Abstract Introduction/Objective Alveolar soft part sarcoma (ASPS) is an exceedingly rare malignant neoplasm, typically arising in the lower limbs or the head and neck region of children and young adults. Very few cases of primary ASPS have been reported arising in the breast. Methods/Case Report A 16-year-old female presented with a slowly growing mass of the left breast for three years. Clinical and imaging features were initially consistent with a fibroadenoma. Palpable increase in size prompted repeat ultrasound revealing a 3.4 cm oval, complex, cystic and solid mass. Due to its complexity by imaging and interval growth, biopsy was recommended. The biopsy demonstrated a cellular, vascular, and nested tumor consisting of polygonal cells with abundant granular eosinophilic cytoplasm and round nuclei with prominent nucleoli. Tumor cell discohesion and pseudoalveolar growth pattern were also seen in several areas, while necrosis and increased mitoses were not identified. The histologic findings were not consistent with a fibroepithelial lesion. The differential diagnosis included apocrine adenosis, granular cell tumor, melanoma, acinic cell carcinoma and ASPS. By immunohistochemistry, the lesion demonstrated strong and diffuse positivity for TFE3, MyoD1 and desmin. It was negative for pancytokeratin, CD68, S-100, HMB45 and smooth muscle actin. A TFE3 gene rearrangement was detected by FISH. The morphologic, immunohistochemical, and molecular findings were most consistent with ASPS. At resection, the tumor was entirely confined to the breast, with no involvement of the chest wall. No other potential primary sites were found by imaging work-up. Results (if a Case Study enter NA) NA Conclusion Although ASPS has distinctive histologic and molecular features, it may cause diagnostic dilemmas when arising in unusual sites. Here we report a highly unusual case of a primary ASPS arising in the breast of a teenager, which clinically mimicked a fibroadenoma. While this is a rare entity, it supports the biopsy of any breast mass with interval growth.

Background: Microwave ablation (MWA) is a safe and established method for achieving locoregional control of both primary and secondary hepatic malignancies.This technology has expanded the indications for liver-directed therapy for a broad range of cancers, but long-term data on oncologic outcomes are lacking.Although CT-guided microwave ablation is the most commonly used localization modality, a laparoscopic approach utilizing intraoperative ultrasound offers the additional benefit of evaluating the abdominal cavity and liver for unidentified tumors with minimal added morbidity.This study reports the 10-year use of laparoscopic-assisted microwave ablation in a high-volume hepatobiliary practice at a large tertiary care center.Methods: A prospectively maintained registry of laparoscopic-assisted MWAs performed in a single high-volume center was retrospectively queried for all patients who underwent laparoscopic MWA from January 1, 2010 through December 31, 2019.Patient demographics, intraoperative details, and postoperative outcomes were collected.Follow up imaging was analyzed to determine rates of incomplete ablation as identified on the first computed tomography scan performed postoperatively (typically within 4-6 weeks), and locoregional recurrence.Comparative statistics was performed as appropriate.Results: Overall, 777 separate ablation procedures for a total of 1317 lesions within the 10-year time interval was performed.Patients were 33% female; 76% Caucasian, and 18% African American.The majority of patients had an ASA score of III (76%, n=540) and average BMI of 29kg/ m2.There was an average number of 1.7 lesions ablated per patient surgery with an average lesion diameter of 2.4 cm (range: < 0.5 to 8.0 cm).Hepatocellular carcinoma (58%, n=397) was the most frequent lesion ablated, followed by colorectal metastasis (20%, n=135).Patients had a median intraoperative blood loss of 50 mL and the majority of patients had no major 30-day morbidity or mortality (96% of patients with highest Clavien-Dindo classification < 3).Median length-of-stay was 1 hospital day (range 0 to 46 days).At postoperative follow up, 5.7% of patients had an incomplete ablation.The local recurrence rate was 18.2% with median time to local recurrence of 8.9 months (range: 0.7 to 90 months).The regional recurrence rate was 48.9% with median time to regional recurrence of 7.5 months (range: 0.5 to 103 months).Conclusion: Laparoscopic MWA is a viable treatment for locoregional control of both primary and secondary liver lesions.This surgery is performed in a minimally invasive fashion with assistance of intraoperative ultrasound to aid in visualization of subclinical lesions.This is an established safe technique with low associated morbidity and mortality and short associated length of stay.Additionally, locoregional recurrence in this study is comparable to historical controls of liver resection, suggesting comparable efficacy with this approach.

Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is similar to 4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. Patients and methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Objective— Vascular smooth muscle cell (SMC) migration is regulated by cytoskeletal remodeling as well as by certain transient receptor potential (TRP) channels, nonselective cation channels that modulate calcium influx. Proper function of multiple subfamily C TRP (TRPC) channels requires the scaffolding protein Homer 1, which associates with the actin-binding protein Drebrin. We found that SMC Drebrin expression is upregulated in atherosclerosis and in response to injury and investigated whether Drebrin inhibits SMC activation, either through regulation of TRP channel function via Homer or through a direct effect on the actin cytoskeleton. Approach and Results— Wild-type (WT) and congenic Dbn −/+ mice were subjected to wire-mediated carotid endothelial denudation. Subsequent neointimal hyperplasia was 2.4±0.3-fold greater in Dbn −/+ than in WT mice. Levels of globular actin were equivalent in Dbn −/+ and WT SMCs, but there was a 2.4±0.5-fold decrease in filamentous actin in Dbn −/+ SMCs compared with WT. Filamentous actin was restored to WT levels in Dbn −/+ SMCs by adenoviral-mediated rescue expression of Drebrin. Compared with WT SMCs, Dbn −/+ SMCs exhibited increased TRP channel activity in response to platelet-derived growth factor, increased migration assessed in Boyden chambers, and increased proliferation. Enhanced TRP channel activity and migration in Dbn −/+ SMCs were normalized to WT levels by rescue expression of not only WT Drebrin but also a mutant Drebrin isoform that binds actin but fails to bind Homer. Conclusions— Drebrin reduces SMC activation through its interaction with the actin cytoskeleton but independently of its interaction with Homer scaffolds.

Objectives: Obesity has been associated with increased risk and worse outcomes in ovarian cancer (OC). In addition, we found obesity to be associated with increased tumor aggressiveness in a genetically engineered mouse model of serous OC. We sought to evaluate the association between obesity and angiogenesis to determine if obesity alters the tumor microenvironment in high-grade serous OCs in mice and women.Methods: We used the K18-gT121+/-; p53fl/fl;Brca1fl/fl (KpB) OC mouse model. KpB mice were subjected to 60% calories derived from fat in a high-fat diet (HFD) to mimic diet-induced obesity versus 10% calories from fat in a low-fat diet (LFD). Tumors from obese and lean KpB mice were analyzed using custom Agilent 244K chip arrays for differential expression of angiogenic genes and validated using qualitative polymerase chain reaction (qPCR). Confirmation of findings in human OCs was performed using institutionally derived patient specimens (IDB) and TCGA database.Results: As previously reported, diet-induced obesity resulted in a tripling of tumor size in KpB mice compared with those fed a LFD. Fourteen angiogenic-related genes were differentially expressed in the obese versus lean mice (P < 0.01). After adjusting for multiple comparisons, thrombospondin4 (THBS4) and eregulin (EREG) demonstrated 2- and 1.6-fold higher expression in lean compared with obese mice (adjusted P value (q) < .01). In contrast, natriuretic peptide receptor 1 (NPR1) and MMP12 demonstrated 1.9- and 2.7-fold higher expression in obese compared with lean mice (q < .005). Alterations in gene expression were confirmed in 57% (8/14) by PCR. Body mass index (BMI) data were available for 209 patients of 412 patients (IDB [41/51]; TCGA [168/361]). High BMI was associated with low EREG expression (P = .03).Conclusions: Obesity may alter the tumor microenvironment and promote tumor progression via differential modulation of angiogenic pathways. Differentially expressed angiogenic genes may serve as novel therapeutic targets unique to obesity-driven OCs. Objectives: Obesity has been associated with increased risk and worse outcomes in ovarian cancer (OC). In addition, we found obesity to be associated with increased tumor aggressiveness in a genetically engineered mouse model of serous OC. We sought to evaluate the association between obesity and angiogenesis to determine if obesity alters the tumor microenvironment in high-grade serous OCs in mice and women. Methods: We used the K18-gT121+/-; p53fl/fl;Brca1fl/fl (KpB) OC mouse model. KpB mice were subjected to 60% calories derived from fat in a high-fat diet (HFD) to mimic diet-induced obesity versus 10% calories from fat in a low-fat diet (LFD). Tumors from obese and lean KpB mice were analyzed using custom Agilent 244K chip arrays for differential expression of angiogenic genes and validated using qualitative polymerase chain reaction (qPCR). Confirmation of findings in human OCs was performed using institutionally derived patient specimens (IDB) and TCGA database. Results: As previously reported, diet-induced obesity resulted in a tripling of tumor size in KpB mice compared with those fed a LFD. Fourteen angiogenic-related genes were differentially expressed in the obese versus lean mice (P < 0.01). After adjusting for multiple comparisons, thrombospondin4 (THBS4) and eregulin (EREG) demonstrated 2- and 1.6-fold higher expression in lean compared with obese mice (adjusted P value (q) < .01). In contrast, natriuretic peptide receptor 1 (NPR1) and MMP12 demonstrated 1.9- and 2.7-fold higher expression in obese compared with lean mice (q < .005). Alterations in gene expression were confirmed in 57% (8/14) by PCR. Body mass index (BMI) data were available for 209 patients of 412 patients (IDB [41/51]; TCGA [168/361]). High BMI was associated with low EREG expression (P = .03). Conclusions: Obesity may alter the tumor microenvironment and promote tumor progression via differential modulation of angiogenic pathways. Differentially expressed angiogenic genes may serve as novel therapeutic targets unique to obesity-driven OCs.

