Nancy L. Cho

Thyroid Nodule Size and Prediction of Cancer

CONTEXT Thyroid nodule size is routinely measured, although its impact on thyroid cancer risk is unclear. OBJECTIVE Our objective was to evaluate the association of nodule size upon cancer risk. DESIGN, SETTING, AND PATIENTS We conducted a retrospective cohort analysis at an academic hospital with 4955 consecutive patients evaluated between 1995 and 2009. INTERVENTION Ultrasound and ultrasound-guided fine-needle aspiration of nodules >1 cm was done. Indeterminate and malignant nodules were referred for surgery, and histopathology was reviewed. MAIN OUTCOME MEASURE The presence and histological subtype of cancer was evaluated. RESULTS Of 7348 evaluated nodules, 927 (13%) were cancerous. Of those 1.0 to 1.9 cm in diameter, 10.5% were cancerous. In contrast, of those >2.0 cm, 15% were cancerous (P < .01). However, nodules 2.0 to 2.9, 3.0 to 3.9, and >4 cm were cancerous in 14%, 16%, and 15% of cases (P = .14), respectively, demonstrating no graded increase in risk beyond the 2-cm threshold. When malignant, the proportion of papillary carcinoma decreased (nodules 1.0-1.9 cm, 92% of cases; 2.0-2.9 cm, 88%; 3.0-3.9 cm, 83%; >4 cm, 74% [P < .01]), while follicular carcinoma increased (1.0-1.9 cm, 6%; 2.0-2.9 cm, 7%; 3.0-3.9 cm, 12%; >4 cm, 16% [P < .01]) as nodules enlarged. Nodules size did not influence cytology distribution or risk of false-negative aspirates. CONCLUSIONS Increasing thyroid nodule size impacts cancer risk in a nonlinear fashion. A threshold is detected at 2.0 cm, beyond which cancer risk is unchanged. However, the risk of follicular carcinomas and other rare thyroid malignancies increases as nodules enlarge.

Estrogen Receptors α and β Are Inhibitory Modifiers of Apc-Dependent Tumorigenesis in the Proximal Colon of Min/+ Mice

Estrogen replacement therapy in postmenopausal women is associated with a reduction in colorectal cancer risk, potentially via interactions between 17β-estradiol (E2) and the estrogen receptors (ER) α and β. To study the role of E2 in intestinal tumor inhibition, we separately crossed C57BL/6J-Min/+ (Min/+) mice with Erα +/− and Erβ +/− mice to generate ER -deficient Min/+ progeny. We found an increased incidence of visible colon tumors and dysplastic microadenomas in ER -deficient Min/+ relative to Er +/+Min/+ controls. Small intestinal tumor numbers were unaffected. Invasive carcinomas were found only in Erα +/−Min/+ mice, suggesting that ERα plays additional non–cell autonomous roles that limit tumor progression. Histologic analyses of ER-deficient Min/+ colons, as well as colons from ovariectomized Min/+ mice (OvxMin/+) and E2-treated OvxMin/+ mice (OvxMin/+ +E2), revealed significant differences in crypt architecture, enterocyte proliferation, and goblet cell differentiation relative to Min/+ and Er +/+ Apc +/+ (wild-type) controls. The expression of ERα and ERβ was regionally compartmentalized along the colonic crypt axis, suggesting functional antagonism. Our results indicate that ERα and ERβ are inhibitory modifiers of Apc -dependent colon tumorigenesis. As a result, loss of E2 and ER signaling in postmenopausal women may contribute to colorectal cancer development. [Cancer Res 2007;67(5):2366–72]

