complication rates of endovascular revascularization for below-the-elbow (BTE) peripheral artery disease. Materials and Methods: A retrospective review was performed of 19 patients (mean age 63 years; 12 men) with critical hand ischemia (CHI) who underwent 25 interventions in 19 arms between October 2010 and June 2017. Access was attained using 4-F or 5-F sheaths via antegrade brachial, retrograde radial, or fistula/graft access routes depending on the target vessel. A 0.018-inch hydrophilic microwire was used for intimal or subintimal recanalization. Angioplasty was performed over a 0.014-inch guidewire using low-profile balloons. The primary endpoint of the study was technical success, defined as successful lesion crossing/dilation, with residual stenosis

The purpose of the study was to evaluate prognostic factors for survival outcomes following embolotherapy for neuroendocrine tumor (NET) liver metastases.This was a multicenter retrospective study of 155 patients (60 years mean age, 57 % male) with NET liver metastases from pancreas (n = 71), gut (n = 68), lung (n = 8), or other/unknown (n = 8) primary sites treated with conventional transarterial chemoembolization (TACE, n = 50), transarterial radioembolization (TARE, n = 64), or transarterial embolization (TAE, n = 41) between 2004 and 2015. Patient-, tumor-, and treatment-related factors were evaluated for prognostic effect on hepatic progression-free survival (HPFS) and overall survival (OS) using unadjusted and propensity score-weighted univariate and multivariate Cox proportional hazards models.Median HPFS and OS were 18.5 and 125.1 months for G1 (n = 75), 12.2 and 33.9 months for G2 (n = 60), and 4.9 and 9.3 months for G3 tumors (n = 20), respectively (p 0.05). Tumor burden 50 % hepatic volume demonstrated 5.5- and 26.8-month shorter median HPFS and OS, respectively, versus burden ≤50 % (p 0.05). There were no significant differences in HPFS or OS between gut or pancreas primaries. In multivariate HPFS analysis, there were no significant differences among embolotherapy modalities. In multivariate OS analysis, TARE had a higher hazard ratio than TACE (unadjusted Cox model: HR 2.1, p = 0.02; propensity score adjusted model: HR 1.8, p = 0.11), while TAE did not differ significantly from TACE.Higher tumor grade and tumor burden prognosticated shorter HPFS and OS. TARE had a higher hazard ratio for OS than TACE. There were no significant differences in HPFS among embolotherapy modalities.

The management of endoleaks remains an inherent challenge to endovascular aneurysm repair (EVAR), particularly as evolving techniques and devices have allowed treatment of increasingly complex aneurysm anatomy. Endovascular techniques are the favored modality for endoleak repair and include techniques to bridge the endoleak defector and embolize the endoleak nidus and inflow/outflow vessels. Conversion to surgical repair remains the definitive option in cases where less invasive methods have failed or are precluded. In this article, the authors review evidence on the indications, approach, and outcomes of current techniques for endoleak management.

The treatment for iliofemoral deep venous thrombosis (DVT) is challenging, as the use of anticoagulation alone can be insufficient for restoring venous patency and thus lead to prolongation of acute symptoms and an increased risk of chronic complications, including venous insufficiency and postthrombotic syndrome (PTS). In these cases, earlier and more complete thrombus removal can ameliorate acute symptoms and reduce long-term sequelae. Endovascular therapies involving the use of pharmacologic, mechanical, and combined pharmacomechanical modalities have been developed to achieve these goals. The most frequently used of these techniques, catheter-directed thrombolysis (CDT), involves the infusion of a thrombolytic agent through a multiple-side-hole catheter placed within the thrombosed vein to achieve high local doses and thereby break down the clot while minimizing systemic thrombolytic agent exposure. Randomized controlled trial results have indicated decreased PTS rates and improved venous patency rates in patients treated with CDT compared with these rates in patients treated with anticoagulation. The use of newer pharmacomechanical techniques, as compared with conventional CDT, reduces procedural times and thrombolytic agent doses and is the subject of ongoing investigations. Endovascular thrombus removal techniques offer a means to improve venous valvular function and decrease the risk of debilitating long-term complications such as PTS and are a promising option for treating patients with iliofemoral DVT. (©)RSNA, 2016.

