Thomas S. Winokur

Live Three‐Dimensional Transthoracic Echocardiographic Assessment of Left Atrial Tumors

This preliminary study demonstrates the superiority of live three‐dimensional transthoracic echocardiography (3D TTE) over two‐dimensional (2D) TTE in the assessment of left atrial (LA) tumors in four patients studied by us (three myxomas, one hemangioma, all subsequently pathologically proven). Because of the unique ability of live 3D TTE to systematically section and view the contents of an intracardiac mass, LA myxomas in the three patients studied could be more confidently diagnosed by noting isolated echolucent areas consistent with hemorrhage/necrosis in the tumor mass. On the other hand, a definite echolucent area was found by 2D TTE in only two of the three patients with myxoma. In the fourth patient with a hemangioma, live 3D TTE showed much more extensive and closely packed echolucencies with little solid tissue as compared to a myxoma consistent with a highly vascularized tumor. In contrast, 2D TTE demonstrated only two isolated echolucencies in the tumor suggesting an erroneous diagnosis of myxoma.

Cardiomyopathy in a carrier of duchenne’s muscular dystrophy

During the third trimester of her pregnancy, a 25-year-old carrier of Duchennes muscular dystrophy developed severe cardiac failure and required mechanical circulatory support and transplantation. Her cardiac function improved during 311 days of circulatory support. However this improvement was not sufficient to allow removal of her left ventricular assist device before transplantation.

Dynamic telecytopathology of on site rapid cytology diagnoses for pancreatic carcinoma

Background Diagnosis of pancreatic lesions can be accurately performed by endoscopic ultrasound guided fine needle aspiration (EUS-FNA) with onsite cytopathologists to assess specimen adequacy and to determine a preliminary diagnosis. Considerable time is needed to perform on-site assessments. This takes away work time of cytopathologists and prohibits them from serving remote locations. It is therefore logical to ask if real-time telecytopathology could be used to assess specimen adequacy and if telecytopathology diagnosis has the same level of agreement to the final diagnosis as that of onsite evaluation. In this study, we compare agreement between cytodiagnoses rendered using telecytopathology with onsite and final interpretations. Method 40 Diff-Quik-stained EUS-FNA were re-evaluated retrospectively (patient ages 31–62, 19:21 male:female, 15 non-malignant lesions, 25 malignant lesions as classified by final diagnosis). Each previously assessed by a cytopathologist and finally reviewed by the same or different cytopathologist. Blinded to the final diagnosis, a resident pathologist re-screened all slides for each case, selected a slide and marked the diagnostic cells most representative of the lesion. Blinded to the diagnosis, one cytopathologist assessed the marked cells through a real time remotely operated telecytopathology system (MedMicroscopy). Diagnosis and time spent were recorded. Kappa statistic was used to compare agreements between telecytopathology vs. original onsite vs. final diagnoses. Results Time spent for prescreening ranged from 1 to 5 minutes (mean 2.6 +/- 1.3 minutes) and time spent for telecytopathology diagnosis ranged from 2–20 minutes (mean 7.5 +/- 4.5 minutes). Kappa statistics, K, was as follows: telecytopathology versus onsite diagnosis K, 95% CI = 0.65, 0.41–0.88, for telecytopathology versus final K, 95% CI = 0.61, 0.37–0.85 and for onsite diagnosis versus final K, 95% CI = 0.79, 0.61–0.98. There is no significant difference in agreement between onsite and telecytopathology diagnoses. Kappa values for telecytopathology were less than onsite evaluation when compared to the final diagnosis; however, the difference was not statistically significant. Conclusion This retrospective study demonstrates the potential use of telecytopathology as a valid substitute for onsite evaluation of pancreatic carcinoma by EUS-FNA.

Differential expression and biodistribution of cytokeratin 18 and desmoplakins in non-small cell lung carcinoma subtypes

Adenocarcinoma (AC), squamous cell carcinoma (SCC) and adenosquamous carcinoma (ASC) of the lung are morphologically distinguished in part by cyto-architectural features. However, little is known about the relative expression and distribution of cyto-architectural proteins among AC, SCC and ASC. Initial microarray analysis revealed significant differences in expression of two cyto-architectural genes in AC, SCC and ASC. Desmoplakin (DP) 1 and 2, which link desmosomes to intermediate filaments, was strongly expressed in SCC relative to AC and ASC. Cytokeratin 18 (CK18), an intermediate filament that is commonly linked to desmoplakin, was strongly expressed in AC and ASC relative to SCC. Western blot analysis demonstrated that AC and ASC had abundant CK18 protein, whereas CK18 was weakly detected in SCC. DP 1 and 2 are strongly expressed in SCC and minimally expressed in AC and ASC. However, the ratio of one to the other is the same in SCC and AC, but DP2 is lost in ASC. Microscopic analysis with fluorescence-labeled antibodies for CK18 and DP 1 and 2 revealed abundant membrane localization of DP and minimal perinuclear localization of CK18 in SCC. In contrast, in both AC and ASC, the CK18 protein was diffusely distributed within the cytoplasm, and DP showed both membranous and cytoplasmic localization. In conclusion, the data here shows that AC, SCC and ASC each have specific patterns of DP 1 and 2 and CK18 gene expression, protein content and biodistribution.

