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Background This study evaluates the safety and efficacy of active surveillance for low-risk papillary thyroid carcinoma. Methods MEDLINE, EMBASE, and PubMed were searched from inception for relevant studies of active surveillance for low-risk papillary thyroid carcinoma, defined as T1a or T1b, N0, M0 disease. Main outcomes of interest were growth of primary tumor, metastatic spread, thyroid cancer-related mortality, and disease recurrence after delayed thyroid surgery. Results Nine publications with 4,156 patients were included. Primary analysis of the 9 studies revealed pooled proportion of tumor growth during active surveillance to be 4.4% (95% confidence interval 3.2–5.8%). The pooled rate of metastatic spread to cervical nodes was 1.0% (95% confidence interval 0.7–1.4%), and pooled mortality due to thyroid cancer was 0.03% (95% confidence interval 0.0005–0.2%). Eight studies assessed incidence of delayed thyroid surgery with pooled proportion of 9.9% (95% confidence interval 6.4–14.0%). The main indication for surgery was patient preference, not disease progression, at 51.9% (95% confidence interval 44.9–58.9%). The pooled proportion of recurrence after delayed thyroid surgery was 1.1% (95% confidence interval 0.1–3.8%). Conclusion Active surveillance appears to be a safe alternative to surgery for the management of low-risk papillary thyroid carcinoma, without increased risk of recurrence or death. This strategy allows for avoidance of exposure to surgical risk and need for subsequent thyroid replacement therapy.

Summary Function of the thyroid follicular cell depends on nuclear expression of thyroid transcription factor 1 (TTF1). Regulation of this key protein regulating iodide transport is not well known, but its loss is linked to the most lethal of thyroid malignancies. We examined TTF1 nuclear expression in the context of adverse pathological features, disease recurrence, and BRAF status in papillary thyroid carcinomas with (n = 182) and without (n = 303) nodal metastases. Overall nuclear expression level of TTF1 was strong and diffuse in approximately 73%, whereas 27% exhibited lower levels or a paucity of nuclear staining. In the same cohort, approximately 59% exhibited the BRAF mutation. On univariate analysis, low levels of TTF1 nuclear expression was linked to vascular invasion, extrathyroidal extension, and nodal metastases. Multivariate analysis indicated that low levels of TTF1 were most strongly linked to nodal metastases and vascular invasion. Interestingly, TTF1 levels were not linked to the BRAF mutation. TTF1 staining alone predicted disease recurrence, but when combined with BRAF status, the 2 markers exhibited a more marked influence. Patients lacking the BRAF mutation and exhibiting normal levels of TTF1 exhibited very low levels of disease recurrence (11% at 10 years). Conversely, patient tumors with low levels of TTF1 and the BRAF mutation recurred in 31% of cases in the same time frame. The mixed expression of BRAF under varying levels of differentiation may explain, in part, the contradictory studies regarding the impact of BRAF mutations on patient prognosis and also indicates a complex genomic signature for dedifferentiated thyroid cancer.

Biosensor development has relied on the process of anodization of sputtered aluminum‑tantalum thin films to develop specific optical properties for interference color generation. The anodization of thin sputtered films of aluminum (140 nm) on tantalum (230 nm) on silicon was completed in 0.4 M phosphoric acid under potentiostatic conditions (4 V) and with various additives: 0.1 M and 0.4 M citric acid, 3% ( v /v) and 10% (v/v) of a commercial anodizing solution consisting of glycerol and glycolic acid, and 0.1 M and 0.4 M oxalic acid. The microstructural and optical properties of these films were analyzed using scanning electron microscopy, X-ray diffraction, and ellipsometry. The interference colors produced by the anodic aluminum and tantalum oxides on top of the tantalum metal layer were also observed. The addition of 0.1 M citric acid, 3% ( v /v) glycerol and glycolic acid-based solution, and 0.1 or 0.4 M oxalic acid all produced changes to the porous microstructure of the anodic alumina, including lower roughness and more homogeneous surfaces by inhibition of the dissolution from phosphoric acid. Oxalic acid acted as the strongest inhibitor and significantly reduced surface roughness and pore size, increased the composite refractive index of the anodized film, and significantly changed the interference colors compared to films where no additive was used.

