Intraoperative Radiotherapy for Breast Cancer Treatment in a Rural Community.

BACKGROUND: Access to health care poses particular challenges for patients living in rural communities. Intraoperative radiotherapy (IORT) offers a treatment alternative to traditional whole-breast radiation therapy (WBRT) for select patients. This study aimed to analyze the use of IORT for patients undergoing breast-conserving surgery at an academic institution located in a rural state. METHODS: A retrospective review analyzed all patients at a single institution with a diagnosis of ductal carcinoma in situ (DCIS) or invasive breast cancer from April 2012 to January 2017 who were undergoing breast-conserving surgery with either IORT or WBRT. Student's t test or Fisher's exact test was used to make statistical comparisons. RESULTS: Patients undergoing IORT (n = 117) were significantly older than patients treated with WBRT (n = 191) (65.6 vs 58.6 years; p < 0.001) and had smaller tumors on both preoperative imaging (1.04 vs 1.66 cm; p < 0.05) and final pathology (0.99 vs 1.48 cm; p < 0.05). Patients receiving IORT lived farther from the treating facility than patients treated with WBRT (67.2 vs 30.8 miles; p < 0.05). To account for biases created in the IORT selection criteria, subgroup analysis was performed for women receiving WBRT who fulfilled IORT selection criteria, and distance traveled remained significant (67.2 vs 31.4 miles; p < 0.05). Neither recurrence nor survival differed between the IORT and WBRT groups. Medicare reimbursement for IORT was approximately 50% more than for WBRT. CONCLUSIONS: For women from rural communities, IORT appears to be an attractive option because these women tend to be older and to live farther from the treatment facility.

Receptor Tyrosine Kinase Expression Predicts Response to Sunitinib in Breast Cancer.

BACKGROUND: Preliminary data indicate that tyrosine kinase inhibitors (TKIs) function through rearranged during transfection (RET) in breast cancer. However, TKIs are not specific and can block several receptor tyrosine kinases (RTKs). This study used cell lines and primary breast cancer specimens to determine factors associated with TKI response. METHODS: Proliferation was assessed after short interfering RNA knockdown with or without sunitinib in breast cancer cell lines by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Breast cancer tissue and matched normal breast was obtained from 30 women with invasive breast carcinoma. Gene expression was assessed by reverse transcriptase-polymerase chain reaction. Fresh tissue was treated in vitro with sunitinib or control media for 30 min, and response was assessed by phosphorylation-specific western blot. RESULTS: The RTKs including epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR1-3), platelet-derived growth factor receptor (PDGFRa/b), and Kit were overexpressed in triple-negative breast tumors relative to HER2- and estrogen receptor-alpha (ERα)-positive tumors and normal breast tissue. Knockdown of EGFR reduced in vitro proliferation in MCF-7 and MDA-MB-231 but not in SKBR-3 or ZR-75-1 breast cancer cells. With the exception of RET, response to sunitinib was independent of RTK expression in all four cell lines. Both ERα-positive and low-EGFR-expressing tumors had an increased in vitro sunitinib response, as determined by alteration of Erk activation. Expression of other RTKs and additional clinical factors were not associated with response. CONCLUSION: Triple-negative breast cancers overexpress RTKs but have decreased in vitro response to the TKI sunitinib. In addition to RET, TKIs that block EGFR may increase the therapeutic efficacy of TKIs in breast cancer.

Resident involvement in postoperative conversations: an underused opportunity.

BACKGROUND: Because of established attending-patient and family relationships and time constraints, residents are often excluded from the immediate postoperative conversation with family. Interpersonal and communication skills are a core competency, and the postoperative conversation is an opportunity to develop these skills. Our objective is to assess attitudes, experience, and comfort regarding resident participation during postoperative conversations with families. MATERIALS AND METHODS: Residents and attending surgeons in an academic surgery center were surveyed regarding resident involvement in the postoperative conversation with families. Paper surveys were administered anonymously. Nonparametric statistics compared responses. RESULTS: There were 45 survey respondents (23 residents, 22 attendings). All residents rated postoperative conversations with families, as "important" or "very important". Residents reported being "comfortable" or "very comfortable" with postoperative conversations. However, on average, residents reported fewer than 10 postoperative conversation experiences per year. Feedback was received by <30% on postoperative communication skills, but 88% wanted feedback. Most attendings reported it is "important" or "very important" for residents to communicate well with families during postoperative conversations, but rated residents' performance as significantly lower than the residents' self-assessments (P < 0.001). Attendings on average were only "somewhat comfortable" or "moderately comfortable" with residents conducting postoperative conversations with families, and only 68% reported allowing residents to do so. When bad news was involved, only 27% allowed resident participation. Most attendings (86%) believed residents need more opportunities with postoperative conversations. CONCLUSIONS: Although most residents reported being comfortable with postoperative conversations, these survey results indicate that they have few opportunities. Developing a workshop on communication skills focused on the postoperative conversations with families may be beneficial.

