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Universal screening for Lynch syndrome in colorectal cancer is recommended, and immunohistochemistry for the mismatch repair proteins is commonly used. To reduce cost, some screen using only MSH6 and PMS2, with reflex to the partner stain if either are absent (two-stain method). An expression pattern revealing absent MSH2 and intact MSH6 is not expected, but could result in failed Lynch syndrome detection. We analyzed tumors with absent MSH2 but any degree of MSH6 expression to determine if the two-stain method could miss MSH2 mutations. One-thousand seven-hundred thirty colorectal cancer patients from the Ohio Colorectal Cancer Prevention Initiative underwent tumor screening using microsatellite instability and immunohistochemistry. The two-stain method was used for 1235 cases; staining for all four proteins was completed for 495 cases. The proportion of positive cells and staining intensity were reviewed for MSH6, as well as MSH2 when available. Patients with mismatch repair deficiency underwent next-generation sequencing of germline DNA for mismatch repair genes. If negative, tumor next-generation sequencing was performed to assess for somatic mutations. Overall, thirty-three (1.9%, 33/1730) MSH2-absent cases were identified. Of those, fourteen had no MSH6 expression but eight (0.5%, 8/1730) had ambiguous and eleven (0.6%, 11/1730) had convincing MSH6 expression that could have been interpreted as intact. Germline next-generation sequencing identified MSH2 mutations in 11/14 cases with absence of both stains, 7/8 cases with ambiguous MSH6 expression, and 9/11 cases with convincing MSH6 expression. All remaining cases, except one, had double somatic mutations. The two-stain method fails to detect some patients with Lynch syndrome: (1) significant staining weaker than the control may be incorrectly interpreted as intact MSH6, or (2) Weak or focal/patchy MSH6 can be retained with the absence of MSH2. Accordingly, we recommend the four-stain method be used for optimal Lynch syndrome screening detection.

Background: The quality and limitations of digital slides are not fully known. We aimed to estimate intrapathologist discrepancy in detecting specific microscopic features on glass slides and digital slides created by scanning at ×20. Methods: Hematoxylin and eosin and periodic acid–Schiff glass slides were digitized using the Mirax Scan (Carl Zeiss Inc., Germany). Six pathologists assessed 50–71 digital slides. We recorded objective magnification, total time, and detection of the following: Mast cells; eosinophils; plasma cells; pigmented macrophages; melanin in the epidermis; fungal bodies; neutrophils; civatte bodies; parakeratosis; and sebocytes. This process was repeated using the corresponding glass slides after 3 weeks. The diagnosis was not required. Results: The mean time to assess digital slides was 176.77 s and 137.61 s for glass slides (P < 0.001, 99% confidence interval [CI]). The mean objective magnification used to detect features using digital slides was 18.28 and 14.07 for glass slides (P < 0.001, 99.99% CI). Parakeratosis, civatte bodies, pigmented macrophages, melanin in the epidermis, mast cells, eosinophils, plasma cells, and neutrophils, were identified at lower objectives on glass slides (P = 0.023–0.001, 95% CI). Average intraobserver concordance ranged from κ = 0.30 to κ = 0.78. Features with poor to fair average concordance were: Melanin in the epidermis (κ = 0.15–0.58); plasma cells (κ = 0.15–0.49); and neutrophils (κ = 0.12–0.48). Features with moderate average intrapathologist concordance were: parakeratosis (κ = 0.21–0.61); civatte bodies (κ = 0.21–0.71); pigment-laden macrophages (κ = 0.34–0.66); mast cells (κ = 0.29–0.78); and eosinophils (κ = 0.31–0.79). The average intrapathologist concordance was good for sebocytes (κ = 0.51–1.00) and fungal bodies (κ = 0.47–0.76). Conclusions: Telepathology using digital slides scanned at ×20 is sufficient for detection of histopathologic features routinely encountered in dermatitis cases, though less efficient than glass slides.

Nonhepatosplenic/noncutaneous γδ peripheral T-cell lymphoma (NHNCγδ PTCL) represents a miscellaneous group of unrelated T-cell lymphomas of which only isolated cases have been reported. We describe two cases of transformation from T-lymphoblastic leukemia/lymphoma to NHNCγδ PTCL. Transformation into more aggressive disease is a rare event in T-cell lineage-derived hematologic malignancies compared to B-cell neoplasms. Nevertheless, both of our cases involved relapse as PTCL manifested with skin involvement and an overt shift from blastic morphology to large granular leukemia-like mature T cells. Among other notable molecular characteristics, expression of immature markers such as TdT was lost in both cases. Based on cytogenetics, phenotype, and morphology, both patients represent a novel phenomenon of clonal transformation from T-ALL to PTCL which has rarely been reported in the literature. Such transformation may carry important diagnostic and biological implications.