BACKGROUND: Researchers increasingly use intraoperative muscle biopsy to investigate mechanisms of skeletal muscle atrophy in patients with cancer. Muscles have been assessed for morphological, cellular, and biochemical features. The aim of this study was to conduct a state-of-the-science review of this literature and, secondly, to evaluate clinical and biological variation in biopsies of rectus abdominis (RA) muscle from a cohort of patients with malignancies.METHODS: Literature was searched for reports on muscle biopsies from patients with a cancer diagnosis. Quality of reports and risk of bias were assessed. Data abstracted included patient characteristics and diagnoses, sample size, tissue collection and biobanking procedures, and results. A cohort of cancer patients (n = 190, 88% gastrointestinal malignancies), who underwent open abdominal surgery as part of their clinical care, consented to RA biopsy from the site of incision. Computed tomography (CT) scans were used to quantify total abdominal muscle and RA cross-sectional areas and radiodensity. Biopsies were assessed for muscle fibre area (μm2 ), fibre types, myosin heavy chain isoforms, and expression of genes selected for their involvement in catabolic pathways of muscle.RESULTS: Muscle biopsy occurred in 59 studies (total N = 1585 participants). RA was biopsied intraoperatively in 40 studies (67%), followed by quadriceps (26%; percutaneous biopsy) and other muscles (7%). Cancer site and stage, % of male participants, and age were highly variable between studies. Details regarding patient medical history and biopsy procedures were frequently absent. Lack of description of the population(s) sampled and low sample size contributed to low quality and risk of bias. Weight-losing cases were compared with weight stable cancer or healthy controls without considering a measure of muscle mass in 21 out of 44 studies. In the cohort of patients providing biopsy for this study, 78% of patients had preoperative CT scans and a high proportion (64%) met published criteria for sarcopenia. Fibre type distribution in RA was type I (46% ± 13), hybrid type I/IIA (1% ± 1), type IIA (36% ± 10), hybrid type IIA/D (15% ± 14), and type IID (2% ± 5). Sexual dimorphism was prominent in RA CT cross-sectional area, mean fibre cross-sectional area, and in expression of genes associated with muscle growth, apoptosis, and inflammation (P < 0.05). Medical history revealed multiple co-morbid conditions and medications.CONCLUSIONS: Continued collaboration between researchers and cancer surgeons enables a more complete understanding of mechanisms of cancer-associated muscle atrophy. Standardization of biobanking practices, tissue manipulation, patient characterization, and classification will enhance the consistency, reliability, and comparability of future studies.

Objective The purpose of this study was to assess the efficacy of Lu-labeled peptide receptor radionuclide therapy (PRRT) induction treatments for patients with unresectable metastatic neuroendocrine tumors. Methods MEDLINE, EMBASE, and Ovid were systematically searched with keywords "lutetium," "Lu-177," "PRRT," "neuroendocrine," and "prognosis." Studies evaluating treatment with Lu-labeled PRRT were assessed for disease response and/or disease control rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 or 1.1, modified RECIST, Southwest Oncology Group (SWOG), or modified SWOG criteria. Pooled proportions of disease response and control rates were calculated for both fixed- and random-effects models. Results Eighteen studies with 1920 patients were included (11 with 1268 patients using RECIST and 6 with 804 patients using SWOG). By RECIST criteria, the pooled disease response rate by random-effects model was 29.1% (95% confidence interval [CI], 20.2%-38.9%), and disease control rate was 74.1% (95% CI, 67.8%-80.0%). By SWOG criteria, the pooled disease response rate by random-effects model was 30.6% (95% CI, 20.7%-41.5%), and disease control rate was 81.1% (95% CI, 76.4%-85.4%). Conclusions Induction therapy, typically 4 treatments, with Lu PRRT is an effective method of treating unresectable metastatic neuroendocrine tumors with significant disease response and control rates.

