Weekly chemotherapy with radiation versus high‐dose cisplatin with radiation as organ preservation for patients with HPV‐positive and HPV‐negative locally advanced squamous cell carcinoma of the oropharynx

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106948/1/hed23339.pd

Acute Vision Loss Following Endoscopic Sinus Surgery

A 41-year-old female with a history of uterine cancer and Celiac and Raynaud’s Disease presented to our institution with frequent migraines and nasal congestion. She underwent functional endoscopic sinus surgery (FESS) and experienced acute unilateral vision loss postoperatively. Rapid recognition of the etiology and effective treatment are paramount given the permanent and irreversible vision loss that can result. Arterial vasospasm following FESS is rare. Patients with autoimmune diseases have perhaps an increased risk for vasospasm secondary to an increased vasoreactive profile. We present the first documented case of nitroglycerin sublingual therapy to successfully treat ophthalmic artery vasospasm following FESS. Nitroglycerin sublingual therapy is a promising treatment for ophthalmic vasospasm secondary to its ability to cross the blood-ocular barrier, its rapid onset of action, and its ability to promote relaxation of vascular smooth muscle

Ternary Complex Formation on the Adenovirus Packaging Sequence by the IVa2 and L4 22-Kilodalton Proteins▿

Assembly of infectious adenovirus particles requires seven functionally redundant elements at the left end of the genome, termed A repeats, that direct packaging of the DNA. Previous studies revealed that the viral IVa2 protein alone interacts with specific sequences in the A repeats but that additional IVa2-containing complexes observed during infection require the viral L4 22-kDa protein. In this report, we purified a recombinant form of the 22-kDa protein to characterize its DNA binding properties. In electrophoretic mobility shift assay analyses, the 22-kDa protein alone did not interact with the A repeats but it did form complexes on them in the presence of the IVa2 protein. These complexes were identical to those seen in extracts from infected cells and had the same DNA sequence dependence. Furthermore, we provide data that the 22-kDa protein enhances binding of the IVa2 protein to the A repeats and that multiple binding sites in the packaging sequence augment this activity. These data support a cooperative role of the IVa2 and 22-kDa proteins in packaging and assembly

Presence of the Adenovirus IVa2 Protein at a Single Vertex of the Mature Virion▿

Assembly of adenovirus particles is thought to be similar to that of bacteriophages, in which the double-stranded DNA genome is inserted into a preformed empty capsid. Previous studies from our and other laboratories have implicated the viral IVa2 protein as a key component of the encapsidation process. IVa2 binds to the packaging sequence on the viral chromosome in a sequence-specific manner, alone and in conjunction with the viral L4 22K protein. In addition, it interacts with the viral L1 52/55-kDa protein, which is required for DNA packaging. Finally, a mutant virus that does not produce IVa2 is unable to produce any capsids. Therefore, it has been proposed that IVa2 nucleates capsid assembly. A prediction of such a model is that the IVa2 protein would be found at a unique vertex of the mature virion. In this study, the location of IVa2 in the virion has been analyzed using immunogold staining and electron microscopy, and the copy number of IVa2 in virions was determined using three independent methods, quantitative mass spectrometry, metabolic labeling, and Western blotting. The results indicate that it resides at a unique vertex and that there are approximately six to eight IVa2 molecules in each particle. These findings support the hypothesis that the IVa2 protein plays multiple roles in the viral assembly process

Patterns of nodal metastasis and prognosis in human papillomavirus–positive oropharyngeal squamous cell carcinoma

Background The current American Joint Committee on Cancer (AJCC) staging system may not accurately reflect survival in patients with human papillomavirus (HPV)‐positive oropharyngeal squamous cell carcinoma (SCC). The purpose of this study was to develop a system that more precisely predicts survival. Methods CT scans from 156 patients who underwent chemoradiation for advanced‐stage oropharyngeal SCC with >2 years follow‐up were reviewed. We modeled patterns of nodal metastasis associated with different survival rates. We defined HPV+ N1 as a single node <6 cm, ipsilaterally, contralaterally, or bilaterally. HPV+ N2 was defined as a single node ≥6 cm or ≥2 nodes ipsilaterally/contralaterally or ≥3 nodes bilaterally. HPV+ N3 was defined as matted nodes. Results There was no significant difference in disease‐specific survival (DSS; p = .14) or overall survival (OS; p = .16) by AJCC classification. In patients grouped by HPV+ N1, HPV+ N2, and HPV+ N3 nodal classification, significant differences in DSS (100%, 92%, and 55%, respectively; p = .0001) and OS (100%, 96%, and 55%, respectively; p = .0001) were found. Conclusion A staging system with reclassification of size, bilaterality, and matted nodes more accurately reflects survival differences in this cohort of patients. Review of the AJCC staging system with these criteria should be considered for HPV‐positive oropharyngeal SCC. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1233–1240, 2014Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108284/1/hed23438.pd

Correlation of Crtc1/3-Maml2 fusion status, grade and survival in mucoepidermoid carcinoma

ObjectiveMucoepidermoid carcinoma (MEC) is the most common malignant tumor of the salivary glands. Tumor stage and grade have historically been important predictors of survival. An oncogenic CRTC1- or CRTC3-MAML2 gene fusion has been identified in a number of MECs. Historically, these gene fusions have been associated with lower grade tumors and better survival. However, reported gene fusion rates and prognosis varies widely across studies, and have not controlled for tumor grade. We sought to identify gene fusion rates and outcomes in our cohort of MEC patients.Materials and methodsAn IRB-approved retrospective cohort of patients with MEC was identified at the University of Michigan. Clinical, histologic, and outcome data was collected from medical records. RNA was isolated from formalin fixed paraffin-embedded tumor sections, and qRT-PCR was performed to identify CRTC1/3-MAML2 gene fusions. Sanger sequencing of qRT-PCR products was used to confirm gene fusions.ResultsOverall, 90 patient MEC tumors were collected (58 low-grade, 25 intermediate-grade, and 7 high-grade). Gene fusions were identified in 59% (53/90) of tumors. On univariate and bivariate analysis, fusion status did not significantly associate with grade or survival.ConclusionWe have identified a high rate of CRTC1/3-MAML2 gene fusions in a large cohort of MEC. We do not identify any correlation between fusion status with tumor grade or survival. These findings suggest further characterization of MECs is needed before considering the CRTC1/3-MAML2 gene fusion as a prognostic biomarker. Additional genetic drivers may account for survival and grade in MECs

Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial

The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment