Faculty Bibliography

Current diagnosis of organ rejection following transplantation relies on tissue biopsy, which is not ideal due to sampling limitations and risks associated with the invasive procedure.We have previously shown that cellular magnetic resonance imaging (MRI) of iron-oxide labeled immune-cell infiltration can provide a noninvasive measure of rejection status by detecting areas of hypointensity on T 2*-weighted images. In this study, we tested the feasibility of using a fluorine-based cellular tracer agent to detect macrophage accumulation in rodent models of acute allograft rejection by fluorine-19 ((19) F) MRI and magnetic resonance spectroscopy. This study used two rat models of acute rejection, including abdominal heterotopic cardiac transplant and orthotopic kidney transplant models. Following in vivo labeling of monocytes and macrophages with a commercially available agent containing perfluoro-15-crown-5-ether, we observed (19) F-signal intensity in the organs experiencing rejection by (19) F MRI, and conventional (1) H MRI was used for anatomical context. Immunofluorescence and histology confirmed macrophage labeling. These results are consistent with our previous studies and show the complementary nature of the two cellular imaging techniques. With no background signal, (19) F MRI/magnetic resonance spectroscopy can provide unambiguous detection of fluorine labeled cells, and may be a useful technique for detecting and quantifying rejection grade in patients.

Educational Objective: At the conclusion of this presentation, the participants should be able to define "collision tumor", describe a novel collision tumor of the parotid, and discuss the complexity in managing similar unexpected operative findings.
Objective(s): 1) To present a novel collision tumor of the parotid gland: concurrent squamous cell carcinoma and small cell lymphoma; and 2) to analyze the operative approach to collision tumors.
Study Design: Case report. Abridged Case History: A 75 year old male with left ear lobule melanoma was concurrently found to have a right parotid mass. Pre-operative CT showed a right parotid mass and all FNA attempts were non-diagnostic. The patient was taken to the operating room for excision of the left ear melanoma, as well as for right superficial parotidectomy and right modified neck dissection. The operation was complicated by frozen pathology suggestive of a novel collision tumor.
Result(s): The final histopathology revealed components of both squamous cell carcinoma and small cell lymphoma in both the parotid tumor and ipsilateral cervical lymph nodes. The combination of a parotid collision tumor containing squamous cell carcinoma and small cell lymphoma has never been described and poses a diagnostic and therapeutic challenge. This particular tumor combination is especially complex as the therapeutic approach to each tumor is distinct: squamous cell carcinoma is most often approached surgically, whereas lymphoma is primarily treated with chemotherapy. Ultimately, each tumor must be treated independently and consideration should be given to treating the more lethal component, though the timing and method of such treatment is still a path yet uncharted.
Conclusion(s): Given the rarity of collision tumors, it is difficult to establish a standardized treatment plan, however, perhaps through future reporting of similar cases better therapeutic recommendations can be made

Introduction: Diplopia following cerebellopontine angle (CPA) surgery is usually attributed to neuropathy of III, IV or VI cranial nerves. Diplopia in the absence of cranial neuropathy following CPA surgery is rare. We present a series of patients who developed vertical diplopia from skew deviation following resection of tumors in the CPA or labyrinthectomy. Primarily associated with brainstem lesions, this vertical misalignment of the visual axis is postulated to result from unilateral disruption of supranuclear input from the otolithic organs.
Method(s): Retrospective review of patients with complaints of diplopia following CPA surgery. Patients underwent neuroophthalmologic consultation and examination, including opticokinetic testing, confrontational visual field assessment, color plate, pupillary reflex, slit lamp examination and Head Tilt Test.
Result(s): Four patients with residual hearing preoperatively developed skew deviation immediately following surgical intervention, including translabyrinthine(n=1) and retrosigmoid (n=2) approaches to the CPA and labyrinthectomy (n=1). Neuroophthalmologic exam demonstrated intact extraocular movements, and 2-14 mm prism diopter hypertropia on both primary gaze and Head Tilt Testing. In all cases, skew deviation resolved spontaneously with normalization of the neuroophthalmologic examination within 10 weeks.
Conclusion(s): Patients undergoing CPA surgery or labyrinthectomy can develop postoperative diplopia due to skew deviation as a consequence of acute vestibular deafferentation. Patients with significant hearing preoperatively, a probable marker for residual vestibular function, may be specially at risk for developing skew deviation. As vestibular ablation occurs routinely with each of these procedures, skew deviation likely occurs more frequently than is currently diagnosed. Complaints of diplopia should prompt neuro-ophthalmologic consultation to reliably diagnose skew deviation and exclude cranial neuropathy. Patients can be reassured as spontaneous resolution typically occurs within 10 weeks

