Lawrence J. Marentette

Radiation Concurrent With Gemcitabine for Locally Advanced Head and Neck Cancer: A Phase I Trial and Intracellular Drug Incorporation Study

PURPOSE To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. PATIENTS AND METHODS Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured. RESULTS Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2). CONCLUSION A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.

Mutations in linker histone genes HIST1H1 B, C, D and E, OCT2 (POU2F2), IRF8 and ARID1A underlying the pathogenesis of follicular lymphoma

Follicular lymphoma (FL) constitutes the second most common non-Hodgkin lymphoma in the western world. FL carries characteristic recurrent structural genomic aberrations. However, information regarding the coding genome in FL is still evolving. Here, we describe the results of massively parallel exome sequencing and single nucleotide polymorphism 6.0 array genomic profiling of 11 highly purified FL cases, and 1 transformed FL case and the validation of selected mutations in 102 FL cases. We report the identification of 15 novel recurrently mutated genes in FL. These include frequent mutations in the linker histone genes HIST1H1 B-E (27%) and mutations in OCT2 (also known as POU2F2; 8%), IRF8 (6%), and ARID1A (11%). A subset of the mutations in HIST1H1 B-E affected binding to DNMT3B, and mutations in HIST1H1 B-E and in EZH2 or ARID1A were largely mutually exclusive, implicating HIST1H1 B-E in epigenetic deregulation in FL. Mutations in OCT2 (POU2F2) affected its transcriptional and functional properties as measured through luciferase assays, the biological analysis of stably transduced cell lines, and global expression profiling. Finally, multiple novel mutated genes located within regions of acquired uniparental disomy in FL are identified. In aggregate, these data substantially broaden our understanding of the genomic pathogenesis of FL.

Sinonasal undifferentiated carcinoma: Case series and review of the literature

OBJECTIVE AND IMPORTANCEWe report on four cases of sinonasal undifferentiated carcinoma (SNUC), a relatively newly described clinicopathological entity of the nasal cavity and paranasal sinuses. SNUC tends to present with advanced-stage disease, often with intracranial invasion, and requires an aggressive treatment approach that includes surgical resection. A review of the literature identified several reports of SNUC in pathology and otolaryngology journals since its initial description in 1986, but no report has yet appeared in the neurosurgery literature. CLINICAL PRESENTATIONFour patients presented with various symptoms related to the nose and/or orbit, including one or more of the following: obstruction, epistaxis, decreased visual acuity, diplopia, and pain. All patients were noted to have masses in the nasal cavity or paranasal sinuses, with or without intracranial extension. INTERVENTIONAll four patients underwent multimodal treatment with chemotherapy, radiotherapy (60–65 Gy), and aggressive surgical resection via a combined bifrontal craniotomy and a subcranial approach to the anterior cranial fossa. Three of four patients died as a result of their disease, an average of 15 months after diagnosis. Only one patient remains alive, although with metastatic intracranial disease, at 24 months after diagnosis. CONCLUSIONSNUC is a rare neoplasm with a poor prognosis despite an aggressive multimodal approach to treatment. On the basis of our experience, we advocate radical resection as part of the initial combined therapy for patients who present with locally advanced, nonmetastatic disease but we suggest reserving surgery for patients with early brain invasion until there has been a radiographically proven central nervous system response to adjuvant therapy.

Fate of rigid fixation in pediatric craniofacial surgery

The advantages of rigid fixation in adult craniofacial surgery are well documented, and implanted hardware is not routinely removed unless specifically indicated. There is a tendency, however, to remove hardware in children because of concerns with growth restriction, plate migration, and the lack of information on the fate of miniplates when used in pediatric craniofacial surgery. It has been our practice during the past decade not to remove hardware in children unless specifically indicated. Our study included a total of 121 procedures in 96 children, with an average age of 3.9 years and an average follow-up of 5 years. We placed 375 titanium plates and 1944 screws from 3 manufacturers. Complications encountered in children with titanium plates were as follows: 5 cases of delayed growth and 1 instance of restricted growth, 4 screw migrations (none intracranial), 9 palpable plates causing pain, 3 fluid accumulations over plates, 2 cases of meningitis, and 8 instances of plate and screw removal from the above complications. Twenty-two of 96 patients (23%) had a total of 27 complications from 121 procedures (22%). There were 6 cases in which pain precipitated removal of hardware, 1 case of an excessively mobile plate, and 1 case of documented growth restriction requiring removal; therefore our overall reoperation rate for plate removal was 8%, with no intracranial plate or screw migration.

Sinonasal undifferentiated carcinoma: a 13-year experience at a single institution.