Nonalcoholic fatty liver disease (NAFLD) is prevalent in obese patients. We sought to determine the effects of bariatric surgery on the histological features of NAFLD. Two blinded pathologists graded liver biopsies done during bariatric procedures and subsequent operations in 160 patients using the Brunt classification. Data are mean ± SD. Interval between biopsies was 31 ± 26 months. Initial biopsies demonstrated steatosis 77 %, lobular inflammation 39 %, and chronic portal inflammation 56 %. Steatohepatitis was present in 27 %. Grade 2–3 fibrosis was present in 27 %, and cirrhosis was present in one patient. On post-bariatric biopsy, steatosis resolved in 75 %, lobular inflammation resolved in 75 %, chronic portal inflammation resolved in 49 %, and steatohepatitis resolved in 90 %. Fibrosis of any grade resolved in 53 % and improved in another 3 % of patients. Grade 2 fibrosis resolved in 58 %, improved in 3 %, and did not worsen in 11 %. Bridging fibrosis resolved in 29 %, improved in 29 %, and did not worsen in 29 %. Bariatric surgery is associated with resolution of steatosis or steatohepatitis in the majority of patients. More importantly, grade 2 or 3 (bridging) fibrosis is resolved or improved in 60 % of patients. Bariatric surgery should be considered as a treatment of NAFLD in severely obese patients.

PAX8 is a transcription factor involved in the regulation of organogenesis of the thyroid gland, kidney, and Müllerian system. It is commonly expressed in epithelial tumors of thyroid and parathyroid glands, kidney, thymus, and female genital tract. PAX8 is increasingly used in the establishment of tissue of origin in carcinomas and has recently been identified in a subset of small blue round cell tumors including Ewing sarcomas/PNETs. However, it is unclear if this association in ES/PNETs is due to renal origin or is PNET specific. In this study we investigated the PAX8 staining pattern of primary renal and extra-renal ES/PNETs to explore its potential diagnostic and prognostic role. A tissue microarray (TMA) of 22 cases of extra-renal Ewing/PNETs and two separate cases of primary renal PNET whole slide sections were immunohistochemically stained with rabbit polyclonal PAX8 antibody. PAX8 was positive in 2 of 2 primary renal PNETs and in 14 (64 %) cases of the extra renal PNETs. The association between PAX8 immunoreactivity and Ewing/PNET was identified in both primary renal and extra-renal Ewing/PNETs for the first time. Further studies are warranted to verify these findings and to shed light in the tumorigenesis of Ewing/PNET. However, PAX8 is not useful in establishing a diagnosis of Ewing/PNET due to its presence in different tumors like carcinomas, lymphomas and sarcomas. PAX8 does not seem to have prognostic value.

This dissertation describes the experimental analysis and design of a second generation robotic laser system used for ophthalmic surgery. The goal of our research project is to develop an automated laser delivery and retinal observation system that is capable of placing multiple lesions of predetermined sizes into known locations in the retina. The purpose of my work is to show that from an economic, scientific, and engineering standpoint, my proposed design for this new system is feasible. The first generation laser system is the slit lamp microscope with a laser delivery system, where the laser is controlled by the manual dexterity of the ophthalmologist. This new system is designed to augment the ophthalmologist, making him/her more efficient with less training. We intend to rid the surgical process of unnecessary gadgetry while improving accuracy, speed, and safety. This task can be divided into three areas. The first is to completely develop an automated retinal observation system, which will allow the computer to observe all areas of the retina automatically. The second part of the task is to design a computer controlled pointing and tracking system for the laser, which will keep the laser positioned onto one spot on the retina during small movements of the eye. The third portion is to design and test a reflectance measuring system that monitors and controls the size of the lesion. All three parts must be integrated into one cohesive, economical system. The work presented in this dissertation sets the groundwork for the project. A design is presented and justified. The areas of the design that are questionable from an engineering standpoint are investigated and analyzed. These areas include the tracking of the retina, placement of the lesions for diabetic retinopathy, and real-time monitoring of the lesion growth. Integrating the many ideas into a cohesive design and analyzing the feasibility of this design form the basis of this dissertation.

In this tightly focused, lucidly written andthoroughly researched book, [Ferenc Morton Szasz], a professor of history at the University of New Mexico, describes the events, personalities and scientific processes that led to the detonation of the first atomic bomb in an isolated stretch of New Mexican desert. He is the first historian to study the recently declassified Manhattan Project papers. At Los Alamos, from 1943 to 1945, were gathered the world's greatest physicists - J. Robert Oppenheimer, Edward Teller, Enrico Fermi and I.

The existing literature indicates that interactive-engagement (IE) based general physics classes improve conceptual learning relative to more traditional lecture-oriented classrooms. Very little research, however, has examined quantitative problem-solving outcomes from IE based relative to traditional lecture-based physics classes. The present study included both pre- and post-course conceptual-learning assessments and a new quantitative physics problem-solving assessment that included three representative conservation of energy problems from a first-semester calculus-based college physics course. Scores for problem translation, plan coherence, solution execution, and evaluation of solution plausibility were extracted for each problem. Over 450 students in three IE-based sections and two traditional lecture sections taught at the same university during the same semester participated. As expected, the IE-based course produced more robust gains on a Force Concept Inventory than did the lecture course. By contrast, when the full sample was considered, gains in quantitative problem solving were significantly greater for lecture than IE-based physics; when students were matched on pre-test scores, there was still no advantage for IE-based physics on gains in quantitative problem solving. Further, the association between performance on the concept inventory and quantitative problem solving was minimal. These results highlight that improved conceptual understanding does not necessarily support improved quantitative physics problem solving, and that the instructional method appears to have less bearing on gains in quantitative problem solving than does the kinds of problems emphasized in the courses and homework and the overlap of these problems to those on the assessment.