PURPOSE/OBJECTIVE:Tumor-specific biomarkers that predict resistance to DNA damaging agents may improve therapeutic outcomes by guiding the selection of effective therapies and limiting morbidity related to ineffective approaches. XPF (ERCC4) is an essential component of several DNA repair pathways and XPF-deficient cells are exquisitely sensitive to DNA damaging agents. The purpose of this study was to determine whether XPF expression levels predict clinical response to DNA damaging agents in head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN/METHODS:Quantitative immunohistochemistry was used to measure XPF expression in tumors from a cohort of 80 patients with newly diagnosed HNSCC treated with radiation therapy with or without platinum-based chemotherapy; samples were collected prospectively. Genomic DNA isolated from blood samples was analyzed for nine single nucleotide polymorphisms (SNP) in the XPF gene by using a custom array. The primary endpoint was progression-free survival (PFS). RESULTS:XPF expression was higher in tumors from the oral cavity than from the other sites (P < 0.01). High XPF expression correlated with early time to progression both by univariate (HR = 1.87, P = 0.03) and multivariate analysis (HR = 1.83, P = 0.05). The one year PFS for high expressers was 47% (95% CI = 31-62) compared with 72% (95% CI = 55-83) for low expressers. In addition, we identified four XPF SNPs that showed marginal association with treatment failure. CONCLUSIONS:Expression level of XPF in HNSCC tumors correlates with clinical response to DNA damaging agents. XPF has potential to guide next generation personalized cancer therapy.

Advanced stage non-small cell lung cancer and head and neck squamous cell carcinoma are both treated with DNA damaging agents including platinum-based compounds and radiation therapy. However, at least one quarter of all tumors are resistant or refractory to these genotoxic agents. Yet the agents are extremely toxic, leading to undesirable side effects with potentially no benefit. Alternative therapies exist, but currently there are no tools to predict whether the first-line genotoxic agents will work in any given patient. To maximize therapeutic success and limit unnecessary toxicity, emerging clinical trials aim to inform personalized treatments tailored to the biology of individual tumors. Worldwide, significant resources have been invested in identifying biomarkers for guiding the treatment of lung and head and neck cancer. DNA repair proteins of the nucleotide excision repair pathway (ERCC1) and of the base excision repair pathway (XRCC1), which are instrumental in clearing DNA damage caused by platinum drugs and radiation, have been extensively studied as potential biomarkers of clinical outcomes in lung and head and neck cancers. The results are complex and contradictory. Here we summarize the current status of single nucleotide polymorphisms, mRNA, and protein expression of ERCC1 and XRCC1 in relation to cancer risk and patient outcomes.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To describe the clinical presentation, pathophysiology, and treatment of spontaneous cerebrospinal fluid (CSF) leaks of the sphenoid bone, with an emphasis on a previously undescribed form in this location, in which CSF is trapped under the mucosa of the sinonasal cavity or in the soft tissue of the skull base. STUDY DESIGN/METHODS:Case series and literature review. METHODS:Analysis of cases through medical records and literature review. RESULTS:Four examples of unusual spontaneous CSF leaks of the skull base are presented. In each case, a CSF collection was contained behind the sinonasal mucosa of the sphenoid sinus, resembling a nasal polyp or mucocele on exam or imaging. In one case, the fluid collection was also associated with significant bone resorption and extravasation into the soft tissue of the infratemporal fossa. In each case, small defects of the ventral skull base (sphenoid bone) were the source of the CSF leaks. Successful treatment was achieved after transnasal endoscopic repair of the skull base defects using a combination of free abdominal fat grafts, free fascial grafts, and pedicled nasoseptal flaps. Postoperatively, a ventriculoperitoneal shunt was placed if the intracranial pressure was elevated. CONCLUSIONS:Spontaneous CSF leaks arising in the sphenoid sinus may not always present with overt CSF rhinorrhea but with a submucosal fluid collection (pseudomeningocele) that may mimic a mucocele or nasal polyp. These bona fide pseudomeningoceles of the skull base may be associated with elevated intracranial pressure and can be managed using endoscopic endonasal surgery.

The final stages of of megakaryocyte (MK) maturation involve a series of steps, including polyploidization and proplatelet formation. Although these processes are highly dependent on dynamic changes in the microtubule (MT) cytoskeleton, the mechanisms responsible for regulation of MTs in MKs remain poorly defined. Stathmin is a highly conserved MT-regulatory protein that has been suggested to play a role in MK differentiation of human leukemic cell lines. However, previous studies defining this relationship have reached contradictory conclusions. In this study, we addressed this controversy and investigated the role of stathmin in primary human MKs. To explore the importance of stathmin down-regulation during megakaryocytopoiesis, we used a lentiviral-mediated gene delivery system to prevent physiologic down-regulation of stathmin in primary MKs. We demonstrated that sustained expression of constitutively active stathmin delayed cytoplasmic maturation (ie, glycoprotein GPIb and platelet factor 4 expression) and reduced the ability of MKs to achieve high levels of ploidy. Moreover, platelet production was impaired in MKs in which down-regulation of stathmin expression was prevented. These studies indicate that suppression of stathmin is biologically important for MK maturation and platelet production and support the importance of MT regulation during the final stages of thrombopoiesis.