Change in maximum standardized uptake value on repeat positron emission tomography after chemoradiotherapy in patients with esophageal cancer identifies complete responders

OBJECTIVE The objective was to identify whether repeat positron emission tomography scan after neoadjuvant chemoradiotherapy in patients with esophageal cancer predicted a complete response. METHODS A retrospective study using a prospective database was performed. Patients had esophageal cancer and underwent neoadjuvant chemoradiotherapy, an initial and repeat positron emission tomography, endoscopic ultrasound with fine-needle aspiration (at the same institution), and Ivor Lewis esophagogastrectomy with lymph node resection. RESULTS There were 221 patients who underwent Ivor Lewis, 86 of whom had their initial and repeat positron emission tomography scans performed at the same center. Of these, 37 patients (43%) were complete responders. The median maximum standardized uptake value of esophageal cancer decreased by 72% in the 37 patients who were complete responders, by 58% in the 31 patients who were partial responders, and by 37% in the 18 patients who had a minimal pathologic response. When the maximum standardized uptake value decreased by more than 64%, the patient was likely to be a complete responder (P = .003, area under the curve = 0.75). CONCLUSION When initial and repeat positron emission tomography scans are performed at the same center at least 30 days after the completion of preoperative chemoradiotherapy, the percent change in the maximum standardized uptake value is a predictor of the response to chemoradiotherapy by a patient with esophageal cancer. When the maximum standardized uptake value decreases by 64% or more, it is likely that the patient is a complete responder. These data may help guide neoadjuvant therapy and identify patients for a future randomized study that compares observation with surgical resection in patients with esophageal cancer who appear to be complete responders.

Mechanical circulatory support for myocarditis: How much recovery should occur before device removal?

A 12-year-old girl with presumed myocarditis was supported with right and left ventricular assist devices for 68 days before device removal. During this time, the patient underwent echocardiography and right heart catheterization for evaluation of cardiac recovery. This case report serves as the basis for a discussion of criteria for deciding when to terminate mechanical circulatory support in a patient with recovery after acute myocarditis.

Using a higher cutoff for the percentage of HER2+ cells decreases interobserver variability in the interpretation of HER2 immunohistochemical analysis.

The effect of using a 30% cutoff for the proportion of HER2+ cells on the interobserver variability in the interpretation of HER2 immunohistochemical results was evaluated. Immunostained sections from 96 cases of breast carcinoma were reviewed by 10 pathologists and scored as positive (3+) when uniform strong membranous staining was identified in at least 10% of tumor cells; the actual percentage of cells with such staining was also estimated. The agreement rates and the kappa values using a 30% cutoff were compared with those using a 10% cutoff. These proved to be higher in 62% and 66% of measurements, respectively, with average interobserver rates and kappa values of 72% and 0.54 using the 30% cutoff and 70% and 0.49 using the 10% cutoff (P=.001 for all comparisons). Using a 30% cutoff for the percentage of HER2+ cells by immunohistochemical analysis modestly decreased interobserver variability in the interpretation of HER2 immunohistochemical results.

Angiomyolipoma of the anterior mediastinum

Angiomyolipoma is a benign tumor composed of varying proportions of smooth muscle cells, blood vessels, and adipose tissue that most commonly occurs in the kidney. Sporadic lesions and lesions arising in the setting of the tuberous sclerosis complex have been reported in extrarenal sites. We present the case of an incidentally discovered angiomyolipoma in the anterior mediastinum. Thymoma was suspected clinically, and the lesion was composed mainly of spindled-to-epithelioid cells arranged in a histologic pattern reminiscent of hemangiopericytoma, a pattern that has been described in thymoma. Immunohistochemical stains revealed positivity for smooth muscle actin and HMB-45, revealing the expression of smooth muscle and melanocytic markers characteristic of angiomyolipoma and other lesions in the PEComa family.

Histologic grading of invasive lobular carcinoma: does use of a 2-tiered nuclear grading system improve interobserver variability?

