Faculty Bibliography

Positive surgical margins represents incomplete resection by the surgeon, and the elimination of positive margins represents the only clinical feature during radical prostatectomy that can lead directly to improved cancer outcomes. The introduction of new robot-assisted technology and technical refinements has led to declines of positive surgical margins. Although margins induced by incomplete cancer resection by the surgeon have been reduced for organ-confined disease, the 'Holy Grail' of zero margins is not yet attainable in prostatectomy, and is more problematic in cancer that has penetrated beyond the prostate. Intraoperative frozen biopsies are imprecise. The union of real-time optical coherence tomography technology of the da Vinci robotic platform for identification of positive margin sites, and technical advances with wider excisions during surgery may provide promise for further reduction of surgical margins to zero.

Although cardiac sarcomas are rare in comparison to their soft tissue counterparts, they are the second most common type of primary cardiac neoplasm. Of the few hundred cases reported, most has been based on autopsy series. A series of 27 cardiac sarcomas removed at surgery for curative and diagnostic intent were reviewed for clinicopathologic features with correlation to available postoperative follow-up data in 17 patients. There were 6 angiosarcomas, 6 myxofibrosarcomas, 3 malignant peripheral nerve sheath tumors, 3 leiomyosarcomas, 2 synovial sarcomas, 1 epithelioid hemangioendothelioma, 1 chondrosarcoma, 1 osteosarcoma, and 4 poorly differentiated sarcomas. There was a wide age and size range with slight female predilection. There were 20 cases that arose in the atria/pulmonary vessels, 4 in the ventricles, 1 in mitral valve, and 2 in epi/pericardium. There was a slight left predilection. The histologic grade was low in 4, moderate in 3, and high in 20 cases. Six high-grade and 1 low-grade tumors were also treated with adjuvant chemotherapy and/or radiation. In 17 patients with follow-up data, 6 of 12 patients with high-grade tumor died (4 within 5 days of the initial surgery, 1 in 21 months, and 1 in 131 months), and 1 patient with moderate-grade tumor and all 4 patients with low-grade tumor were alive without evidence of disease at the end of follow-up. Tumor grade appeared to be prognostically important in cardiac sarcoma. Long survival was achieved in patients who survived the initial surgery well.

Primary and secondary pleural cancer remains an important clinical problem, with research progress limited by the lack of a suitable moderate- to large-sized (3 to 4 kg) animal model of pleural cancer. Many potential pleura-based imaging and treatment modalities cannot be investigated sufficiently by using currently available small murine animal models because their pleural space is not comparable to that of humans and therefore does not allow for the use of standard thoracoscopic techniques. Here we describe the development of a reproducible model of pleural malignancy in moderate-sized immunocompetent rabbits. Under thoracoscopic guidance, 9-15 x 10(6) VX2 carcinoma cells were inoculated into the plural space of 3 to 4 kg New Zealand white rabbits that had undergone gentle pleural abrasion. Malignant tumor involvement developed on the visceral and parietal pleural surfaces in an average of 2 to 4 wk. This novel pleural tumor model induction method likely will facilitate a broad range of investigations of pleural cancer diagnostics and therapeutics.

BACKGROUND:Intramyocardial fat deposition occurs as an age-related process and in multiple pathologic processes. OBJECTIVE:We evaluated the presence of left ventricular (LV) and right ventricular (RV) intramyocardial fat with 64-slice multidetector computed tomography (MDCT). METHODS:One hundred persons with no history of coronary artery disease (47 women, 53 men; mean age [+/- SD], 53 +/- 12.2 years) and 25 patients with CT findings of myocardial infarction (17 men, 8 women; mean age, 71.3 +/- 9.6 years) were studied for intramyocardial fat in defined segments of the ventricles (17 LV and 10 RV segments) at 3 levels. Fat deposition was defined as density range of -30 to -190 Hounsfield units on images both before and after contrast. RESULTS:In healthy persons, LV intramyocardial fat was primarily located in the basal segments (5% anteroseptal, 5% inferior), and RV intramyocardial fat was primarily located in the anterolateral (24% of base, 23% of mid) and inferolateral (27% base, 27% mid) segments. Older age was associated with an increased odds of RV (sex-adjusted odds ratio [OR] per decade increment, 1.61; 95% confidence interval [CI], 1.11-2.33; P = 0.012) but not LV (OR, 0.97; 95% CI, 0.67-1.40; P = 0.85) intramyocardial fat. Compared with women, men had a lower risk of LV (95% CI, 0.1-0.64; P = 0.004) but not RV (95% CI, 0.35-1.87; P = 0.62) intramyocardial fat. Patients with old myocardial infarction (>3 years) had increased percentage of fat in infarcted left ventricles at all 3 levels (P <or= 0.004). CONCLUSIONS:Intramyocardial fat can be detected by MDCT and is common in healthy and infarcted myocardium.