We present our experience with sinonasal undifferentiated carcinoma at the University of Michigan over 13 years and review prior published data. We conducted a retrospective review of 19 patients who presented to a tertiary care academic center multidisciplinary skull base clinic with sinonasal undifferentiated carcinoma between 1995 and 2008. Overall survival was 22% at 5 years, and the estimated 5-year distant metastasis-free survival was 35%. At 2 years, local control was 83%, regional control was 50%, and distant control was 83%. Local control was best in those patients treated nonsurgically, as was median survival, though this was not statistically significant. Nodal disease in the neck, either at presentation or at recurrence, was noted in 26% of patients. Survival for sinonasal undifferentiated carcinoma remains poor. It is possible that up-front radiation or chemoradiation will lead to better local control rates, though surgery remains a mainstay of treatment. In all cases, the cervical nodes should be addressed with primary treatment.

Usefulness of percutaneously injected ethylene-vinyl alcohol copolymer in conjunction with standard endovascular embolization techniques for preoperative devascularization of hypervascular head and neck tumors: Technique, initial experience, and correlation with surgical observations

BACKGROUND AND PURPOSE: Few reports have described the embolization of head and neck lesions by using direct percutaneous techniques. We report our preliminary experience in the direct percutaneous embolization of hypervascular head and neck tumors by using Onyx in conjunction with standard endovascular embolization techniques. We describe the technical aspects of the procedure and its efficacy in reducing intraoperative blood loss. MATERIALS AND METHODS: We retrospectively studied 14 patients (3 females and 11 males; mean age, 33.4 years; range, 11–56 years) with 15 hypervascular tumors of the head and neck that underwent direct percutaneous embolization with Onyx in conjunction with particulate embolization. Nine paragangliomas and 6 JNAs underwent treatment. Documented blood loss was obtained from operative reports in these 15 patients with surgical resection performed 24–48 hours after the embolization. RESULTS: Intratumoral penetration with progressive blood flow stasis was achieved during each injection. A mean of 3.1 needles (20-gauge, 3.5-inch spinal needle) were placed percutaneously into the lesion (range, 1–6). The mean intraoperative blood loss was 780 mL (range, <50–2200 mL). Near total angiographic devascularization was achieved in 13 of 15 tumors. There were no local complications or neurologic deficits from the percutaneous access or embolization of these hypervascular tumors. CONCLUSIONS: In this study, the use of percutaneous injected Onyx in conjunction with standard endovascular embolization techniques in patients with hypervascular head and neck tumors seemed to enhance the ability to devascularize these tumors before operative removal.

Esthesioneuroblastoma: Results and Outcomes of a Single Institution's Experience.

OBJECTIVES Analysis of outcomes of a cohort of patients with esthesioneuroblastoma. DESIGN Retrospective cohort analysis. SETTING PATIENTS presenting with esthesioneuroblastoma from 1994 to 2006 in a tertiary care academic medical center. PATIENTS Fifteen consecutive patients diagnosed as having esthesioneuroblastoma were treated during this time period using a subcranial resection. The mean follow-up is 75 months (range, 2 to 240 mos). RESULTS The overall survival was 100% and the overall disease-free survival was 49% and 24% at 5 and 15 years, respectively. PATIENTS treated with radiation therapy following surgical resection had a 5- and 15-year disease-free survival of 83.3% compared with a 5- and 15-year disease-free survival of 26.7% and 0%, respectively, for patients whose initial treatment was surgery alone. The mean time to recurrence was 82.1 months. None of the patients had a decrease in Karnofsky Performance Score following subcranial resection. CONCLUSIONS PATIENTS with esthesioneuroblastoma whose initial treatment consists of surgical resection followed by radiation therapy have a longer disease-free survival than patients treated with surgery alone. However, initial treatment modality did not have an effect on survival. Long-term, close follow-up is necessary to identify recurrences, which can be treated with a high degree of success.

Subcranial Approach to Tumors of the Anterior Cranial Base: Analysis of Current and Traditional Surgical Techniques:

Tumors of the anterior cranial base have previously required a craniofacial resection to allow adequate tumor extirpation. An analysis of current and traditional techniques demonstrates a significant reduction in operative time, complication rate, and intensive care unit and total hospital length of stay with the use of the subcranial approach as compared with the traditional frontal craniotomy and lateral rhinotomy approach. The subcranial approach is both cost and time efficient and provides comparable morbidity and mortality rates.

The mandibular swing stabilization of the midline mandibular osteotomy.

Cette technique donne une consolidation fiable chez tous les malades quel que soit leur etat nutritionnel ou radiotherapeutique

Restoration of the orbital aesthetic subunit in complex midface defects

Objectives/Hypothesis: Although various options exist for restoration of the orbital defect in complex craniofacial resections, the aesthetic appearance and functional result of the orbit are optimized when the bony orbital architecture, orbital volume, and facial contour are specifically addressed. The study describes an approach using free tissue transfer for restoration of the native orbital aesthetic subunit.