Tumor resection in a shared-resource magnetic resonance operating room: experience at the University of Cincinnati.

INTRODUCTION: At the University of Cincinnati, we have developed a shared-resource magnetic resonance operating suite that facilitates performance of both neurosurgical and diagnostic procedures in a single unit. METHODS: The shared-resource magnetic resonance operating suite utilizes a Hitachi AIRIS II, 0.3-T, vertical field, open MRI unit located in the MROR. This magnet can be used for both diagnostic and interventional procedures. The addition of a rotating-operating table permits neurosurgical procedures to be performed outside of the 5-G line using standard neurosurgical equipment and operating microscopes. RESULTS: We review our results with the shared-resource magnetic resonance operating room including the tabulated results from 30 transsphenoidal procedures and 63 glioma procedures. In addition, 2832 diagnostic procedures have been performed in the first 4 years of use. CONCLUSION: The shared-resource intraoperative MRI facility produces high-quality intraoperative imaging studies, equal to those of high-resolution magnets, and is valuable in enabling the surgeon to achieve the planned degree of resection of glioma and pituitary tumors. The ability to perform diagnostic procedures in a shared unit has been a cost-effective solution for our institution.

Glioma resection in a shared-resource magnetic resonance operating room after optimal image-guided frameless stereotactic resection.

OBJECTIVE: We describe a shared-resource intraoperative magnetic resonance imaging (MRI) design that allocates time for both surgical procedures and routine diagnostic imaging. We investigated the safety and efficacy of this design as applied to the detection of residual glioma immediately after an optimal image-guided frameless stereotactic resection (IGFSR). METHODS: Based on the twin operating rooms (ORs) concept, we installed a commercially available Hitachi AIRIS II, 0.3-tesla, vertical field, open MRI unit in its own specially designed OR (designated the magnetic resonance OR) immediately adjacent to a conventional neurosurgical OR. Between May 1998 and October 1999, this facility was used for both routine diagnostic imaging (969 diagnostic scans) and surgical procedures (50 craniotomies for tumor resection, 27 transsphenoidal explorations, and 5 biopsies). Our study group, from which prospective data were collected, consisted of 40 of these patients who had glioma (World Health Organization Grades II-IV). These 40 patients first underwent optimal IGFSRs in the adjacent conventional OR, where resection continued until the surgeon believed that all of the accessible tumor had been removed. Patients were then transferred to the magnetic resonance OR to check the completeness of the resection. If accessible residual tumor was observed, then a biopsy and an additional resection were performed. To validate intraoperative MRI findings, early postoperative MRI using a 1.5-tesla magnet was performed. RESULTS: Intraoperative images that were suitable for interpretation were obtained for all 40 patients after optimal IGFSRs. In 19 patients (47%), intraoperative MRI studies confirmed that adequate resection had been achieved after IGFSR alone. Intraoperative MRI studies showed accessible residual tumors in the remaining 21 patients (53%), all of whom underwent additional resections. Early postoperative MRI studies were obtained in 39 patients, confirming that the desired final extent of resection had been achieved in all of these patients. One patient developed a superficial wound infection, and no hazardous equipment or instrumentation problems occurred. CONCLUSION: Use of an intraoperative MRI facility that permits both diagnostic imaging and surgical procedures is safe and may represent a more cost-effective approach than dedicated intraoperative units for some hospital centers. Although we clearly demonstrate an improvement in volumetric glioma resection as compared with IGFSR alone, further study is required to determine the impact of this approach on patient survival.

Intraoperative magnetic resonance imaging to determine the extent of resection of pituitary macroadenomas during transsphenoidal microsurgery.

