Validation of mammalian target of rapamycin biomarker panel in patients with clear cell renal cell carcinoma.

BACKGROUND: This was an external validation of the prognostic benefit of mammalian target of rapamycin (mTOR) marker panel in patients with clear cell renal cell carcinoma (ccRCC). METHODS: Immunohistochemistry for 5 mTOR pathway markers was performed on tissue microarrays of patients with nonmetastatic ccRCC treated surgically at 4 centers. The markers employed were phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), phosphorylated-mTOR (p-mTOR), phosphorylated-S6 (p-S6), and phosphorylated 4E-binding protein-1 (p-4EBP1). Cox regression was used to correlate marker status and oncologic outcomes. Discrimination of the models was determined using area under the curve and net reclassification improvement. RESULTS: Five hundred twenty-eight patients with a median follow-up of 56.5 months were included. Expression of PI3K, PTEN, p-mTOR, p-4EBP1, and p-S6 was altered in 52%, 78%, 25%, 86%, and 30% of patients, respectively. The number of altered biomarkers predicted recurrence-free survival (RFS) in multivariate analysis adjusted for stage, grade, and lymph node status (HR, 3.20; P = .02 for patients with 4-5 altered biomarkers compared with 0-1 altered markers). A biomarker panel consisting of only 2 markers (p-S6 and p-4EBP1) independently predicted for worse RFS (HR, 4.38; P = .003 for patients with 2 altered markers compared to patients with 0 altered markers). The biomarker score increased predictive accuracy when added to the clinical Cox regression model. CONCLUSIONS: m-TOR pathway biomarkers add prognostic information in addition to standard clinicopathologic variables in ccRCC patients and may identify patients who could benefit from additional treatments or closer postoperative surveillance.

BAP1 immunohistochemistry predicts outcomes in a multi-institutional cohort with clear cell renal cell carcinoma.

PURPOSE: Mutations in the tumor suppressor gene BAP1 occur in approximately 15% of clear cell renal cell carcinoma cases. Sequencing efforts demonstrated worse outcomes in patients with BAP1 mutated clear cell renal cell carcinoma. We investigated the clinicopathological significance and oncologic outcomes of BAP1 loss using a previously validated immunohistochemical assay. MATERIALS AND METHODS: Immunohistochemistry for BAP1 was performed on tissue microarray sections from 559 nonmetastatic clear cell renal cell carcinoma cases treated with nephrectomy at multiple institutions. The association of BAP1 expression with clinicopathological parameters was analyzed using the Wilcoxon rank sum and Cochran-Mantel-Haenszel tests. Survival was assessed by Cox regression analysis, which also identified independent predictors of time dependent outcomes. RESULTS: At a median followup of 50 months (range 0 to 183) 86 of 483 patients (17.8%) experienced recurrence and 121 of 559 (21.6%) had died. BAP1 was negative in 82 of 559 tumors (14.7%). BAP1 loss was associated with adverse clinicopathological variables, including high Fuhrman grade (p <0.0001), advanced pT stage (p = 0.0021), sarcomatoid dedifferentiation (p = 0.0001) and necrosis (p <0.0001). Cox regression revealed that patients with BAP1 negative tumors had significantly worse disease-free survival (HR 2.9, 95% CI 1.8-4.7, p <0.0001) and overall survival (HR 2.0, 95% CI 1.3-3.1, p = 0.0010) than patients with BAP1 positive tumors. CONCLUSIONS: Immunohistochemistry for BAP1 serves as a powerful marker to predict poor oncologic outcomes and adverse clinicopathological features in patients with nonmetastatic clear cell renal cell carcinoma. BAP1 assessment using immunohistochemistry on needle biopsy may benefit preoperative risk stratification and guide treatment planning in the future.

Cavernous hemangioma of the submandibular gland with parapharyngeal extension in an adult: Case report.