Career Satisfaction of Women in Surgery: Perceptions, Factors, and Strategies

BACKGROUND With the current and projected shortages of general surgeons, more attention is being paid to the increasing pool of women physicians. This study seeks to understand the variables leading to career satisfaction for women surgeons to better recruit, retain, and support them. STUDY DESIGN Eighteen semi-structured interviews of 12 female and 6 male surgeons 2 to 12 years into practice were qualitatively analyzed and converted to coded, categorized data. Significance was derived by Fishers exact test. Participants were recruited by snowball sampling. RESULTS Our sample represents a highly satisfied group of female and male surgeons. Although both women and men describe with equal frequency having made career tradeoffs for personal and family time, and vice versa, women far more frequently than men cite reasons related to their personal time, predictable time, and family relationships as why they are currently satisfied with their career (34.1% versus 8.7%; p < 0.05). Both cite being satisfied by career content equally. When describing strategies used in developing a successful surgical career, women most frequently cite social networks as a key to success (88% versus 12% by men; p < 0.05), and men more frequently cite reasons related to training (29% versus 0% by women; p < 0.05) and compensation (24% versus 0% by women; p < 0.05). CONCLUSIONS Although both men and women make tradeoffs of career for family and family for career, womens perception of satisfaction comes from viewing their surgical career within the broader context of their lives. Women might be attracted to a career that acknowledges and values the whole person beyond the surgeon, and could benefit from work infrastructures that enhance networking.

Aberrant crypt foci in the Adenoma Prevention with Celecoxib trial

Abstract Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients randomized to placebo (n = 17), celecoxib (200 mg twice daily; n = 15), or celecoxib (400 mg twice daily; n = 13) in the Adenoma Prevention with Celecoxib (APC) trial. Magnification chromoendoscopy was done to identify, count, and biopsy ACF within the rectum at baseline and after 8 to 12 months of treatment. A total of 655 ACF were identified in 45 patients. We examined 70 of these ACF histologically, and all 70 were nondysplastic. Cohort characteristics and APC trial treatment results for substudy patients were similar to those of the overall APC trial. There was no significant modulation of ACF by celecoxib (versus placebo; P = 0.77). Immunohistochemical comparison of ACF with adjacent normal mucosa showed that ACF had an increased proliferative index as determined by Ki-67 (P < 0.0001), but lacked other features of neoplasia such as increased cyclooxygenase-2 expression and microvessel density, nuclear localization of β-catenin, or decreased expression of the tumor suppressors SMAD4, Estrogen Receptor α, or MGMT. Only baseline SMAD4 expression in ACF correlated with posttreatment adenoma recurrence (independent of treatment arm; P = 0.01). The presence or number of nondysplastic ACF did not correlate with a higher risk of synchronous advanced or recurrent adenomas. Our overall results indicated that nondysplastic ACF were not accurate surrogate endpoint biomarkers of recurrent colorectal adenomas in the APC trial.

Necroptosis is a novel mechanism of radiation-induced cell death in anaplastic thyroid and adrenocortical cancers

BACKGROUND Necroptosis is a recently described mechanism of programmed cellular death. We hypothesize that necroptosis plays an important role in radiation-induced cell death in endocrine cancers. METHODS Thyroid and adrenocortical carcinoma cell lines were exposed to increasing doses of radiation in the presence of necroptosis inhibitor Nec-1 and/or apoptosis-inhibitor zVAD. H295R cells deficient in receptor interacting protein 1 (RIP1), an essential kinase for necroptosis, were used as controls. Survival curves were generated at increasing doses of radiation. RESULTS Nec-1 and zVAD increased cellular survival with increasing doses of radiotherapy in 8505c, TPC-1, and SW13. Both inhibitors used together had an additive effect. At 6 Gy, 8505c, TPC-1, and SW13 cell survival was significantly increased compared to controls by 40%, 33%, and 31% with Nec-1 treatment, by 53%, 47%, and 44% with zVAD treatment, and by 80%, 70%, and 65% with both compounds, respectively (P < .05). H295R showed no change in survival with Nec-1 treatment. The radiobiologic parameter quasithreshold dose was significantly increased in 8505c, TPC-1, and SW13 cells when both Nec-1 and zVAD were used in combination to inhibit necroptosis and apoptosis together, revealing resistance to standard doses of fractionated therapeutic radiation. CONCLUSION Necroptosis contributes to radiation-induced cell death. Future studies should investigate ways to promote the activation of necroptosis to improve radiosensitivity.