OBJECTIVE: Well-established surgical goals for pituitary macroadenomas include gross total resection for noninvasive tumors and debulking with optic chiasm decompression for invasive tumors. In this report, we examine the safety, reliability, and outcome of intraoperative magnetic resonance imaging (iMRI) used to assess the extent of resection, and thus the achievement of preoperative surgical goals, during transsphenoidal microneurosurgery. METHODS: Our magnetic resonance operating room contains a Hitachi AIRIS II 0.3-T, vertical-field open magnet (Hitachi Medical Systems America, Inc., Twinsburg, OH). A motorized scanner tabletop moves the patient between the imaging and operative positions. For transsphenoidal surgery, the patient is positioned directly on the scanner tabletop so that the surgical field is located between 1.2 and 1.6 m from the magnet isocenter. At this location, the magnetic field strength is low (<20 G), thus permitting the use of many conventional surgical instruments. Thirty consecutive patients with pituitary macroadenomas underwent tumor resection in our magnetic resonance operating room by use of a standard transsphenoidal approach. After initial resection, the patient was advanced into the scanner for imaging. If residual tumor was demonstrated and deemed surgically accessible, the patient underwent immediate re-exploration. RESULTS: iMRI was performed successfully in all 30 patients. In one patient, iMRI was used to clarify the significance of hemorrhage from the sellar region and resulted in immediate conversion of the procedure to a craniotomy. In the remaining 29 patients, initial iMRI demonstrated that the endpoint for extent of resection had been achieved in only 10 patients (34%) after an initial resection attempt, whereas 19 patients (66%) still had unacceptable residual tumor. All 19 of these latter patients underwent re-exploration. Ultimately, re-exploration resulted in the achievement of the planned endpoint for extent of resection in all of the 29 completed transsphenoidal explorations. Operative time was extended in all cases by at least 20 minutes. CONCLUSION: iMRI can be used to safely, reliably, and objectively assess the extent of resection of pituitary macroadenomas during the transsphenoidal approach. The surgeon is frequently surprised by the extent of residual tumor after an initial resection attempt and finds the intraoperative images useful for guiding further resection.

Determination of lung as the primary site of cerebral metastatic adenocarcinomas using monoclonal antibody to thyroid transcription factor-1.

Determining the primary site of a cerebral metastatic adenocarcinoma is complicated by the histologic similarity of most adenocarcinomas. Thyroid Transcription Factor-1 (TTF-1) is a highly specific marker of peripheral airway cell neoplasms. Formalin fixed tissue from 30 patients with brain metastasis whose primary sources were clinically and histologically known with certainty were analyzed for immunoreactivity to TTF-1. There were 18 cases of metastatic lung adenocarcinoma. Other metastases were from breast (6), colon (1), prostate (1), kidney (1), paranasal sinus (1), melanoma (1), and intestinal carcinoid (1). No patients with carcinoma of the thyroid were found. Positivity was regarded as intense nuclear reactivity. Twelve (67%) metastatic lung adenocarcinomas stained for TTF-1. None of the cerebral metastases from other body sites showed positivity. In addition, normal brain tissue and astrocytic tumors did not stain for TTF-1. These data show that TTF-1 is a highly specific and reasonably sensitive marker for peripheral airway cell metastasis to the brain.

Lung cell-specific expression of the murine surfactant protein A (SP-A) gene is mediated by interactions between the SP-A promoter and thyroid transcription factor-1.

Cis-acting elements determining lung epithelial cell-selective transcription of the murine surfactant protein A (SP-A) gene were identified between nucleotide positions -255 and -57. This region of the murine SP-A gene contained nucleotide sequences consistent with thyroid transcription factor-1 (TTF-1) binding motifs. An SP-A-CAT plasmid containing the TTF-1 binding sites was transcriptionally active in mouse lung epithelial (MLE-15) cells but not in HeLa, 3T3, or H441 cells. However, transcription of the SP-A-CAT construct was activated after cotransfection of HeLa cells with a vector expressing recombinant TTF-1, pCMV-TTF-1. Recombinant TTF-1 homeodomain protein bound to four distinct binding sites located between nucleotides -166 to -117 [corrected]. Proteins in nuclear extracts of MLE-15 cells bound TTF-1 binding sites and were supershifted by TTF-1 antibody. Mutations of three of the TTF-1 binding sites in this region reduced expression of the SP-A-CAT construct in transfected MLE-15 cells and reduced transactivation in HeLa cells. TTF-1 interacts with complex protein/DNA binding sites located in the 5'-flanking region of the murine SP-A gene enhancing lung epithelial cell-specific expression in vitro.

Structure and function of the mouse surfactant protein B gene.