Metastasis is the leading cause of mortality in breast cancer patients and lysophosphatidate (LPA) signaling promotes this process. LPA signaling is attenuated by lipid phosphate phosphatase-1 (LPP1) whose activity is decreased in cancers. Consequently, increasing LPP1 levels suppresses breast tumor growth and metastasis. This study shows that increasing LPP1 in breast cancer cells decreases transcription through cFos and cJun. This decreases production of cyclin D1/D3 and matrix metalloproteinases (MMPs), which provides new insights into the role of LPP1 in controlling tumor growth and metastasis. Methods: Invasiveness was determined by a Matrigel invasion assay. MMP expression was measured by qPCR, multiplex LASER bead technology and gelatin zymography. Levels of cJUN, cFOS, FRA1, cyclin D1, and cyclin D3 were determined by qPCR and western blotting. Collagen was determined by Picro-Sirius Red staining. Results: Increasing LPP1 expression inhibited invasion of MDA-MB-231 breast cancer cells through Matrigel. This was accompanied by decreases in expression of MMP-1, -3, -7, -9, -10, -12 and -13, which are transcriptionally regulated by the AP-1 complex. Increasing LPP1 attenuated the induction of mRNA of MMP-1, -3, cFOS, and cJUN by EGF or TNFα, but increased FRA1. LPP1 expression also decreased the induction of protein levels for cFOS and cJUN in nuclei and cytoplasmic fractions by EGF and TNFα. Protein levels of cyclin D1 and D3 were also decreased by LPP1. Although FRA1 in total cell lysates or cytoplasm was increased by LPP1, nuclear FRA1 was not affected. LPP1-induced decreases in MMPs in mouse tumors created with MDA-MB-231 cells were accompanied by increased collagen in the tumors and fewer lung metastases. Knockdown of LPP1 in MDA-MB-231 cells increased the protein levels of MMP-1 and -3. Human breast tumors also have lower levels of LPP1 and higher levels of cJUN, cFOS, MMP-1, -7, -8, -9, -12, -13, cyclin D1, and cyclin D3 relative to normal breast tissue. Conclusion: This study demonstrated that the low LPP1 expression in breast cancer cells is associated with high levels of cyclin D1/D3 and MMPs as a result of increased transcription by cFOS and cJUN. Increasing LPP1 expression provides a novel approach for decreasing transcription through AP-1, which could provide a strategy for decreasing tumor growth and metastasis.

Breast cancer patients are usually treated with multiple fractions of radiotherapy (RT) to the whole breast after lumpectomy. We hypothesized that repeated fractions of RT would progressively activate the autotaxin&ndash, lysophosphatidate-inflammatory cycle. To test this, a normal breast fat pad and a fat pad containing a mouse 4T1 tumor were irradiated with X-rays using a small-animal &ldquo, image-guided&rdquo, RT platform. A single RT dose of 7.5 Gy and three daily doses of 7.5 Gy increased ATX activity and decreased plasma adiponectin concentrations. The concentrations of IL-6 and TNF&alpha, in plasma and of VEGF, G-CSF, CCL11 and CXCL10 in the irradiated fat pad were increased, but only after three fractions of RT. In 4T1 breast tumor-bearing mice, three fractions of 7.5 Gy augmented tumor-induced increases in plasma ATX activity and decreased adiponectin levels in the tumor-associated mammary fat pad. There were also increased expressions of multiple inflammatory mediators in the tumor-associated mammary fat pad and in tumors, which was accompanied by increased infiltration of CD45+ leukocytes into tumor-associated adipose tissue. This work provides novel evidence that increased ATX production is an early response to RT and that repeated fractions of RT activate the autotaxin&ndash, lysophosphatidate-inflammatory cycle. This wound healing response to RT-induced damage could decrease the efficacy of further fractions of RT.