Alveolar rhabdomyosarcoma (aRMS) is an aggressive sarcoma of skeletal muscle characterized by expression of the paired box 3-forkhead box protein O1 (PAX3-FOXO1) fusion oncogene. Despite its discovery nearly two decades ago, the mechanisms by which PAX3-FOXO1 drives tumor development are not well characterized. Previously, we reported that PAX3-FOXO1 supports aRMS initiation by enabling bypass of cellular senescence checkpoints. We have now found that this bypass occurs in part through PAX3-FOXO1-mediated upregulation of RASSF4, a Ras-association domain family (RASSF) member. RASSF4 expression was upregulated in PAX3-FOXO1-positive aRMS cell lines and tumors. Enhanced RASSF4 expression promoted cell cycle progression, senescence evasion, and tumorigenesis through inhibition of the Hippo pathway tumor suppressor MST1. We also found that the downstream Hippo pathway target Yes-associated protein 1 (YAP), which is ordinarily restrained by Hippo signaling, was upregulated in RMS tumors. These data suggest that Hippo pathway dysfunction promotes RMS. This work provides evidence for Hippo pathway suppression in aRMS and demonstrates a progrowth role for RASSF4. Additionally, we identify a mechanism used by PAX3-FOXO1 to inhibit MST1 signaling and promote tumorigenesis in aRMS.

Background: In early-stage breast cancer, adjuvant chemotherapy is associated with significant systemic toxicity with only a modest survival benefit. Therefore, there is considerable interest in identifying predictive markers of response to therapy. Doxorubicin, one of the most common drugs used to treat breast cancer, is an anthracycline chemotherapeutic agent, a class of drugs known to be affected by hypoxia. Accordingly, we examined whether expression of the endogenous hypoxia marker carbonic anhydrase IX (CA IX) is predictive of outcome in early-stage breast cancer patients treated with doxorubicin. Methods: We obtained 209 early-stage pre-treatment surgically-resected breast tumours from patients, who received doxorubicin in their chemotherapeutic regimen and had >10 years of follow-up. Immunohistochemistry was used to detect CA IX, and we used fluorescence in situ hybridisation to detect both human epidermal growth factor receptor ( HER2 ) and DNA topoisomerase II-alpha ( TOP2A ) gene amplification. Results: Carbonic anhydrase IX intensity was significantly correlated with progression-free survival (PFS) and overall survival (OS) in patients receiving 300 mg m −2 of doxorubicin (HR=1.82 and 3.77; P =0.0014 and 0.010, respectively). There was a significant, inverse correlation between CA IX score and oestrogen receptor expression, but no significant correlations were seen with either HER2 or TOP2A ratio. Conclusion: We demonstrate that CA IX expression is correlated with worse PFS and OS for breast cancer patients treated with doxorubicin, independent of HER2 or TOP2A gene amplification. This study provides evidence that using CA IX to detect hypoxia in surgically-resected breast tumours may be of clinical use in choosing an appropriate chemotherapy regimen.

