John H. Yim

Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation.

BACKGROUND To date, a mutation of the BRAF oncogene is the most common genetic alteration found in papillary thyroid carcinoma (PTC) and is associated with extrathyroidal extension, lymph node metastasis, and tumor recurrence. It is not known whether pre-operative identification of BRAF mutations in cytologic specimens should alter surgical management. METHODS From 2006 to 2008, the clinical, cytologic, and pathologic parameters of 106 consecutive surgically treated patients with BRAF-positive PTC were compared with a concurrent cohort of 100 patients with BRAF-negative PTC. RESULTS In all, 99 BRAF-positive PTC patients underwent initial treatment, and 7 BRAF-positive patients had surgical resection of recurrent/persistent PTC. BRAF mutations were identified on preoperative cytologic samples (31 patients) or after thyroidectomy (75 patients). All 31 patients with BRAF-positive fine-needle aspiration (FNA) had PTC at thyroidectomy (specificity 100%). At short-term follow-up, 11/106 BRAF-positive patients have required reoperation for recurrent/persistent disease compared with 3 BRAF-negative patients (P = .04). Preoperative knowledge of BRAF mutation positivity could have productively altered initial PTC surgical management in 24% of patients. CONCLUSION In PTC, BRAF mutations are associated with cervical recurrence and with reoperation. Pre-operative cytologic identification of BRAF mutation has high specificity and may guide the initial extent of thyroidectomy and node dissection.

Mammographically detected breast cancer. Benefits of stereotactic core versus wire localization biopsy.

OBJECTIVE The authors evaluated the differences between stereotactic core needle biopsy (SCNBx) and needle localization surgical biopsy (NLBx) in cost and treatment course for patients with mammographically detected breast cancer. SUMMARY BACKGROUND DATA Stereotactic core needle breast biopsy is a reproducible and reliable alternative to surgical biopsy for histologic diagnosis of mammographic lesions. METHODS Records from 52 consecutive patients with invasive breast cancer diagnosed by SCNBx (n = 21) or NLBx (n = 31) over 2 years were reviewed. Episode-of-care costs were extracted from the Barnes Hospital billing system database. RESULTS At the time of excision, surgical margins were statistically more frequently positive in patients treated with NLBx (55%) than patients treated with SCNBx (0%, p < 0.0001). Furthermore, patients in the NLBx group undergoing breast conservation surgery required re-excision more frequently (74%) than those in the SCNBx group (0%, p = 0.001). There were no complications in either group after the diagnostic procedure. All SCNBx results were correct in the diagnosis of invasive breast cancer. The median cost of SCNBx was approximately

Underlying pathology in mammary Paget's disease.

1000 less than the median cost of NLBx. This cost difference was carried through the definitive procedure, whether it was breast conservation or mastectomy. CONCLUSIONS This study shows the advantage of SCNBx to diagnose breast cancer and definitive operative care at a single procedure. The preoperative diagnosis of breast cancer eliminated positive operative margins and procedures to re-excise breast tissue. The use of SCNBx also saved approximately

IRF-1 expression induces apoptosis and inhibits tumor growth in mouse mammary cancer cells in vitro and in vivo

1000 per patient compared with the use of NLBx. Our data suggest that SCNBx is the diagnostic procedure of choice for mammographically detected cancers.

Localization of Parathyroid Adenomas by Sonography and Technetium Tc 99m Sestamibi Single-Photon Emission Computed Tomography Before Minimally Invasive Parathyroidectomy Are Both Studies Really Needed?

AbstractBackground: Management of patients with mammary Pagets disease is controversial; recent recommendations range from primary radiotherapy to modified radical mastectomy. This review correlates associated breast findings with disease stage and outcome to help guide evaluation and treatment. Methods: Retrospective review of clinical, mammographic and pathologic data from 38 women with mammary Pagets disease treated between 1979 and 1995 was performed. Mastectomies were performed on all but two patients with the entire breast and lymph nodes evaluated for histopathologic evidence of carcinoma. Results: Underlying carcinoma (ductal carcinoma in situ and/or invasive ductal cancer) was found in most patients (92%) even when no palpable mass was evident (85%); this carcinoma is often multifocal (73%). Mammography fails to identify the underlying disease in many patients with no palpable mass and multifocal underlying disease (64%). Patients with Pagets disease and a palpable mass have a much greater incidence of invasive cancer, multifocal lesions, and positive lymph nodes, and have worse survival. Conclusions: Although some patients with Pagets disease might be well treated by breast conservation therapy, many patients have underlying multifocal carcinoma (including invasive cancer), which can be inapparent by examination and mammography. Selecting candidates with disease amenable to complete excision without mastectomy is problematic.