Mesenchymal Stromal Cell Mutations and Wound Healing Contribute to the Etiology of Desmoid Tumors

Desmoid tumors are nonmalignant neoplasms of mesenchymal origin that mainly contain fibroblast lineage cells. These tumors often occur in patients with familial adenomatous polyposis (FAP) coli who have germ line mutations in the APC gene. Given emerging data that has implicated multipotent mesencyhmal stromal cells (MSC) in the origin of mesenchymal tumors, we hypothesized that desmoid tumors may arise in patients with FAP after MSCs acquire somatic mutations during the proliferative phase of wound healing. To test this idea, we examined 16 desmoid tumors from FAP-associated and sporadic cases, finding that all 16 of 16 tumors expressed stem cell markers, whereas matching normal stromal tissues were uniformly negative. Desmoid tumors also contained a subclass of fibrocytes linked to wound healing, angiogenesis, and fibrosis. Using an MSC cell line derived from an FAP-associated desmoid tumor, we confirmed an expected loss in the expression of adenomatous polyposis coli (APC) and the transcriptional repressor BMI-1 while documenting the coexpression of markers for chondrocytes, adipocytes, and osteocytes. Together, our findings argue that desmoid tumors result from the growth of MSCs in a wound healing setting that is associated with deregulated Wnt signaling due to APC loss. The differentiation potential of these MSCs combined with expression of BMI-1, a transcriptional repressor downstream of Hedgehog and Notch signaling, suggests that desmoid tumors may respond to therapies targeting these pathways.

Changes in Antitumor Response in C57BL/6J-Min/+ Mice during Long-term Administration of a Selective Cyclooxygenase-2 Inhibitor

Selective cyclooxygenase-2 (COX-2) inhibitors are widely prescribed for severe arthritis and are currently under study in human chemoprevention trials. Recently, long-term use of these agents has come under scrutiny due to reports of treatment-associated cardiovascular toxicity. On short-term administration, the selective COX-2 inhibitor celecoxib inhibits adenoma growth in animal tumor models, including the C57BL/6J-Min/+ (Min/+) mouse. With uninterrupted long-term celecoxib administration, intestinal tumors in Min/+ mice initially regressed and then recurred to levels comparable with untreated controls. Celecoxib treatment initially suppressed COX-2 and prostaglandin E2 (PGE2) expression, but long-term use produced significantly higher levels of these molecules and reactivated PGE2-associated growth factor signaling pathways in tumor and normal tissues. These results indicate that COX-2 is an important chemoprevention target and that inhibition of this enzyme alters a paracrine enterocyte regulatory pathway. Chronic uninterrupted celecoxib treatment, however, induces untoward effects that enhance early progression events in intestinal tumorigenesis and may contribute to treatment toxicity.

Estrogen receptor α or β loss in the colon of Min/+ mice promotes crypt expansion and impairs TGFβ and HNF3β signaling

Adenomatous polyposis coli (APC)-regulated Wnt and transforming growth factor-β (TGFβ) signaling cooperate in the intestine to maintain normal enterocyte functions. Human clinical trials showed that estrogen [17β-estradiol (E2)], the ligand of nuclear receptors estrogen receptor α (ERα) and ERβ, inhibited colorectal cancer (CRC) in women. Consistent with this finding, we reported that E2, ERα and ERβ suppressed intestinal tumorigenesis in the C57BL/6J-Min/+ (Min/+) mouse, a CRC model. Here, we extended our results with further comparisons of colon and small intestine from intact female Apc (+/+) (WT), Min/+ and ER-deficient Min/+ mice. In the colon of ER-deficient Min/+ mice, ER loss reduced TGFβ signaling in crypt base cells as evidenced by minimal expression of the effectors Smad 2, 3 and 4 in these strains. We also found reduced expression of Indian hedgehog (Ihh), bone morphogenetic protein 4 and hepatocyte nuclear factor 3β or FoxA2, factors needed for paracrine signaling between enterocytes and mesenchyme. In proximal colon, ER loss produced a >10-fold increased incidence of crypt fission, a marker for wound healing and tumor promotion. These data, combined with our previous work detailing the specific roles of E2, ERα and ERβ in the colon, suggest that ER activity helps to maintain the intestinal stem cell (ISC) microenvironment by modulating epithelial-stromal crosstalk in ways that regulate cytokine, Wnt and Ihh availability in the extracellular matrix (ECM).