OBJECTIVES/OBJECTIVE:The purpose of this study was to evaluate the feasibility of noninvasive imaging of angiotensin II (AT) receptor upregulation in a mouse model of post-myocardial infarction (MI) heart failure (HF). BACKGROUND:Circulating AT levels do not reflect the status of upregulation of renin-angiotensin axis in the myocardium, which plays a central role in ventricular remodeling and evolution of HF after MI. Appropriately labeled AT or AT receptor blocking agents should be able to specifically target AT receptors by molecular imaging techniques. METHODS:AT receptor imaging was performed in 29 mice at various time points after permanent coronary artery ligation or in controls using a fluoresceinated angiotensin peptide analog (APA) and radiolabeled losartan. The APA was used in 19 animals for intravital fluorescence microscopy on a beating mouse heart. Tc-99m losartan was used for in vivo radionuclide imaging and quantitative assessment of AT receptor expression in 10 mice. After imaging, hearts were harvested for pathological characterization using confocal and 2-photon microscopy. RESULTS:No or little APA uptake was observed in control animals or within infarct regions on days 0 and 1. Distinct uptake occurred in the infarct area at 1 to 12 weeks after MI; the uptake was at maximum at 3 weeks and reduced markedly at 12 weeks after MI. Ultrasonographic examination demonstrated left ventricular remodeling, and pathologic characterization revealed localization of the APA tracer with collagen-producing myofibroblasts. Tc-99m losartan uptake in the infarct region (0.524 +/- 0.212% injected dose/g) increased 2.4-fold as compared to uptake in the control animals (0.215 +/- 0.129%; p < 0.05). CONCLUSIONS:The present study demonstrates the feasibility of in vivo molecular imaging of AT receptors in the remodeling myocardium. Noninvasive imaging studies aimed at AT receptor expression could play a role in identification of subjects likely to develop heart failure. In addition, such a strategy could allow for optimization of anti-angiotensin therapy in patients after MI.

Smoke inhalation injury causes acute airway injury that may result in airway compromise with significant morbidity and mortality. We investigate the ability of high resolution endobronchial optical coherence tomography (OCT) to obtain real-time images for quantitatively assessing regional differences between upper tracheal versus lower tracheal and bronchial airway injury responses to smoke inhalation in vivo using a prototype spectral domain (SLD)-OCT system we constructed, and flexible fiber optic probes. 33 New Zealand White rabbits are intubated and mechanically ventilated. The treatment groups are exposed to inhaled smoke. The OCT probe is introduced through the endotracheal tube and maintained in place for 5 to 6 h. Images of airway mucosa and submucosa are obtained at baseline and at specified intervals postexposure. Starting within less than 15 min after smoke inhalation, there is significant airway thickening in the smoke-exposed animals. This is maintained over 5 h of imaging studies. The lower tracheal airway changes, correlating closely with carboxyhemoglobin levels, are much greater than upper tracheal changes. Significant differences are seen in lower trachea and bronchi after acute smoke inhalation compared to upper trachea as measured in vivo by minimally invasive OCT. OCT is capable of quantitatively detecting regional changes in airway swelling following inhalation injury.

Noninfectious aortitis typically involves the ascending aorta and causes aneurysms that result in aortic root repair. Aortitis is clinically categorized into groups that include Takayasu disease, giant cell aortitis, and isolated aortitis. We present a histopathologic classification of 52 patients with aortitis, without reference to clinical findings, which are often unknown to the diagnostic pathologist. The largest group (43 patients) was designated necrotizing aortitis (NA), characterized by zonal medial laminar necrosis, rimmed by giant cells. Healed areas were common and were characterized by extracellular accumulation of proteoglycans imparting the appearance of medial degeneration. NA had a bimodal age distribution with a separation at age 65 (adult NA versus elderly NA). Adult NA (24 patients; 50% female; age range, 24-60) was generally isolated, but 2 patients had associated autoimmune disease (Crohn disease and lupus erythematosus, respectively). Elderly NA (19 patients; 94% female; age range, 68-80) was likewise usually isolated, but 1 patient had temporal giant cell arteritis and 1 seronegative arthritis. Subsequent complete rheumatologic workup on 17 patients with NA was negative. Adult NA differed significantly from elderly NA (fewer women, P = .002; greater adventitial scarring, P = .007). The second group of aortitis was designated non-NA (NNA), characterized by the absence of necrosis, with diffuse medial inflammation. The NNA group was composed of 3 men and 6 women, all older than 65 years (mean, 72 +/- 6 years). Four had a history of temporal arteritis. NNA patients differed from elderly NA (more frequent temporal arteritis, P = .03; less medial destruction and proteoglycan deposits, P < .01; increased medial T-lymphocytes, P = .05; and more frequent dissection, P = .002). We conclude that NA is usually isolated, has distinct histologic features based on age less than or more than 65 years, and is clinicopathologically distinct from NNA. NNA is less often isolated and best classified as giant cell aortitis. Adult NA has histologic features classically associated with Takayasu disease but is limited primarily to the ascending aorta and has no sex predominance.

Chemotherapeutic agents that bind tubulin cause mitotic arrest, which may be seen histologically. Such mitotic arrest has been reported to occur in the skin, alimentary canal, lungs, liver, bone marrow, endometrium, breasts, or in ascites following treatment with paclitaxel, vincristine, colchicine, podophyllotoxin, or maytansine. Mitotic arrest as a result of docetaxel, a taxane that binds tubulin, has yet to be reported. Mitotic arrest in the gallbladder has also yet to be reported. We recently encountered a case of dramatic mitotic arrest as a result of docetaxel, involving the gallbladder of a 66-year-old man with metastatic bronchogenic carcinoma. Strikingly abundant bizarre mitoses initially prompted a diagnosis of primary carcinoma. Carcinoma was eventually excluded based on the absence of dysplasia in all cells at interphase and the history of recent administration of docetaxel. This is the first case of mitotic arrest involving docetaxel or the gallbladder. Awareness of this phenomenon is necessary to avoid misdiagnosing carcinoma.

The majority of mitochondrial DNA (mtDNA) mutations that cause human disease are mild to moderately deleterious, yet many random mtDNA mutations would be expected to be severe. To determine the fate of the more severe mtDNA mutations, we introduced mtDNAs containing two mutations that affect oxidative phosphorylation into the female mouse germ line. The severe ND6 mutation was selectively eliminated during oogenesis within four generations, whereas the milder COI mutation was retained throughout multiple generations even though the offspring consistently developed mitochondrial myopathy and cardiomyopathy. Thus, severe mtDNA mutations appear to be selectively eliminated from the female germ line, thereby minimizing their impact on population fitness.