Objective: The ARID1A gene plays a role in regulating expression of other genes through effects on chromatin remodeling. Inactivating somatic mutations in ARID1A have recently been described in a significant fraction of clear cell and endometrioid ovarian cancers, and these usually lead to loss of the corresponding protein (BAF250a). In this study we examined expression of BAF250a in clear cell and endometrioid ovarian cancers that were accrued prospectively in a molecular epidemiology study to determine whether loss of this gene is associated with clinical and epidemiologic features.

Objective: To resolve controversial issues regarding vulvar Paget disease through analysis of a substantial number of cases.Study design: The medical records and pathology slides of 56 patients with a diagnosis of vulvar Paget disease were reviewed. Possible correlation between clinical and pathological data was examined.Results: Most patients were Caucasian and their mean age at diagnosis was 69 years. The average length of follow-up was 5.6 years. The most common symptom was pruritus, almost always accompanied by erythematous-white plaques. Substantial delay between appearance of symptoms and diagnosis was observed in many patients, and was significantly associated with larger lesions. Recurrence rate after surgical management was 32%, with disease involving the perineum being the only statistically significant risk factor. Patients with positive surgical margins had an increased recurrence rate, but this was not statistically significant. Intra-operative frozen section analysis of the margins as well as radical surgery as initial treatment did not reduce recurrence rate. In general, stromal invasion was not associated with worse prognosis, but the single patient who died of disease had the deepest stromal invasion. Radiation therapy given to five patients who either had multiple positive surgical margins or experienced disease recurrence and refused additional surgery resulted in complete response with no further recurrences. On the last day of follow-up 24 patients (43%) had no evidence of disease, 24 patients (43%) were dead of other causes, 5 patients (9%) were alive with disease, 2 patients (3%) were lost to follow-up, and 1 (2%) died due to vulvar Paget disease with invasive adenocarcinoma.Conclusions: Vulvar Paget disease only rarely results in a patient's death, but long term follow-up is required, as recurrences are common and can be noted many years after the initial treatment. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Desmoplastic small round cell tumor (DSRCT) is a rare abdominal malignancy usually diagnosed in young adult males. Most patients have widespread disease at presentation, with an organ of origin difficult to ascertain. A 33-year-old female presented to her gynecologist with complaints of suprapubic pressure, abdominal pain, and increased abdominal girth. She had a large intraabdominal tumor on ultrasound, thought to be ovarian cancer. She underwent surgical exploration, which confirmed a malignancy, but the exact etiology was uncertain. Final pathology was consistent with DSRCT. DSRCT is a rare malignancy that can mimic other more commonly seen tumors such as lymphoma and ovarian cancer. When encountering an extensive intraabdominal malignancy of uncertain etiology, DSRCT should be in the differential diagnosis.

INTRODUCTION:The aim of our study was to apply longitudinal force to the small bowel to increase the length of intestine in juvenile rats.METHODS:Fifty juvenile rats had double barrelled, blind loop ostomies created using an isolated segment of bowel. Our intestinal lengthening device was inserted into one of the loops and the second loop served as a control. Once the device was deployed, the experimental, control, and in situ segments of bowel were evaluated for length, weight, histology, and disaccharidase enzyme activity.RESULTS:Mechanical tension increased intestinal length by 149%. The lengthened bowel also exhibited a greater total weight (218%), greater mucosal weight (122%), and increased protein mass (164%) compared with the control limb of bowel. Histologically, there was a markedly increased thickness of the muscularis propria in the lengthened bowel (200% increase compared with the control limb). Functionally, we found increased total disaccharidase activity in the lengthened bowel (between 47% and 350%, depending on the particular enzyme tested; p<0.01).CONCLUSION:Mechanical tension induces intestinal growth by increasing length, weight of the bowel and mucosa, and protein mass. Histological changes, such as increases in Paneth cells, suggest that increased proliferation and reorganisation of the mucosa and muscularis propria are a response to mechanical tension. Functionally, increased intestinal length corresponds with increased disaccharidase activity, thus implying potential increased absorptive capacity of the lengthened bowel.