Sulindac Reverses Aberrant Expression and Localization of β-Catenin in Papillary Thyroid Cancer Cells with the BRAFV600E Mutation

BACKGROUND Activation of the Wnt/beta-catenin signaling pathway is implicated in thyroid tumorigenesis, and up to 90% of papillary thyroid cancer (PTC) demonstrate aberrant expression of beta-catenin. Nonsteroidal antiinflammatory drugs reverse aberrant beta-catenin expression and localization in colon cancer. In this study, we tested the hypothesis that the nonsteroidal antiinflammatory drug sulindac would reverse aberrant beta-catenin activity in thyroid cancer cells. METHODS beta-catenin protein levels were determined in thyroidectomy specimens from six consecutive patients and in three different thyroid cancer cells lines (8505-C, KTC-1, and TPC-1) by immunoblotting. Cells of 8505-C and KTC-1 harbor the BRAF(V600E) mutation, and TPC-1 has the RET/PTC rearrangement. All cell lines were treated with sulindac (100 microM for up to 72 hours). Protein levels of c-myc and cyclin D1 were detected by immunoblotting, and beta-catenin localization was determined by immunocytochemistry in the PTC cell lines. PCCL3 rat thyroid cells that conditionally overexpress either BRAF(V600E) or RET/PTC were also treated with sulindac. RESULTS All PTC specimens and cell lines expressed high levels of beta-catenin protein and displayed aberrant nuclear and cytoplasmic localization of beta-catenin. Exposure to sulindac for 48 hours reduced beta-catenin expression in 8505-C and KTC-1 cells, but not in TPC-1 cells. Further, sulindac treatment reduced c-myc and cyclin D1 levels in 8505-C and KTC-1 cells, but had no effect in TPC-1 cells. Immunocytochemistry demonstrated that sulindac treatment redistributed beta-catenin from the nucleus to the membrane in 8505-C and KTC-1 cells. However, sulindac did not affect beta-catenin localization in TPC-1 cells. Finally, sulindac was effective in decreasing beta-catenin expression and cellular proliferation in BRAF(V600E)-overexpressing cells, but not in RET/PTC3-overexpressing cells. CONCLUSIONS Taken together, our findings demonstrate that sulindac treatment reverses beta-catenin activity in 8505-C and KTC-1 cell lines with the BRAF(V600E), but not in TPC-1 cells with the RET/PTC mutation. Future studies should investigate the potential for beta-catenin-directed therapy for patients with advanced thyroid cancers.

Global tyrosine kinome profiling of human thyroid tumors identifies Src as a promising target for invasive cancers

BACKGROUND Novel therapies are needed for the treatment of invasive thyroid cancers. Aberrant activation of tyrosine kinases plays an important role in thyroid oncogenesis. Because current targeted therapies are biased toward a small subset of tyrosine kinases, we conducted a study to reveal novel therapeutic targets for thyroid cancer using a bead-based, high-throughput system. METHODS Thyroid tumors and matched normal tissues were harvested from twenty-six patients in the operating room. Protein lysates were analyzed using the Luminex immunosandwich, a bead-based kinase phosphorylation assay. Data was analyzed using GenePattern 3.0 software and clustered according to histology, demographic factors, and tumor status regarding capsular invasion, size, lymphovascular invasion, and extrathyroidal extension. Survival and invasion assays were performed to determine the effect of Src inhibition in papillary thyroid cancer (PTC) cells. RESULTS Tyrosine kinome profiling demonstrated upregulation of nine tyrosine kinases in tumors relative to matched normal thyroid tissue: EGFR, PTK6, BTK, HCK, ABL1, TNK1, GRB2, ERK, and SRC. Supervised clustering of well-differentiated tumors by histology, gender, age, or size did not reveal significant differences in tyrosine kinase activity. However, supervised clustering by the presence of invasive disease showed increased Src activity in invasive tumors relative to non-invasive tumors (60% v. 0%, p<0.05). In vitro, we found that Src inhibition in PTC cells decreased cell invasion and proliferation. CONCLUSION Global kinome analysis enables the discovery of novel targets for thyroid cancer therapy. Further investigation of Src targeted therapy for advanced thyroid cancer is warranted.