Background Spinal cord cavernous malformations (CMs) are associated with 2 types of angiographically occult "cryptic venous anomalies," which differ in location with respect to the spinal cord. The anatomic distinction between superficial and intramedullary is important in that the latter heighten the risks of CM resection. Objective To report the observations of both types of cryptic venous anomalies documented during spinal digital subtraction angiography enhanced with flat-panel catheter angiotomography (FPCA). Methods Spinal digital subtraction angiography enhanced with FPCA was performed in 2 adult patients with magnetic resonance imaging--documented intramedullary spinal cord CMs and prominent, nonspecific flow voids at the same levels. FPCA was obtained by selective injection of left T4 (case 1) and left T9 (case 2) with 5F Cobra 2 catheters (Terumo, Japan) during a 20-second rotational acquisition. Thirty milliliters of a 75% saline and 25% contrast solution (Omnipaque 300; GE) was administered. The rotational data set was reconstructed on a dedicated workstation (Leonardo; Siemens, Erlangen, Germany) through the use of regular and high-resolution matrixes, 0.4- and 0.1-mm voxel size, respectively. Results Spinal digital subtraction angiography was unremarkable in both cases. In case 1, FPCA findings indicated an atypical network of prominent posterior perimedullary veins. In case 2, FPCA identified radially oriented channels forming a caput medusae pattern collecting into an enlarged intramedullary vein. Conclusion The unique ability of FPCA to image the spinal venous system enables the angiographic detection and characterization of abnormal spinal veins associated with CMs. Differentiating between the types of associated cryptic venous malformations may aid in surgical planning because the intramedullary type is associated with a higher risk of surgical complication.

Objective: Spinal digital subtraction angiography (SpDSA) continues to be the imaging gold standard for the evaluation of spinal cord vascular disorders. The safety of this procedure has a poor historical reputation and there are few current reports on complication rates. We hypothesized that modern SpDSA can be performed with an acceptably low risk of iatrogenic complications. Methods: In this retrospective series, we reviewed 302 consecutive spinal angiograms performed during a 10-year period at our institution for the frequency of intraprocedural and postprocedural neurologic, non-neurologic, and local complications. Indications for SpDSA, prior noninvasive imaging findings, and angiographic diagnoses for each case were assessed to evaluate the diagnostic contribution of the procedure. Results: There were no intraprocedural or postprocedural neurologic complications in the studied cohort. Systemic complications occurred in 2 cases (0.7%), in the form of back spasms in one patient and pulmonary edema in the other. Both recovered promptly and were discharged at baseline status. Access-site complications included 3 groin hematomas (1.0%), all managed conservatively. MRI findings showed 51% sensitivity and 83% specificity for spinal vascular malformations. A total of 31% of patients with the preangiographic diagnosis of transverse myelitis were found to have a vascular malformation. Conclusion: SpDSA carries very low risks of neurologic and systemic complications, while offering a gold-standard level of diagnostic confidence for the evaluation of the normal and pathologic vasculature of the spinal cord.

Congenital cerebral vascular anomalies include a spectrum of conditions that result from perturbation of normal developmental processes. Although some of these conditions are asymptomatic and well compensated by collateral circulation, others can cause significant morbidity or produce a range of complications for affected patients. Knowledge of the underlying developmental etiologies and the associated imaging characteristics helps fully elucidate the morphologic and hemodynamic details of these lesions and determine the necessity for any intervention.