The Nottingham histologic grade (NHG) is a prognostic marker for infiltrating ductal carcinoma. Its usefulness for invasive lobular carcinoma (ILC) has been less clear, given that 2 of the 3 parameters, tubule formation and mitotic activity, show little variation in ILC, placing much of the emphasis on nuclear grade. We have previously reported a trend for improved overall and relapse-free survival in patients with ILC of low nuclear grade, as classified by a 2-tiered nuclear grading system. Given the inherent potential for interobserver variability with any grading system, the goal of this study is to compare interobserver variability in the grading of ILC using a 2-tiered nuclear grade vs the NHG. Thirty-eight cases of ILC were graded independently by 5 pathologists using NHG criteria. Tumors were also categorized by a nuclear grading system as low grade (grade 1 nuclei) or high grade (grades 2-3 nuclei). Pairwise kappa values and interobserver agreement rates were calculated for both NHG and nuclear grade. Results were compared using the paired t test. Mean interobserver agreement rates and kappa values improved with use of the nuclear grading system as compared to NHG (83% vs 70%, 0.4738 vs 0.3228, respectively). The differences between the 2 were statistically significant. Because histologic grade has significant prognostic implications for patients with breast cancer, accurate reporting is paramount. For ILC, where use of the NHG places substantial weight on nuclear pleomorphism, a 2-tiered nuclear grading system may reduce interobserver variability yet still provide useful prognostic information.

Implementation and utilization of the molecular tumor board to guide precision medicine

BACKGROUND With rapid advances in genomic medicine, the complexity of delivering precision medicine to oncology patients across a university health system demanded the creation of a Molecular Tumor Board (MTB) for patient selection and assessment of treatment options. The objective of this report is to analyze our progress to date and discuss the importance of the MTB in the implementation of personalized medicine. MATERIALS AND METHODS Patients were reviewed in the MTB for appropriateness for comprehensive next generation sequencing (NGS) cancer gene set testing based on set criteria that were in place. Because profiling of stage IV lung cancer, colon cancer, and melanoma cancers were standard of care, these cancer types were excluded from this process. We subsequently analyzed the types of cases referred for testing and approved with regards to their results. RESULTS 191 cases were discussed at the MTB and 132 cases were approved for testing. Forty-six cases (34.8%) had driver mutations that were associated with an active targeted therapeutic agent, including BRAF, PIK3CA, IDH1, KRAS, and BRCA1. An additional 56 cases (42.4%) had driver mutations previously reported in some type of cancer. Twenty-two cases (16.7%) did not have any clinically significant mutations. Eight cases did not yield adequate DNA. 15 cases were considered for targeted therapy, 13 of which received targeted therapy. One patient experienced a near complete response. Seven of 13 had stable disease or a partial response. CONCLUSIONS MTB at University of Alabama-Birmingham is unique because it reviews the appropriateness of NGS testing for patients with recurrent cancer and serves as a forum to educate our physicians about the pathways of precision medicine. Our results suggest that our detection of actionable mutations may be higher due to our careful selection. The application of precision medicine and molecular genetic testing for cancer patients remains a continuous educational process for physicians.Background With rapid advances in genomic medicine, the complexity of delivering precision medicine to oncology patients across a university health system demanded the creation of a Molecular Tumor Board (MTB) for patient selection and assessment of treatment options. The objective of this report is to analyze our progress to date and discuss the importance of the MTB in the implementation of personalized medicine. Materials and Methods Patients were reviewed in the MTB for appropriateness for comprehensive next generation sequencing (NGS) cancer gene set testing based on set criteria that were in place. Because profiling of stage IV lung cancer, colon cancer, and melanoma cancers were standard of care, these cancer types were excluded from this process. We subsequently analyzed the types of cases referred for testing and approved with regards to their results. Results 191 cases were discussed at the MTB and 132 cases were approved for testing. Forty-six cases (34.8%) had driver mutations that were associated with an active targeted therapeutic agent, including BRAF, PIK3CA, IDH1, KRAS, and BRCA1. An additional 56 cases (42.4%) had driver mutations previously reported in some type of cancer. Twenty-two cases (16.7%) did not have any clinically significant mutations. Eight cases did not yield adequate DNA. 15 cases were considered for targeted therapy, 13 of which received targeted therapy. One patient experienced a near complete response. Seven of 13 had stable disease or a partial response. Conclusions MTB at University of Alabama-Birmingham is unique because it reviews the appropriateness of NGS testing for patients with recurrent cancer and serves as a forum to educate our physicians about the pathways of precision medicine. Our results suggest that our detection of actionable mutations may be higher due to our careful selection. The application of precision medicine and molecular genetic testing for cancer patients remains a continuous educational process for physicians.