Cavernous hemangiomas of the submandibular gland are rare. Signs and symptoms typically resemble those of sialolithiasis and chronic sialadenitis. If a lesion extends into the parapharyngeal space, otalgia and sore throat can result. Spontaneous regression is not a characteristic of cavernous hemangiomas. Surgical excision is a management option. We report the case of an adult with a submandibular gland cavernous hemangioma with parapharyngeal extension.

Mediastinal Hibernoma: A Rare Case with Radiologic-Pathologic Correlation.

Hibernomas, especially located in the mediastinum, are extremely rare benign tumors, which are important to consider in the differential diagnosis of a heterogeneously enhancing mass with areas of fat attenuation on imaging of an often incidentally discovered mass. Other common possibilities in the differential include malignant tumors, such as liposarcoma, hence histopathology is usually required to confirm the diagnosis. Hibernomas often follow the distribution of sites of persistence of brown fat in adults, and intrathoracic locations are unusual. We present a very rare case of a mediastinal hibernoma in a 53-year-old woman. She presented to the emergency department with severe, progressive right neck and shoulder pain with radiation down her arm and was found to have a right apical posterior mediastinal mass on imaging. Initial radiographs of the shoulder showed a soft tissue mass within the apical right hemithorax. Further imaging with CT revealed a well circumscribed, heterogeneously enhancing mass with areas of fat attenuation. Pathology confirmed the diagnosis of mediastinal hibernoma, and the mass was completely excised. Fourteen months after surgery, the patient had a normal chest radiograph, and thirty-two months after surgery, she remains asymptomatic.

Lymphatic filariasis disseminating to the upper extremity.

Lymphatic filariasis is the most common cause of acquired lymphedema worldwide (Szuba and Rockson, 1998). It is endemic to tropical and subtropical regions, and its effects are devastating. With over 100 million infected persons, it ranks second only to leprosy as the leading cause of permanent and long-term disability. Wuchereria bancrofti is the etiologic agent in 90% of cases. There is a dearth of published MRI findings with pathologically proven active infections, making this entity even more of a diagnostic dilemma. Imaging may provide the first clue that one is dealing with a parasite and may facilitate proper treatment and containment of this disease. This is the first report of pathologic correlation with MRI findings in the extremity in active filariasis. The magnetic resonance images demonstrate an enhancing, infiltrative, mass-like appearance with partial encasement of vasculature that has not been previously described in filariasis. Low signal strands in T2-hyperintense dilated lymphatic channels are seen and may depict live adult worms. We hypothesize that the low signal strands correspond to the collagen rich acellular cuticle. This, in combination with the surrounding hyperintense T2 signal, corresponding to a dilated lymphatic channel, may provide more specific MRI findings for active nematodal infection, which can prompt early biopsy, pathological correlation, and diagnosis.

Miniaturized electrochemical flow cells.

Several novel types of miniaturized electrochemical flow cells are described. The flow cells are fabricated in fluorinated ethylene propylene using a novel technique where channels with inner diameters down to 13 microm are integrated with electrodes. The channel is formed by shrinking and simultaneous melting of a heat shrink/melt tubing around a channel template (a tungsten wire) and electrodes followed by removal of the channel template. The technique allows incorporation of different electrode materials of different sizes. The electrode configuration consists of one or two working electrodes inside the channel and a counter electrode located in the channel outlet reservoir. Electrode configurations with different channel and working electrode sizes, different electrode materials including carbon fibers, glassy carbon rods, poly(tetrafluoroethylene)/carbon composite material, and platinum wires, and different arrangements have been assembled. Hydrodynamic voltammograms in dual-electrode (generator-collector) experiments indicate good potential control for cells with 25-microm channels, while there is some iR drop in cells with 13-microm channels. Cells prepared with a cylindrical working electrode tangent and perpendicular to a flow channel show a flow rate dependence consistent with thin-layer cell behavior. Electrode areas can be made in the range of 10(-10)-10(-8) m2.