A Pilot Study of Preoperative Vandetanib on Markers of Proliferation and Apoptosis in Breast Cancer.

INTRODUCTION: Preclinical data supports antitumor activity of tyrosine kinase inhibitor vandetanib with Ret as the therapeutic target in breast cancer. We investigated the effect of preoperative vandetanib on markers of proliferation and apoptosis in breast cancer. METHODS: Patients with invasive breast cancer were randomly assigned vandetanib 300 mg or placebo PO daily for 2 weeks before operative resection from January 2014 to June 2017. Pretreatment and posttreatment specimens were analyzed by immunohistochemistry for Ki-67, TUNEL, and p-ERK with stratification by Ret expression by immunohistochemistry. RESULTS: Ten patients were enrolled. There was no statistically significant difference in ERK activation compared with placebo (P=0.45); however, ERK activation was reduced 74% compared with pretreatment biopsy with vandetinib treatment (P=0.005) without a significant reduction in the placebo group (-29%, P=0.55). Mean change in Ki-67 after vandetanib treatment was +0.3% compared with +2.0% in placebo treated patients, P=0.72. Mean change in TUNEL was +0.48 apoptotic nuclei per HPF in the vandetanib arm compared with +1.02 in the placebo arm, P=0.32. In vandetanib treated patients, Ki-67 was reduced 0.3% in RET-positive tumors compared with increased 1.0% in RET-negative tumors, P=0.43 and TUNEL was increased 0.77 in RET-positive tumors and 0.2 in RET-negative tumors, P=0.21. CONCLUSIONS: In this pilot study, no statistically significant differences on prespecified markers were seen with vandetanib compared with placebo. In accordance with the investigational hypothesis, there was a nonsignificant trend with vandetanib treatment of reduction in p-ERK and increased effects in Ret expressing tumors.

AP-2γ Is Required for Maintenance of Multipotent Mammary Stem Cells.

Mammary gland ductal morphogenesis depends on the differentiation of mammary stem cells (MaSCs) into basal and luminal lineages. The AP-2γ transcription factor, encoded by Tfap2c, has a central role in mammary gland development but its effect in mammary lineages and specifically MaSCs is largely unknown. Here, we utilized an inducible, conditional knockout of Tfap2c to elucidate the role of AP-2γ in maintenance and differentiation of MaSCs. Loss of AP-2γ in the basal epithelium profoundly altered the transcriptomes and decreased the number of cells within several clusters of mammary epithelial cells, including adult MaSCs and luminal progenitors. AP-2γ regulated the expression of genes known to be required for mammary development, including Cebpb, Nfkbia, and Rspo1. As a result, AP-2γ-deficient mice exhibited repressed mammary gland ductal outgrowth and inhibition of regenerative capacity. The findings demonstrate that AP-2γ can regulate development of mammary gland structures potentially regulating maintenance and differentiation of multipotent MaSCs.

Comparative analysis of radioactive iodine versus thyroidectomy for definitive treatment of Graves disease.

BACKGROUND: Management of Graves disease includes antithyroid drugs, 131I therapy, or thyroidectomy. Our aim was to review our institutional experience with definitive treatments for Graves disease. METHODS: This was a retrospective review of patients undergoing 131I therapy (n = 295) or thyroidectomy (n = 103) for Graves disease (2003-2015). Demographic, clinical, pathology, and outcome data were collected from institutional databases. RESULTS: 131I therapy patients were older (39.1 years vs 33.4 years, P = .001). There was no difference in the presence of ophthalmopathy between groups. A larger proportion of children received thyroidectomy than 131I therapy (17.1% vs 9.2%, P = .026). The success rate of the first 131I therapy dose was 81.4%. Overall success rate, including additional doses, was 90.1%. Rapid turnover of iodine correlated with 131I therapy failure (58.3% rapid turnover failure vs 14.9% non-rapid turnover failure, P < .05). All surgical patients underwent total or near-total thyroidectomy. 131I therapy complications included worsening thyrotoxicosis (1%) and deteriorating orbitopathy (0.7%). Operative complications were higher than 131I therapy complications (P < .05) but were transient. There was no worsening orbitopathy or recurrent Graves disease among surgical patients. CONCLUSION: A higher proportion of pediatric Graves disease patients underwent thyroidectomy than 131I therapy. Rapid turnover suggested more effective initial management with operation than 131I therapy. Although transient operative complications were high, 131I therapy complications included worsening of Graves orbitopathy among those with pre-existing orbitopathy.

Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer.