The mouse surfactant protein B (SP-B) gene was isolated from a DBA/2J EMBL3 genomic library, and the nucleotide sequence and transcriptional start site was determined. The SP-B gene was comprised of 11 exons and 10 introns and spanned 9,882 bases. Repetitive elements of the B1, B2, and R families and several other motifs were located within nontranslated regions of the gene. The 5' flanking region of the gene was utilized to express a bacterial chloramphenicol acetyl transferase reporter gene in mouse and human pulmonary adenocarcinoma cell lines. Transcriptionally active regions of the promoter were identified that determined lung epithelial cell-specific gene expression. Regions of the gene promoter shared between the mouse and human SP-B gene were used to locate putative transcription factor binding sites for thyroid transcription factor-1 and hepatocyte nuclear factor-3. The 5' flanking region of the murine SP-B contains cell-specific cis-active elements that regulate SP-B expression in the respiratory epithelium.

The lung-specific surfactant protein B gene promoter is a target for thyroid transcription factor 1 and hepatocyte nuclear factor 3, indicating common factors for organ-specific gene expression along the foregut axis.

We used the lung epithelial cell-specific surfactant protein B (SPB) gene promoter as a model with which to investigate mechanisms involved in transcriptional control of lung-specific genes. In a previous study, we showed that the SPB promoter specifically activated expression of a linked reporter gene in the continuous H441 lung cell line and that H441 nuclear proteins specifically protected a region of this promoter from bp -111 to -73. In this study, we further show that this region is a complex binding site for thyroid transcription factor 1 (TTF-1) and hepatocyte nuclear factor 3 (HNF-3). Whereas TTF-1 bound two highly degenerate and closely spaced sites, HNF-3 proteins bound a TGT3 motif (TGTTTGT) that is also found in several liver-specific gene regulatory regions, where it appears to be a weak affinity site for HNF-3. Point mutations of these binding sites eliminated factor binding and resulted in significant decreases in transfected SPB promoter activity. In addition, we developed a cotransfection assay and showed that a family of lung-specific gene promoters that included the SPB, SPC, SPA, and Clara cell secretory protein (CCSP) gene promoters were specifically activated by cotransfected TTF-1. We conclude that TTF-1 and HNF-3 are major activators of lung-specific genes and propose that these factors are involved in a general mechanism of lung-specific gene transcription. Importantly, these data also show that common factors are involved in organ-specific gene expression along the mammalian foregut axis.

Structure and regulation of the murine Clara cell secretory protein gene.

Clara cell secretory protein (CC10 or CCSP) is an abundant component of airway secretions and has the ability to bind small hydrophobic molecules. Genomic clones were isolated for the murine gene coding for Clara cell secretory protein. Nucleotide sequence analysis revealed that the gene was composed of three exons that span 4316 bp. Organization of the murine CCSP gene was very similar to that of the rabbit gene that codes for the biochemically related uteroglobin protein. Messenger RNAs for both genes were coded for by three exons, counterparts of which encode similar structural and functional protein domains. Transcriptional regulatory elements in the 5' flanking DNA were conserved between species, as were the functional properties of these elements when characterized in assays of promoter function. These data support the notion that Clara cell secretory protein genes from the rat and mouse, and the uteroglobin gene in rabbit, represent interspecies homologues.

Cis-active elements controlling lung cell-specific expression of human pulmonary surfactant protein B gene.

Human surfactant protein B (SPB) is a 79-amino-acid hydrophobic protein that enhances the surface active properties of pulmonary surfactant. SPB is expressed in nonciliated bronchiolar and alveolar type II cells of the respiratory epithelium, and its expression increases markedly late in gestation. In the present study, a human pulmonary adenocarcinoma cell line, H441, was used in both functional and biochemical assays to identify DNA sequences controlling lung cell-specific expression of the SPB gene. DNase I hypersensitive studies demonstrated two distinct regions of lung cell-specific hypersensitivity located proximal to the SPB promoter and within the eighth intron of the gene. To functionally define these DNA sequences, a series of plasmid vectors were constructed in which segments of the human SPB gene and 5'-flanking sequence were linked to a CAT reporter gene and assayed for expression in lung and nonlung cell lines. Whereas far upstream and intronic sequences did not contain enhancer-like elements, a 259-base pair DNA segment (base pair -218 to +41) was sufficient to support lung cell-specific expression. DNase I footprinting demonstrated that this pulmonary epithelial cell-specific promoter fragment contained five nuclear protein-binding sites, two of which bound lung cell-specific nuclear protein complexes. These results suggest that the pulmonary epithelial cell-specific expression of SPB is determined, in part, by both ubiquitous and cell type-specific protein-DNA interactions within the proximal promoter region.