Object Diffuse brainstem tumors are the most difficult type of pediatric CNS malignancy to treat. These inoperable lesions are treated with radiation alone or in combination with chemotherapy, and the survival rate is less than 10%. It is therefore essential to develop a reliable animal model to screen new therapeutic agents for the treatment of this type of tumor. Methods A multipotent human glioblastoma stemlike neurosphere line, 060919, was established from a surgically resected glioblastoma specimen; when cells were implanted intracranially into athymic nude mice, they formed invasive, vascular tumors that exhibited the features of glioblastoma. Ten female Fischer 344 rats received an injection of 75,000 F98 rat glioma cells and 10 female athymic nude rats received an injection of 75,000 060919 human glioblastoma stemlike cells in the pontine tegmentum of the brainstem. A control group of 5 female Fischer rats received an injection of saline in the same location as the animals in the tumor groups. Kaplan-Meier curves were generated for survival, and brains were processed postmortem for histopathological investigation. Results Both F98 cells and 060919 cells grew in 100% of the animals injected. Median survival of animals injected with F98 was 15 days, consistent with the authors' previous reports on the establishment of the brainstem tumor model using the F98 rat glioma line. Median survival of animals injected with 060919 was 31 days. Histopathological analysis of the tumors confirmed the presence of brainstem lesions in animals that received brainstem injections of F98 and in animals that received brainstem injections of 060919. The 060919 brainstem tumors histologically resembled glioblastoma. Conclusions Tumor take and median survival were consistent for animals injected in the brainstem with either the established F98 rat glioma cell line or the 060919 human glioblastoma stemlike neurosphere line. Histopathological features of the 060919 brainstem tumors resembled glioblastoma. Establishment of this human glioblastoma stemlike brainstem animal model will improve the evaluation and identification of more efficacious agents for the treatment of high-grade brainstem tumors.

Members of the tyrosine recombinase (YR) family of site-specific recombinases catalyze DNA rearrangements using phosphoryl transfer chemistry that is identical to that used by the type IB topoisomerases (TopIBs). To better understand the requirements for YR catalysis and the relationship between the YRs and the TopIBs, we have analyzed the in vivo and in vitro recombination activities of all substitutions of the seven active site residues in Cre recombinase. We have also determined the structure of a vanadate transition state mimic for the Cre–loxP reaction that facilitates interpretation of mutant activities and allows for a comparison with similar structures from the related topoisomerases. We find that active site residues shared by the TopIBs are most sensitive to substitution. Only two, the tyrosine nucleophile and a conserved lysine residue that activates the 5′-hydroxyl leaving group, are strictly required to achieve >5% of wild-type activity. The two conserved arginine residues each tolerate one substitution that results in modest recombination activity and the remaining three active site positions can be substituted with several alternative amino acids while retaining a significant amount of activity. The results are discussed in the context of YR and TopIB structural models and data from related YR systems.

Purpose To evaluate readmission rate and complications in patients undergoing same-day discharge following percutaneous thermal ablation of renal tumors. Materials and Methods Patients undergoing same-day discharge following thermal ablation of renal tumors were reviewed. The primary outcome was the rate of readmission within 30 days of same-day discharge. The secondary outcomes included the rate and clinical outcomes of periprocedural complications. Results Same-day discharge occurred in 166/174 patients (95%), of whom 2/166 (1%) required short-term readmission due to pulmonary embolism and acute-on-chronic kidney injury. Both patients recovered without permanent morbidity. Admission due to complications occurred in 8/174 (5%) cases, the majority of which were related to hemorrhage. No significant differences in rates of complications or admission were found between cryoablation and RF ablation. Major complications (Clavien–Dindo grade II or higher, SIR grade C or higher) occurred in 7/174 (4%) cases, the majority related to hemorrhage. All cases were detected in the standard 4 hour postprocedural observation period and managed conservatively. The mean hemorrhage volume was significantly larger in patients requiring admission versus those discharged the same day (289 mL vs 34 mL; P = .02). Higher-volume hemorrhage occurred in larger tumors (mean, 4.0 cm vs 3.0 cm; P = .04). There was no association between major complications and central tumor or age. Conclusions Routine same-day discharge following percutaneous renal tumor thermal ablation can be performed with a low rate of short-term readmission. The majority of periprocedural complications can be managed conservatively, and patients can be discharged the same day.