Ectopic Expression of Interferon Regulatory Factor-1 Promotes Human Breast Cancer Cell Death and Results in Reduced Expression of Survivin

Interferon regulatory factor-1 (IRF-1) is a nuclear transcription factor that mediates interferon and other cytokine effects and appears to have antitumor activity in vitro and in vivo in cancer cells. We have constructed a recombinant adenoviral vector (Ad-IRF-1) that infects mammary cells with high efficiency and results in high levels of functional IRF-1 protein in transfected cells. Overexpression of IRF-1 in two mouse breast cancer cell lines, C3-L5 and TS/A, resulted in apoptosis in these cell lines as assessed by Annexin V staining. The involvement of caspases was confirmed by significant inhibition of apoptosis by a caspase inhibitor, and by demonstration of caspase-3 activity, cleavage of caspase-3, and PARP cleavage. Interestingly, the growth of nonmalignant breast cell lines C127I and NMuMG did not appear to be inhibited by IRF-1 overexpression. Suppression of growth for breast cancer cell lines in vivo was demonstrated by both preinfection of breast cancer cells ex vivo and by intratumoral injection of Ad-IRF-1 into established tumors in their natural hosts. The mechanism of apoptosis may involve the transcriptional upregulation of bak, caspase-8, and caspase-7 expression. These data support the antitumor potential of IRF-1 and the use of agents that increase IRF-1 in breast cancer.

Cystic Parathyroid Lesions: Functional and Nonfunctional Parathyroid Cysts

Objective. The purpose of this study was to determine the utility of radiologist‐performed sonography as the principal modality for parathyroid localization before minimally invasive parathyroidectomy. Methods. Both sonography and technetium Tc 99m sestamibi single‐photon emission computed tomography (SPECT) are commonly performed during imaging evaluation of patients with primary hyperparathyroidism (HPTH). Sonographic examinations ordered during the study period were performed by 1 author (M.E.T.), and results were immediately reported. Findings of a subsequent Tc 99m sestamibi study were recorded blinded to the sonographic results. The sensitivity and specificity of sonography and Tc 99m sestamibi SPECT were assessed with the use of surgery and pathology reports as a reference standard. The 2007 global Medicare reimbursement rates were used to assess the costs of preoperative localization. Results. Parathyroidectomy was performed in 144 of 172 patients evaluated by both modalities. The sensitivity, specificity, and positive predictive value of sonography for identifying abnormal parathyroid glands were 74%, 96%, and 90%, respectively. Sonography correctly localized a single adenoma or suggested multiglandular disease in 112 of 144 patients (78%). The sensitivity, specificity, and positive predictive value of SPECT were 58%, 96%, and 89%. Technetium 99m sestamibi SPECT correctly predicted an adenoma or multiglandular disease in 88 of 144 patients (61%). Five patients with negative sonographic findings were shown to have uniglandular disease on Tc 99m sestamibi SPECT. Selective use of Tc 99m sestamibi SPECT (ie, when sonographic findings were negative or equivocal) would have decreased the cost of imaging by 53%. Conclusions. Radiologist‐performed sonography may potentially be used as a principal imaging modality for patients with HPTH. Selective use of Tc 99m sestamibi in cases with negative or equivocal sonographic findings can decrease the cost of imaging before parathyroid resection considerably.

Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells

The overexpression of the inhibitor of apoptosis protein, survivin, may provide tumor cells with a distinct survival advantage in situ; hence, therapeutic strategies have been designed to inhibit its expression. In this study, we ectopically expressed the interferon regulatory factor (IRF)-1 protein in the breast carcinoma cell lines MDA-MB-468 and SK-BR-3 using a recombinant adenovirus (Ad-IRF-1). By screening microarray analysis of cDNA from the human breast cancer cell line MDA-MB-468 infected with Ad-IRF-1, we observed a 15-fold down-regulation of the survivin gene when compared with uninfected cells. Consequently, we tested survivin expression in Ad-IRF-1-infected MDA-MB-468 and SK-BR-3 breast cancer cell lines. Immunoblotting analyses supported the contention that ectopic expression of the IRF-1 protein results in down-regulation of survivin protein expression that is independent of p53. In addition, Ad-IRF-1 infection of these human breast cancer cell lines induces the expression of p21. We also report that increased apoptosis is observed in tumor cells infected with Ad-IRF-1 compared with Ad-Ψ5 mock-infected cells and that cell death is further augmented when the IRF-1-infected cells are cultured with Adriamycin. Moreover, in a xenogeneic mouse model of breast carcinoma, in vivo treatment of tumor-bearing mice with intratumoral Ad-IRF-1 injections results in tumor growth inhibition. In resected tumors from mice that had been treated with Ad-IRF-1, tumor cells that express the IRF-1 transgene have a predominant IRF-1-positive, survivin-negative phenotype. Collectively, these observations suggest that therapies designed to enhance IRF-1 expression within tumor cells may represent novel treatment strategies for breast cancer.

The role of interferon regulatory factor-1 and interferon regulatory factor-2 in IFN-γ growth inhibition of human breast carcinoma cell lines

HYPOTHESIS Functional parathyroid cysts (FPCs) and nonfunctional parathyroid cysts (NPCs) are 2 distinct clinical and histologic entities. DESIGN Review of prospective clinical database records. SETTING Tertiary academic center. PATIENTS Patients enrolled in a prospective surgical database between January 1, 1990, and May 31, 2007. INTERVENTION Cervical exploration for primary hyperparathyroidism or cervical mass. MAIN OUTCOME MEASURES Age, sex, morbidity, imaging results, pathologic findings, cyst characteristics (size, location, and fluid), and perioperative calcium and parathyroid hormone levels. RESULTS Cystic parathyroid lesions were found in 48 of 1769 patients (3%) studied. Functional parathyroid cysts were more common than NPCs, arising in 41 of 48 patients (85%), and showed no predisposition for sex or embryologic origin. Single-photon emission computed tomographic imaging failed to localize FPCs in 12 of 37 patients (32%). The fluid in FPCs was clear or colorless in 9 of 15 characterized specimens (60%). Rupture of cystic parathyroid lesions during resection was associated with prolonged elevation of intraoperative parathyroid hormone levels (P =.045). Cystic parathyroid lesions weighing 4 g or more were associated with the development of postoperative symptomatic hypocalcemia (P =.03). Functional parathyroid cysts occurred exclusively in adenomas with cystic change, whereas NPCs (with 1 exception) were without associated adenoma on final histologic examination. CONCLUSIONS Cystic parathyroid lesions often contain turbid or colored fluid, and FPCs are more common than NPCs. Neck cysts of uncertain origin should be diagnostically aspirated for parathyroid hormone content. During resection, cyst rupture should be avoided, and patients with large cysts should be managed expectantly to forestall the development of symptomatic hypocalcemia. Functional parathyroid cysts and NPCs are likely 2 separate clinical and histologic entities.

Alkylation of cysteine 468 in Stat3 defines a novel site for therapeutic development

Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that has apoptotic anti-tumor activity. In breast cancer cell types, IRF-1 is implicated in mediating apoptosis by both novel and established anti-tumor agents, including the anti-estrogens tamoxifen and faslodex. Here we demonstrate that in MDA468 breast cancer cells, apoptosis by IFN-γ is mediated by IRF-1 and IFN-γ, and IRF-1-induced apoptosis is caspase-mediated. IRF-1 induction results in cleavage of caspase-8, -3 and -7, and application of caspase inhibitors attenuate activated cleavage products. IRF-1-induced apoptosis involves caspase-8 since apoptosis is significantly decreased by the caspase-8-specific inhibitor IETD, c-FLIP expression and in caspase-8-deficient cancer cells. Furthermore, we demonstrate that IRF-1-induced apoptosis requires fas-associated death domain (FADD) since dominant-negative FADD expressing cells resist IRF-1-induced apoptosis and activated downstream products. Immunofluorescent studies demonstrate perinuclear colocalization of FADD and caspase-8. Despite the known role of FADD in mediating death-ligand induced apoptosis, neutralizing antibodies against classical death receptors do not inhibit IRF-1 induced apoptosis, and no secreted ligand appears to be involved since MDA468 coincubated with IRF-1 transfected cells do not apoptose. Therefore, we demonstrate that IRF-1 induces a ligand-independent FADD/caspase-8-mediated apoptosis in breast cancer cells.