Faculty Bibliography

OBJECTIVE:To characterize the endoscopic anatomy of the sphenoid sinus and the adjacent clivus and cavernous sinus, and to review patient outcomes for neoplasms in this region. STUDY DESIGN/METHODS:Cadaver dissection and chart review. SETTING/METHODS:Cadaver laboratory and tertiary care center. SUBJECTS AND METHODS/METHODS:Fresh-frozen cadaver heads were dissected to study the endoscopic anatomy of the sphenoclival region. Retrospective chart review of patients undergoing endoscopic resection of sphenoclival neoplasms between 2000 and 2008 was performed. RESULTS:Transnasal endoscopic access to the sphenoid sinus was obtained in 10 cadaver heads. A clival window with mean dimensions of 1.4 cm x 1.7 cm was created. Through the clival window, identification and dissection of the basilar and vertebral arteries, mamillary bodies, third ventricle, cranial nerves III through VI, and cervical rootlets were possible. Nineteen patients with mean age of 56.2 years were treated. The most common pathologies were inverted papilloma (5), chordoma (4), squamous cell carcinoma (2), and adenoid cystic carcinoma (2). None of the patients required adjunct craniotomies. Nine patients received adjuvant therapies. Thirteen (68.4%) patients had no evidence of disease, five (26.3%) patients were alive with disease, and one (5.3%) patient died of disease at mean follow-up of 32.6 months. CONCLUSION/CONCLUSIONS:The sphenoclival region poses a significant surgical challenge given its central location at the skull base and proximity to critical structures. This study demonstrates that transnasal endoscopic access to the sphenoclival region is technically feasible and allows successful surgical extirpation of tumors with a low complication rate and acceptable patient outcomes.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:The objective of this study was to review clinical outcomes of minimally invasive endoscopic resection (MIER) for anterior skull base (ASB) neoplasms. STUDY DESIGN/METHODS:Retrospective data review. METHODS:Data analysis was performed on all patients undergoing MIER from October 2000 to December 2008. RESULTS:Thirty-one patients with mean age of 58 years underwent MIER. Malignant and benign tumors were managed in 25 (80.6%) and six (19.4%) cases, respectively. Most common histopathologies were squamous cell carcinoma (six), esthesioneuroblastoma (five), mucosal melanoma (five), and sinonasal undifferentiated carcinoma (four). American Joint Committee on Cancer tumor staging was T3N0M0 and T4N0M0 in 14 (56%) and 11 (44%) of the malignant cases, respectively. Surgical resection with curative intent was performed in 28 cases (90.3%). Multilayered skull base reconstruction was performed in most patients; lumbar drains were used in eight cases (25.8%). Twenty-one patients (67.7%) were disease free, five patients (16.1%) were dead from disease, three patients (9.7%) were alive with disease, and two patients (6.5%) died from unrelated causes at mean follow-up of 31.7 months. CONCLUSIONS:This study validated technical feasibility of MIER for diversity of benign and malignant ASB histopathology. Majority of patients were able to avoid adjunct craniotomy, whereas lumbar drainage was utilized in selective cases. This surgical strategy resulted in low complication rate and acceptable disease-free survival in patients with advanced T3 and T4 malignant lesions. Future studies should focus on multicenter trials to facilitate more robust survival analysis and comparison to open surgical approaches.

OBJECTIVE:The objectives of this study were to 1) evaluate anatomical relationships and 2) develop technical correlates for endoscopic anterior skull base (ASB) surgery. STUDY DESIGN/METHODS:Cadaver study. SETTING/METHODS:Minimally invasive surgery laboratory. SUBJECTS AND METHODS/METHODS:Ten adult fresh-frozen cadaver heads were dissected from December 2006 to December 2007. The endoscopic trans-cribriform, trans-ethmoid approach to the anterior cranial base was refined over these consecutive dissections. Endoscopic orientation along the ventral axis was assessed with 0 degrees , 30 degrees , and 70 degrees rigid telescopes. Anatomical dimensions of the ASB window were measured in the anteroposterior (posterior table of frontal sinus to planum sphenoidale) and transverse (orbit-to-orbit) dimensions at the anterior ethmoid artery (AEA) and posterior ethmoid artery (PEA). RESULTS:Endoscopic cadaveric dissections confirmed technical feasibility of ASB surgery and greatly enhanced understanding of ASB anatomical concepts. The 30 degrees rigid endoscope provided the most optimal view from the frontal sinus to the planum sphenoidale with the least distortion, relative to 0 degrees and 70 degrees scopes. Careful identification of the AEA and PEA was requisite for proper orientation at the ASB. The posterior one third of the ASB was thickest and always required drilling for resection. The mean boundaries of the ASB window were 33.7 mm (anterior to posterior) and 23.5 and 19.1 mm at the AEA and PEA (orbit to orbit), respectively. CONCLUSION/CONCLUSIONS:This prospective cadaveric study outlined key correlates for endoscopic ASB surgery. It serves to highlight the requisite technical steps and anatomical dimensions when the trans-nasal endoscopic route is employed for ASB pathology.