Purpose To evaluate growth kinetics and oncologic outcomes of patients with renal tumors undergoing active surveillance (AS) for residual viable tumor following percutaneous ablation. Materials and Methods Following percutaneous thermal ablation, residual tumor was detected in 21/133 (16%) patients on initial follow-up imaging, and AS was undertaken in 17/21 (81%) patients. Initial tumor volumes and volumes after ablation were assessed from cross-sectional imaging to calculate volumetric growth rate (VGR) and volume doubling time (VDT) of residual tumor. The rate of metastasis, overall survival, and renal cell carcinoma (RCC)–specific survival were compared between patients in the AS group and in the routine follow up group of patients who did not have residual tumor. Results Median tumor volume prior to ablation, after first ablation, and at final follow-up were 25 cm 3 , 6 cm 3 , and 6 cm 3 , respectively, in patients with residual tumor. Stable, mild, and moderate VGR occurred in 8/17 (47%), 4/17 (24%), and 5/17 (29%) cases, respectively. The 4 cases with fastest VDT underwent delayed intervention with ablation (n = 1) and nephrectomy (n = 3) without subsequent residual, recurrence, or metastasis. There was no significant difference in the rates of RCC metastasis, overall survival, or RCC-specific survival between AS and routine follow-up groups. Metastatic RCC and subsequent death occurred in 1 patient in the AS group, after the patient had refused offers for retreatment for local progression over 60.7 months of follow-up. Conclusions In cases when patients are not amenable to further intervention, AS of residual tumor may be an acceptable alternative and allows for successful delayed intervention when needed.

Background Mutations in ras genes are commonly found in human cancers and in animal models. Although mutations at codons 12, 13, and 61 of H-, N- and K-ras genes can activate their oncogenic function, mutations at codon 12 of K-ras are the most common mutations found among the three ras genes in human cancers. To investigate whether codon 12 of human K-ras is especially susceptible to carcinogens and/or whether carcinogen-DNA adducts at this codon are repaired less efficiently, we examined tobacco smoke carcinogen-induced DNA damage in normal human bronchial epithelial and fibroblast cells. Methods We used the UvrABC nuclease incision method in combination with ligation-mediated polymerase chain reaction to map the distribution of DNA adducts induced by benzo[a]pyrene diol epoxide (BPDE) and other bulky carcinogens within exons 1 and 2 in H-ras, N-ras, and K-ras. We also analyzed BPDE-DNA adduct repair efficiency in these three genes using the same method. Results Codons 12 and 14 of the K-ras gene were hotspots for carcinogen-DNA adduct formation, with little and no adduct formation at codons 13 and 61, respectively. The BPDE-DNA adducts formed at codon 14 were repaired almost twice as quickly as those formed at codon 12. There was some BPDE-DNA adduct formation at codons 12 of H-ras and N-ras, but this codon was not a hotspot. Furthermore, no substantial difference in repair rates between codon 12 and the other codons analyzed (codons 3 and 18) was observed in either the H-ras or N-ras genes. Conclusion These findings link the human cancer mutational hotspot at codon 12 of K-ras to preferential DNA damage and poor repair.

We report a case of intravitreal silicone oil migration into the subarachnoid space and cerebral ventricles, as seen on CT and MRI. During several admissions over the course of 23 months, the silicone oil was seen tracking along the optic apparatus and subsequently appeared in the ventricles as free-floating droplets. The patient experienced repeated headaches, but was worked up extensively for possible intracranial hemorrhage before the correct diagnosis was recognized.

Cerebral vasospasm is caused by subarachnoid hemorrhage (SAH) most often secondary to aneurysm rupture. Other less common causes of SAH include hemorrhage from an arteriovenous malformation, vasculitis, reversible cerebral vasoconstriction syndrome as well as cerebral trauma.