Cancer stem cells (CSCs) are expanded in anaplastic thyroid cancer (ATC) and standard treatment approaches have failed to improve survival, suggesting a need to specifically target the CSC population. Recent studies in breast and colorectal cancer demonstrated that inhibition of the SUMO pathway repressed CD44 and cleared the CSC population, mediated through SUMO-unconjugated TFAP2A. We sought to evaluate effects of inhibiting the SUMO pathway in ATC. ATC cell lines and primary ATC tumor samples were evaluated. The SUMO pathway was inhibited by knockdown of PIAS1 and use of SUMO inhibitors anacardic acid and PYR-41. The expression of TFAP2A in primary ATC was examined by immunohistochemistry. All ATC cell lines expressed TFAP2A but only 8505C expressed SUMO-conjugated TFAP2A. In 8505C only, inhibition of the SUMO pathway by knockdown of PIAS1 or treatment with SUMO inhibitors repressed expression of CD44 with a concomitant loss of SUMO-conjugated TFAP2A. The effect of SUMO inhibition on CD44 expression was dependent upon TFAP2A. Treatment with SUMO inhibitors resulted in a statistically improved tumor-free survival in mice harboring 8505C xenografts. An examination of primary ATC tissue determined that TFAP2A was expressed in 4 of 11 tumors surveyed. We conclude that inhibition of the SUMO pathway repressed the CSC population, delaying the outgrowth of tumor xenografts in ATC. The effect of SUMO inhibition was dependent upon expression of SUMO-conjugated TFAP2A, which may serve as a molecular marker for therapeutic effects of SUMO inhibitors. The findings provide pre-clinical evidence for development of SUMO inhibitors for the treatment of ATC.

Inhibiting the SUMO Pathway Represses the Cancer Stem Cell Population in Breast and Colorectal Carcinomas.

Many solid cancers have an expanded CD44+/hi/CD24-/low cancer stem cell (CSC) population, which are relatively chemoresistant and drive recurrence and metastasis. Achieving a more durable response requires the development of therapies that specifically target CSCs. Recent evidence indicated that inhibiting the SUMO pathway repressed tumor growth and invasiveness, although the mechanism has yet to be clarified. Here, we demonstrate that inhibition of the SUMO pathway repressed MMP14 and CD44 with a concomitant reduction in cell invasiveness and functional loss of CSCs in basal breast cancer. Similar effects were demonstrated with a panel of E1 and E3 SUMO inhibitors. Identical results were obtained in a colorectal cancer cell line and primary colon cancer cells. In both breast and colon cancer, SUMO-unconjugated TFAP2A mediated the effects of SUMO inhibition. These data support the development of SUMO inhibitors as an approach to specifically target the CSC population in breast and colorectal cancer.

EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib.

Expression of TFAP2C in luminal breast cancer is associated with reduced survival and hormone resistance, partially explained through regulation of RET. TFAP2C also regulates EGFR in HER2 breast cancer. We sought to elucidate the regulation and functional role of EGFR in luminal breast cancer. We used gene knockdown (KD) and treatment with a tyrosine kinase inhibitor (TKI) in cell lines and primary cancer isolates to determine the role of RET and EGFR in regulation of p-ERK and tumorigenesis. KD of TFAP2C decreased expression of EGFR in a panel of luminal breast cancers, and chromatin immunoprecipitation sequencing (ChIP-seq) confirmed that TFAP2C targets the EGFR gene. Stable KD of TFAP2C significantly decreased cell proliferation and tumor growth, mediated in part through EGFR. While KD of RET or EGFR reduced proliferation (31% and 34%, P < 0.01), combined KD reduced proliferation greater than either alone (52% reduction, P < 0.01). The effect of the TKI vandetanib on proliferation and tumor growth response of MCF-7 cells was dependent upon expression of TFAP2C, and dual KD of RET and EGFR eliminated the effects of vandetanib. The response of primary luminal breast cancers to TKIs assessed by ERK activation established a correlation with expression of RET and EGFR. We conclude that TFAP2C regulates EGFR in luminal breast cancer. Response to vandetanib was mediated through the TFAP2C target genes EGFR and RET. Vandetanib may provide a therapeutic effect in luminal breast cancer, and RET and EGFR can serve as molecular markers for response.

Neuroendocrine tumors arising in Meckel's diverticula: frequency of advanced disease warrants aggressive management.

BACKGROUND: Meckel's diverticulum is a common anomaly of the GI tract, which occasionally gives rise to cancer. The most frequent tumors affecting these diverticula are neuroendocrine tumors (NETs), and whether these should be treated in similar fashion as small bowel NETs or appendiceal NETs is unclear. METHODS: A retrospective chart review was conducted at a single academic medical center between 1998 and 2012. Demographic, radiologic, biochemical, and clinicopathologic data were collected as well as status at last follow-up. RESULTS: Seven patients were identified with NETs involving Meckel's diverticula, including one with limited information other than management of her late metastases. Of the six other patients, all had involvement of regional nodes, including three patients with tumors <2 cm in size, and four had liver metastases at presentation. CONCLUSIONS: NETs in Meckel's diverticula are rare tumors, but when they develop, are often associated with nodal metastases and liver metastases, even when the tumors are small. Therefore, optimal management of these NETs is small bowel resection with regional lymphadenectomy and debulking of liver metastases where feasible.