Background Low muscle radiodensity is associated with mortality in a variety of cancer types. Biochemical and morphological correlates are unknown. We aimed to evaluate triglyceride (TG) content and location as a function of computed tomography (CT)‐derived measures of skeletal muscle radiodensity in cancer patients. Methods Rectus abdominis (RA) biopsies were collected during cancer surgery from 75 patients diagnosed with cancer. Thin‐layer chromatography and gas chromatography were used for quantification of TG content of the muscle. Axial CT images of lumbar vertebra were used to measure muscle radiodensity. Oil Red O staining was used to determine the location of neutral lipids in frozen muscle sections. Results There was wide variation in RA radiodensity in repeated measures (CV% ranged from 3 to 55% based on 10 serial images) as well as within one slice (CV% ranged from 6 to 61% based on 10 subregions). RA radiodensity and total lumbar muscle radiodensity were inversely associated with TG content of RA (r = −0.396, P < 0.001, and r = −0.355, P = 0.002, respectively). Of the total percentage area of muscle staining positive for neutral lipid, 54 ± 17% was present as extramyocellular lipids (range 23.5–77.8%) and 46 ± 17% (range 22.2–76.5%) present as intramyocellular lipid droplets. Conclusions Repeated measures revealed wide variation in radiodensity of RA muscle, both vertically and horizontally. Low muscle radiodensity reflects high level of TG in patients with cancer. Non‐uniform distribution of intramyocellular and extramyocellular lipids was evident using light microscopy. These results warrant investigation of mechanisms resulting in lipid deposition in muscles of cancer patients.

Apoptosis is fundamental to normal animal development and is the target for many anticancer therapies. Recent studies have explored the consequences of “failed apoptosis” where the apoptotic program is initiated but does not go to completion and does not cause cell death. Nevertheless, this failed apoptosis induces DNA double-strand breaks generating mutations that facilitate tumorigenesis. Whether failed apoptosis is relevant to clinical disease is unknown. BCL-2 interacting killer (BIK) is a stress-induced BH3-only protein that stimulates apoptosis in response to hormone and growth factor deprivation, hypoxia, and genomic stress. It was unclear whether BIK promotes or suppresses tumor survival within the context of breast cancer. We investigated this and show that BIK induces failed apoptosis with limited caspase activation and genomic damage in the absence of extensive cell death. Surviving cells acquire aggressive phenotypes characterized by enrichment of cancer stem-like cells, increased motility and increased clonogenic survival. Furthermore, by examining six independent cohorts of patients (total n = 969), we discovered that high BIK mRNA and protein levels predicted clinical relapse of Estrogen receptor (ER)-positive cancers, which account for almost 70% of all breast cancers diagnosed but had no predictive value for hormone receptor-negative (triple-negative) patients. Thus, this study identifies BIK as a biomarker for tumor recurrence of ER-positive patients and provides a potential mechanism whereby failed apoptosis contributes to cancer aggression.

Background Inflammation is a recognized contributor to muscle wasting. Research in injury and myopathy suggests that interactions between the skeletal muscle and immune cells confer a pro-inflammatory environment that influences muscle loss through several mechanisms; however, this has not been explored in the cancer setting. This study investigated the local immune environment of the muscle by identifying the phenotype of immune cell populations in the muscle and their relationship to muscle mass in cancer patients. Methods Intraoperative muscle biopsies were collected from cancer patients (n = 30, 91% gastrointestinal malignancies). Muscle mass was assessed histologically (muscle fiber cross-sectional area, CSA; μm2) and radiologically (lumbar skeletal muscle index, SMI; cm2/m2 by computed tomography, CT). T cells (CD4 and CD8) and granulocytes/phagocytes (CD11b, CD14, and CD15) were assessed by immunohistochemistry. Microarray analysis was conducted in the muscle of a second cancer patient cohort. Results T cells (CD3+), granulocytes/phagocytes (CD11b+), and CD3−CD4+ cells were identified. Muscle fiber CSA (μm2) was positively correlated (Spearman’s r = > 0.45; p = r = ≥ 0.5; p = Conclusion The skeletal muscle immune environment of cancer patients is comprised of immune cell populations from the adaptive and innate immunity. Correlations of T cells, granulocyte/phagocytes, and CD3−CD4+ cells with muscle mass measurements indicate a positive relationship between immune cell numbers and muscle mass status in cancer patients. Further exploration with gene correlation analyses suggests that the presence of CD8 T cells is negatively correlated with components of muscle catabolism.