DNA fragments modified with chemically synthesized 7,12-dimethylbenz[a]anthracene anti-diol epoxide (anti-DMBADE) are sensitive to UvrABC nuclease incision. The incisions occur mainly 7 bases 5' and 4 bases 3' of an anti-DMBADE-modified adenine or guanine residue, and the kinetics of incision at different sequences in a DNA fragment are the same. These results indicate that UvrABC incision on anti-DMBADE-DNA adducts is independent of DNA sequences and is quantitative, the same as on syn-DMBADE-DNA adducts. This method was used to analyze the anti-DMBADE-DNA binding spectrum in the exon 2 region of the mouse H-ras gene, and it was found that anti-DMBADE binds to the two adenine residues at codon 61 of the H-ras gene with an average affinity. Previously, we have demonstrated that syn-DMBADE binds strongly to the adenines at codon 61 of H-ras; these results together suggest that the oncogenic mutation in H-ras may be induced by anti- and syn-DMBADE-DNA adducts.

BACKGROUND AND PURPOSE: While spinal DSA remains the reference standard technique for spinovascular imaging, visualizing spinal veins remains challenging due to their small size and motion artifacts. This study evaluates the ability of FPCA to overcome these obstacles. MATERIALS AND METHODS: Sixty-three FPCAs, performed by intersegmental artery injections in 57 patients, were prospectively evaluated. Entrance skin doses were compared with standard spinal DSA runs, including a venous phase and cerebral FPCAs. FPCA contributions were stratified as 1) provided no added information, 2) complemented spinal DSA findings, 3) assisted therapy planning, and 4) contributed principal diagnostic findings. RESULTS: No complications were observed. Diagnoses included vascular malformations (44%), stroke (9%), venous anomalies (10%), other (9%), and unremarkable (28%). Mean entrance skin doses were of 419 mGy for FPCA, 161 mGy for spinal DSA with venous phase, and 309 mGy for cerebral FPCAs. FPCA contributed the principal diagnostic finding in 16 cases (25.4%), assisted therapy planning in 13 cases (20.6%), complemented spinal DSA findings in 12 cases (19.1%), and provided no additional information in 20 cases (31.7%). In 8 of these 20 cases, FPCA documented a spinal venous anatomy that was poorly visualized or not visualized on spinal DSA. CONCLUSIONS: Spinal FPCA is safe, with a moderate increase in radiation dose, compared with spinal DSA with venous phase or cerebral FPCA. It proved particularly valuable for therapy planning and the diagnosis of venous abnormalities. This study suggests that FPCA has an important role to play in the evaluation of the spinal venous system.

The cerebral vascular architecture is both unique and heterogeneous in its structure, organization, and function. For many years, it was believed that brain vasculature was dominated by nonanastomosing terminal or "end-arteries." This was primarily based upon the observation of discrete distribution of brain infarcts after embolic occlusion of particular vessels. It was not until the detailed anatomy work of Pfeiffer in 1928 that the new concept of an almost-uninterrupted vascular network of brain vasculature was proposed. Since then, the cerebral vascular anatomy and embryology has been studied in great detail. Its full description is beyond the scope of this article, and our aim is to provide a brief overview of the development of cranial arterial anatomy, with special emphasis on commonly encountered anatomical variations that may have clinical implications. The failure to recognize these can lead to misdiagnosis as well as otherwise-preventable iatrogenic injuries and complications. We describe the proposed underlying embryologic processes, pathology and clinical implications of these variations, including aberrant internal carotid arteries, carotid agenesis and hypoplasia, azygous anterior cerebral arteries, arterial fenestrations, and persistent embryonic vessels.