Because primary myelofibrosis (PMF) originates at the level of the pluripotent hematopoietic stem cell (HSC), we examined the effects of various therapeutic agents on the in vitro and in vivo behavior of PMF CD34(+) cells. Treatment of PMF CD34(+) cells with chromatin-modifying agents (CMAs) but not hydroxyurea, Janus kinase 2 (JAK2) inhibitors, or low doses of interferon-α led to the generation of greater numbers of CD34(+) chemokine (C-X-C motif) receptor (CXCR)4(+) cells, which were capable of migrating in response to chemokine (C-X-C motif) ligand (CXCL)12 and resulted in a reduction in the proportion of hematopoietic progenitor cells (HPCs) that were JAK2V617F(+). Furthermore, sequential treatment of PMF CD34(+) cells but not normal CD34(+) cells with decitabine (5-aza-2'-deoxycytidine [5azaD]), followed by suberoylanilide hydroxamic acid (SAHA; 5azaD/SAHA), or trichostatin A (5azaD/TSA) resulted in a higher degree of apoptosis. Two to 6 months after the transplantation of CMAs treated JAK2V617F(+) PMF CD34(+) cells into nonobese diabetic/severe combined immunodeficient (SCID)/IL-2Rγ(null) mice, the percentage of JAK2V617F/JAK2(total) in human CD45(+) marrow cells was dramatically reduced. These findings suggest that both PMF HPCs, short-term and long-term SCID repopulating cells (SRCs), are JAK2V617F(+) and that JAK2V617F(+) HPCs and SRCs can be eliminated by sequential treatment with CMAs. Sequential treatment with CMAs, therefore, represents a possible effective means of treating PMF at the level of the malignant SRC.

The Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are a group of clonal hematopoietic stem cell disorders with overlapping clinical and cytogenetic features and a variable tendency to evolve into acute leukemia. These diseases not only share overlapping chromosomal abnormalities but also a number of acquired somatic mutations. Recently, mutations in a putative tumor suppressor gene, ten-eleven translocation 2 (TET2) on chromosome 4q24 have been identified in 12% of patients with MPN. Additionally 4q24 chromosomal rearrangements in MPN, including TET2 deletions, have also been observed using conventional cytogenetics. The goal of this study was to investigate the frequency of genomic TET2 rearrangements in MPN using fluorescence in situ hybridization as a more sensitive method for screening and identifying genomic deletions. Among 146 MPN patients, we identified two patients (1.4%) who showed a common 4q24 deletion, including TET2. Our observations also indicated that the frequency of TET2 deletion is increased in patients with an abnormal karyotype (5%).

OBJECTIVE:To compare the efficacy of topical treatment with three glucocorticoids in lipopolysaccharide induced otitis media with effusion (OME). METHODS:Chinchillas were divided into seven treatment groups consisting of vehicle and three glucocorticoids: dexamethasone sodium phosphate (DSP), fluticasone propionate (FP), and hydrocortisone, each at concentrations of 0.1% and 1.0%. LPS (300 μg) was injected into the superior bullae of chinchillas to induce OME. Animals were treated with test substances at -2, 24, and 48 h relative to LPS inoculation. After 96 h, chinchillas were euthanized, samples of middle ear effusion (MEE) were collected, and temporal bones were removed for histopathological examination. Reduction of OME was evaluated by measuring MEE volume and thickness of mucosal lining for each bulla. RESULTS:One percent treatment of FP significantly reduced MEE. One percent treatment of DSP and HC significantly reduced the mucosal thickness (MT), DSP (15.0 μM) more than HC (30.8 μM). Treatment with 0.1% glucocorticoids did not lead to any significant reduction. CONCLUSIONS:Clearance of otitis media with effusion seems to be a class effect among glucocorticoids. DSP was the best in reducing MT. It is important to evaluate treatment with various glucocorticoids in order to discover alternative drugs for OME.

Conjugal transfer of chromosomal DNA between strains of Mycobacterium smegmatis occurs by a novel mechanism. In a transposon mutagenesis screen, three transfer-defective insertions were mapped to the lsr2 gene of the donor strain mc(2)155. Because lsr2 encodes a nonspecific DNA-binding protein, mutations of lsr2 give rise to a variety of phenotypes, including an inability to form biofilms. In this study, we show that efficient DNA transfer between strains of M. smegmatis occurs in a mixed biofilm and that the process requires expression of lsr2 in the donor but not in the recipient strain. Testing cells from different strata of standing cultures showed that transfer occurred predominantly at the biofilm air-liquid interface, as other strata containing higher cell densities produced very few transconjugants. These data suggest that the biofilm plays a role beyond mere facilitation of cell-cell contact. Surprisingly, we found that under standard assay conditions the recipient strain does not form a biofilm. Taking these results together, we conclude that for transfer to occur, the recipient strain is actively recruited into the biofilm. In support of this idea, we show that donor and recipient cells are present in almost equal numbers in biofilms that produce transconjugants. Our demonstration of genetic exchange between mycobacteria in a mixed biofilm suggests that conjugation occurs in the environment. Since biofilms are considered to be the predominant natural microhabitat for bacteria, our finding emphasizes the importance of studying biological and physical processes that occur between cells in mixed biofilms.