BackgroundThyroid nodules are an extremely common entity, and surgery is considered the ultimate diagnostic strategy in those with unclear malignant potential. Unfortunately, strategies aiming to predict the risk of malignancy have inadequate specificity. Our group recently found that the microenvironment of thyroid cancer is characterized by an enhanced immune invasion and activated immune response mediated by double-negative T lymphocytes (DN T) (CD3+CD4-CD8-), which are believed to enable or promote tumorigenesis. In the present work, we try to use the DN T cells’ proportion in thyroid fine-needle aspiration (FNA) material as a predictor of the risk of malignancy.MethodsWe recruited 127 patients and obtained ultrasound-guided FNA samples from subjects with cytology-positive or suspicious for malignancy and from those with benign nodular goiter associated with compressive symptoms (such as dysphagia, shortness of breath, or hoarseness), Hashimoto thyroiditis, and Graves’ disease. Out of 127, we investigated 46 FNA samples of patients who underwent total thyroidectomy and for which postoperative histological diagnosis by the academic pathologists was available. We specifically measured the number of cells expressing CD3+CD4-CD8- (DN T) as a function of total CD3+ cells in FNA samples using flow cytometry. We correlated their FNA DN T-cell proportions with the pathological findings.ResultsThe DN T cells were significantly more abundant in lymphocytic infiltrates of thyroid cancer cases compared to benign nodule controls (p < 0.0001). When the DN T-cell population exceeded a threshold of 9.14%, of total CD3+ cells, the negative likelihood ratio of being cancer-free was 0.034 (96.6% sensitivity, 95% CI, 0.915–1.000, p < 0.0001). DN T cells at <9.14% were not found in any subject with benign disease (specificity 100%). The high specificity of the test is promising, since it abolishes a false-positive diagnosis and in turn unnecessary surgical procedures.ConclusionThe present study proposes DN T cells’ proportion as a preoperative diagnostic signature for thyroid cancer that with integration of RNA transcriptomics can provide a simplified technology based on the PCR assay for the ease of operation.
Resection of large lipomatous tumours in the subdeltoid region remains technically challenging due to the risk of injury to the axillary neurovascular bundle. We describe a novel deltoid release and reinsertion technique for resection of large lipomatous tumours of the sub-deltoid region and report the functional and oncologic outcomes of six patients who underwent this procedure. Three cases were diagnosed histologically as atypical lipoma and three cases were diagnosed as lipoma. There was one local recurrence in a case of an atypical lipoma. Rotator cuff function was comparable to that of the contralateral side in all cases and the average Constant Score adopted by the European Shoulder and Elbow Society was 84 (range 81 to 92) out of 100. We conclude that patients with large sub-deltoid lipomatous tumours who undergo resection through a previously undescribed deltoid release and reinsertion technique have excellent functional outcome with a low risk for recurrence.