Diffuse brainstem tumors are the most difficult type of pediatric CNS malignancy to treat. These inoperable lesions are treated with radiation alone or in combination with chemotherapy, and the survival rate is less than 10%. It is therefore essential to develop a reliable animal model to screen new therapeutic agents for the treatment of this type of tumor.A multipotent human glioblastoma stemlike neurosphere line, 060919, was established from a surgically resected glioblastoma specimen; when cells were implanted intracranially into athymic nude mice, they formed invasive, vascular tumors that exhibited the features of glioblastoma. Ten female Fischer 344 rats received an injection of 75,000 F98 rat glioma cells and 10 female athymic nude rats received an injection of 75,000 060919 human glioblastoma stemlike cells in the pontine tegmentum of the brainstem. A control group of 5 female Fischer rats received an injection of saline in the same location as the animals in the tumor groups. Kaplan-Meier curves were generated for survival, and brains were processed postmortem for histopathological investigation.Both F98 cells and 060919 cells grew in 100% of the animals injected. Median survival of animals injected with F98 was 15 days, consistent with the authors' previous reports on the establishment of the brainstem tumor model using the F98 rat glioma line. Median survival of animals injected with 060919 was 31 days. Histopathological analysis of the tumors confirmed the presence of brainstem lesions in animals that received brainstem injections of F98 and in animals that received brainstem injections of 060919. The 060919 brainstem tumors histologically resembled glioblastoma.Tumor take and median survival were consistent for animals injected in the brainstem with either the established F98 rat glioma cell line or the 060919 human glioblastoma stemlike neurosphere line. Histopathological features of the 060919 brainstem tumors resembled glioblastoma. Establishment of this human glioblastoma stemlike brainstem animal model will improve the evaluation and identification of more efficacious agents for the treatment of high-grade brainstem tumors.

Genomic injury induced by environmental carcinogens, such as polycyclic aromatic hydrocarbons and aromatic amines, is the initial step that can trigger mutagenesis and carcinogenesis. In addition to the physico-chemical property of DNA damaging agents, several important factors such as primary sequence, chromatin structure, methylation, protein association, and transcriptional activity can affect not only the initial level and distribution of DNA damage but also the efficiency of repair. Therefore, mapping the DNA damage induced by environmental agents in cancer-related genes such as p53 and ras at the sequence level provides essential information for assessing their carcinogenic potential. Recently, using the E. coli nucleotide excision enzyme complex, UvrABC nucleases in combination with ligation-mediated polymerase chain reaction, we developed a method to map DNA damage in the p53 and ras genes. These studies led us to conclude that targeted DNA damage, in combination with growth selection, contributes greatly in shaping the mutation spectrum in these genes in human cancer. Here we present the rationale and details of this approach, typical experimental results and necessary precautions.

7-Methylpyrido[3,4-c]psoralen has recently been found to photosensitize the crosslinking and cleavage of double-stranded pBR322 DNA (4361 bp) with an unusual degree of site specificity. Following cleavage of the photosensitized pBR322 with the restriction enzymes Pvu II and BamH I, the main fragments were analyzed electrophoretically. Only three possible cleavage areas on the plasmid were suggested by this analysis. They were within the ranges bounded by the positions 801–926, 3172–3303 and 4226–4310. The sensitizer also induced selective cleavage in the related plasmid pUC19 (2686 bp), but the pattern was somewhat more complicated and was not analyzed in detail.

In the P53 tumor suppressor gene, a remarkably large number of somatic mutations are found at methylated CpG dinucleotides. We have previously mapped the distribution of (±) anti -7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[ a ]pyrene (BPDE) adducts along the human P53 gene [Denissenko, M. F., Pao, A., Tang, M.-s. & Pfeifer, G. P. (1996) Science 274, 430–432]. Strong and selective formation of adducts occurred at guanines in CpG sequences of codons 157, 248, and 273, which are the major mutational hot spots in lung cancer. Chromatin structure was not involved in preferential modification of these sites by BPDE. To investigate other possible mechanisms underlying the selectivity of BPDE binding, we have mapped the adducts in plasmid DNA containing genomic P53 sequences. The adduct profile obtained was different from that in genomic DNA. However, when cytosines at CpG sequences were converted to 5-methylcytosines by the CpG-specific methylase Sss I and the DNA was subsequently treated with BPDE, adduct hot spots were created which were similar to those seen in genomic DNA where all CpGs are methylated. A strong positive effect of 5-methylcytosine on BPDE adduct formation at CpG sites was also documented with sequences of the PGK1 gene derived from an active or inactive human X chromosome and having differential methylation patterns. These results show that methylated CpG dinucleotides, in addition to being an endogenous promutagenic factor, may represent a preferential target for exogenous chemical carcinogens. The data open new avenues concerning the reasons that the majority of mutational hot spots in human genes are at CpGs.