Faculty Bibliography

OBJECTIVES/OBJECTIVE:We evaluated the efficacy of the application of selective neck dissection to cases of clinically node-positive disease. METHODS:We performed a retrospective review at the University of Pittsburgh Head and Neck Cancer Database. A database of 65 patients was followed for an average of 36 months (range, 2 to 128 months) after they underwent selective neck dissection for clinically node-positive regional disease. RESULTS:Regional failure occurred in 8 patients (12.3%). In-field failure was experienced in 4 patients (6.1%), and failures outside the field of dissection occurred in 4 patients (6.1%). The overall incidence of extracapsular spread was 33.8% (22 of 65). Only 2 of 8 regional recurrences were associated with extracapsular spread at the initial neck dissection; however, both recurrences were in the contralateral, undissected side of the neck. Four regional failures were salvaged with surgery, with eventual overall regional control in the neck of 93.9%. Only 1 of 4 ipsilateral recurrences (25%) was successfully salvaged. In contrast, 3 of 4 contralateral failures (75%) were successfully salvaged. In our study population, 21 of 65 cases (32%) that were initially staged as clinically node-positive had no evidence of nodal metastases on pathologic examination. CONCLUSIONS:The application of selective neck dissection and postoperative irradiation in patients with clinically Nl and limited N2 clinical disease appears to be oncologically efficacious. Clinical overstaging occurred frequently in this sample, and may put patients at risk for more morbid surgical procedures.

OBJECTIVES/OBJECTIVE:Congenital anterior skull base defects with meningoencephaloceles causing nasal obstruction are rare clinical entities. Nasal obstruction in children may also be a symptom of multiple benign nasal and allergic disorders, making the initial diagnosis of meningoencephalocele difficult. Traditionally, skull base defects have been repaired via a bifrontal craniotomy approach. With the advent of pediatric endoscopic instrumentation, more of these lesions are accessible via an intranasal endoscopic approach, even in the infant population. However, owing to the rarity of these lesions, there is a paucity of data demonstrating successful adaptation of endoscopic skull base techniques to the pediatric population. METHODS:Retrospective review of two cases of endoscopic repair of anterior skull base defects with meningoencephaloceles at a tertiary care medical center. RESULTS:Two children, ages 15 months and 6 years, underwent successful endoscopic closure of their anterior skull base defects and resection of their intranasal meningoencephalocele with resolution of their nasal obstruction and cerebrospinal fluid rhinorrhea. CONCLUSIONS:Pediatric nasal meningoencephaloceles with anterior skull base defects can be successfully repaired via a transnasal endoscopic technique, thus minimizing the complications associated with craniotomy and frontal lobe retraction. Triplanar computed tomographic and magnetic resonance imaging is paramount to evaluate the caliber of the skull base defect, consistency of the herniated intracranial contents, as well as the presence of cerebral vasculature.

OBJECTIVE:To determine whether relative cerebral blood volume (rCBV) can predict patient outcome, specifically tumor progression, in low-grade gliomas (LGGs) and thus provide a second reference standard in the surgical and postsurgical management of LGGs. METHODS:Thirty-five patients with histologically diagnosed LGGs (21 low-grade astrocytomas and 14 low-grade oligodendrogliomas and low-grade mixed oligoastrocytomas) were studied with dynamic susceptibility contrast-enhanced perfusion magnetic resonance imaging. Wilcoxon tests were used to compare patients in different response categories (complete response, stable, progressive, death) with respect to baseline rCBV. Log-rank tests were used to evaluate the association of rCBV with survival and time to progression. Kaplan-Meier time-to-progression curves were generated. Tumor volumes and CBV measurements were obtained at the initial examination and again at follow-up to determine the association of rCBV with tumor volume progression. RESULTS:Wilcoxon tests showed patients manifesting an adverse event (either death or progression) had significantly higher rCBV (P = 0.003) than did patients without adverse events (complete response or stable disease). Log-rank tests showed that rCBV exhibited a significant negative association with disease-free survival (P = 0.0015), such that low rCBV values were associated with longer time to progression. Kaplan-Meier curves demonstrated that lesions with rCBV less than 1.75 (n = 16) had a median time to progression of 4620 +/- 433 days, and lesions with rCBV more than 1.75 (n = 19) had a median time to progression of 245 +/- 62 days (P < 0.005). Lesions with low baseline rCBV (< 1.75) demonstrated stable tumor volumes when followed up over time, and lesions with high baseline rCBV (> 1.75) demonstrated progressively increasing tumor volumes over time. CONCLUSION/CONCLUSIONS:Dynamic susceptibility contrast-enhanced perfusion magnetic resonance imaging may be used to identify LGGs that are either high-grade gliomas, misdiagnosed because of sampling error at pathological examination or that have undergone angiogenesis in the progression toward malignant transformation. This suggests that rCBV measurements may be used as a second reference standard to determine the surgical management/risk-benefit equation and postsurgical adjuvant therapy for LGGs.

Ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia Rad3-related (ATR) and the Mre11/Rad50/Nbs1 complex ensure genome stability in response to DNA damage. However, their essential role in DNA metabolism remains unknown. Here we show that ATM and ATR prevent accumulation of DNA double-strand breaks (DSBs) during chromosomal replication. Replicating chromosomes accumulate DSBs in Xenopus laevis egg extracts depleted of ATM and ATR. Addition of ATM and ATR proteins to depleted extracts prevents DSB accumulation by promoting restart of collapsed replication forks that arise during DNA replication. We show that collapsed forks maintain MCM complex but lose Pol epsilon, and that Pol epsilon reloading requires ATM and ATR. Replication fork restart is abolished in Mre11 depleted extracts and is restored by supplementation with recombinant human Mre11/Rad50/Nbs1 complex. Using a novel fluorescence resonance energy transfer-based technique, we demonstrate that ATM and ATR induce Mre11/Rad50/Nbs1 complex redistribution to restarting forks. This study provides direct biochemical evidence that ATM and ATR prevent accumulation of chromosomal abnormalities by promoting Mre11/Rad50/Nbs1 dependent recovery of collapsed replication forks.