Introduction: Colorectal cancer accounts for ∼10% of cancer deaths in North America. Our group has developed a series of primary tumors from human colorectal cancer tissue obtained during surgery. These tumors are passaged orthotopically in mice and maintain the complexity and heterogeneity of the original patient sample. We have used these tumors to examine the cytotoxic and anti-vascular effects of Irinophore CTM, a liposomal form of irinotecan, which is more efficacious and less toxic than the parent drug. Materials and Methods: Primary tumor tissues from colorectal cancer patients, were validated by a reference pathologist and implanted subcutaneously in SCID mice. Tumors that grew successfully were then passaged orthotopically on the ascending colon of new mice. When these tumors reached ∼200mm3, groups of mice were treated with saline, irinotecan (50mg/kg), or IrinophoreCTM (25mg/kg) once a week for 6 weeks. Separate groups of tumors, A, B and C were harvested on days 3, 21 and 42 after treatment started, respectively. Magnetic resonance imaging (MRI) was used to assess tumor perfusion in mice from group B. Treatment effects on tumor metabolism were assessed with 18F -fluorodeoxyglucose and positron emission tomography (FDG-PET) for groups A and C mice. Immunofluorescence staining was carried out on tumors from all treatment groups to determine levels of cell proliferation, apoptosis, hypoxia, and vessel density. Results: 4 of 14 samples were successfully propagated and maintain their original morphology. Irinophore CTM treatment reduced tumor volume by 54% to 92% compared to the untreated controls depending on the tumor line. No toxic effects were seen with Irinophore CTM. The aggregate data for cell proliferation (Ki67), necrosis (H&E) and cell death (TUNEL) indicate that Irinophore CTM has sustained cytotoxic activity compared to the free drug. Immunostaining data show irinotecan treatment did not change blood vessel density in the tumors; however, Irinophore CTM treatment did reduce vascular density in the tumors. The volume transfer coefficient, Ktrans, derived from MRI, decreased when tumors were treated with irinotecan, but increased with Irinophore CTM treatment. Differences in the metabolic activity of the tumors were also seen. Conclusion: Orthotopic models of colorectal cancer propagated from patient tumors were successfully developed. These models retain the characteristics of the original patient sample and are a good alternative to xenograft models grown from immortalized cell-lines. The anti-tumor activity of Irinophore CTM at lower doses is greater than irinotecan's, and with fewer side effects. Treatment with Irinophore CTM also reduces tumor metabolism and appears to improve vascular function. The data imply that Irinophore CTM has sustained anti-tumor activity and multiple mechanisms of action compared to irinotecan. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5261. doi:1538-7445.AM2012-5261
Introduction: Colorectal cancer is a common cancer that accounts for ∼10% of cancer cell deaths in North America. There are numerous in vivo xenograft models for colorectal cancer available, but in general, these are derived from immortalized cell lines and fail to capture the complexities and heterogeneity of tumors seen in the clinic. Our group has developed a series of orthotopic, primary tumors from samples of human colorectal cancer tissue obtained during surgical resection that maintain the characteristics of the original sample. The effects of Irinophore C™, (a liposomal formulation of irinotecan that is more efficacious and less toxic than the parent drug) on the microenvironment and vascular function of these primary colorectal tumors were examined in the present study. Materials and Methods: Primary tumor tissues, obtained from colorectal cancer patients, were validated by a reference pathologist and implanted subcutaneously in SCID mice. Small pieces of subcutaneous tumors that grew successfully were then passaged orthotopically on the ascending colon of new mice. When these tumors reached ∼200mm3, groups of mice were treated with vehicle control (0.9% saline), irinotecan (50mg/kg), or Irinophore C™ (25mg/kg) once a week for 6 weeks. Separate groups of tumors were harvested on days 3 and 42 after treatment started. Immunofluorescence staining was performed on tumor cryosections followed by computerized image analysis to determine levels of cell proliferation, apoptosis, hypoxia, and vessel density. Results: 4 of 14 samples were successfully propagated orthotopically and were characterized by a reference pathologist. The tumors maintain their original morphology, and one is a highly mucinous adenocarcinoma whereas the others are typical colorectal adenocarcinomas. Treatment with irinotecan and Irinophore C™ reduced tumor volumes by 54% and 92%, respectively, compared to the vehicle control. No toxic effects were seen with Irinophore C™. Immunostaining data showed that the distance between blood vessels remained the same for Irinotecan when compared to control, but increased with Irinophore C™ treatment (+30%; P<0.01). However, perfusion was not significantly different between the three treatment groups. Furthermore, compared to the vehicle treatment group, tumors treated with irinotecan are 42% (P<0.05) more necrotic and tumors treated with Irinophore C™ are 97% less hypoxic. Conclusion: An orthotopic model of colorectal cancer was successfully developed using patient tumor materials that retained the morphology of the primary tumor. Irinophore C™ was more effective in controlling tumor growth than irinotecan despite being delivered at a lower dose. In addition, treatment with Irinophore C™ appeared to improve overall vascular function in the tumor. Based on these data, it is clear that Irinophore C™ has different mechanisms of action and is more efficacious than irinotecan against primary models of colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B12.
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