IntroductionDespite good overall care in Alberta Health Services the local recurrence rates are higher than what is accepted as standard of care for rectal cancer treatment. There are variations in pre-operative staging, application of best surgical techniques and pathological grading, use of neoadjuvant and adjuvant therapies, and in clinical reporting. Objectives and ApproachWe aimed at reducing the variations through the design and implementation of a provincial clinical pathway for rectal cancer by 2018. Our approaches included: 1) multidisciplinary tumor board consultation together with physician education sessions in reviewing standards of care and quality metrics; 2) data linkage and analysis based on chart reviews and extraction of data from Alberta Cancer Registry; and 3) production of provincial reports and individual feedbacks to physicians. CancerControl Alberta and Cancer Strategic Clinical Network collaborated in the linkage and analysis of data as well as mobilization oncology physicians to the initiative. ResultsA review of a set of metrics for producing individual and provincial feedback reports to rectal cancer physicians. The set has 24 key quality metrics includes five, four, eight, and six metrics for radiologists, pathologists, oncologists, and surgeons respectively. Thirty-two surgeons have received individual physician feedback reports. Feedback reports for radiologist, pathologist and oncologist are being finalized with input from key opinion leaders in each physician group. Key impacts to the quality of rectal cancer diagnosis, treatment, and care between 2013 and 2015 include increases in use of rectal cancer pre-operative MRIs for curative resections (+23%), completeness of synoptic MRI reports for pre-operative MRIs (+21%), grade 3 TME of curative resections (+4%), and pathologic reporting of TME assessments (+2%). Conclusion/ImplicationsPhysician feedback report system will enable the Alberta rectal cancer community to sustain the results and address strategies to continuously enhance the quality of rectal cancer care and survival. We recommend ongoing annual dissemination of feedback reports to support continuous improvement of rectal cancer care.

Aim: This study assesses if clinically developed quality of life (QoL) tools are as effective in small bowel neuroendocrine tumors (NETs) as NET-specific research questionnaires. Methods: QoL in patients with small bowel NETs treated with Lu-DOTA-TATE was assessed with The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-GI.NET21 and Edmonton Symptom Assessment System Revised (ESAS-r) at baseline and after four treatments. Repeated measures ANOVA was performed. Results: Both EORTC and ESAS-r demonstrated maintained overall QoL. EORTC demonstrated statistically and clinically significant improvement in insomnia, diarrhea, gastrointestinal, endocrine symptoms and social function. ESAS-r demonstrated statistically and clinically significant improvement in overall total symptom distress score. Conclusion: ESAS-r is quick and easy to interpret. It is not as sensitive to individual symptoms but does track overall function. EORTC assessment is more complex, but better reflects QoL for NET specific symptoms.

Purpose To examine the occurrence of hyperparathyroidism in a cohort of patients undergoing combined parathyroid and thyroid surgery after previous head-and-neck irradiation for childhood malignancy. Methods and Materials This is a retrospective cohort study for the years 1996 to 2007. The study group comprised patients undergoing surgery in the University of Sydney Endocrine Surgical Unit who had received previous head-and-neck irradiation in childhood and who were identified as having pathologic thyroid and parathyroid characteristics. Results A total of 53 patients were identified in whom head-and-neck irradiation for the treatment of childhood malignancy had been documented. In each of the cases, thyroid disease was the primary reason for referral for surgery. Five of these patients (10%) were found to exhibit coexisting hyperparathyroidism. The latency period for hyperparathyroidism was less than 20 years in 4 of the 5 cases. There were four conventional parathyroid adenomas and one parathyroid lipoadenoma. All patients exhibited a significant decrease in postoperative calcium levels after surgery. Conclusions To our knowledge, this is the first study to document the significant risk of hyperparathyroidism after radiation exposure for childhood malignancy. The timeframe for development of disease is much shorter than that published for individuals who have undergone irradiation for benign diseases. High doses of therapeutic radiation at a young age make childhood survivors of malignancy at especially high risk for developing hyperparathyroidism.

Lymph node metastases are common in papillary thyroid cancer (PTC) and can be resistant to surgical extirpation or radioiodine ablation. We examined the role of platelet-derived growth factor receptor (PDGFR) in mediating lymph node metastases in PTC. Clinical specimens of PTC (n = 137) were surveyed in a tissue array and by western blots to examine the relationship between expression of the α and β subunits of PDGFR and lymph node metastases. PDGFR-α was found at high levels in primary tumours with known lymphatic metastases but not in those tumours lacking nodal involvement (p0.0001). However, PDGFR-β expression was not linked to metastatic disease (p = 0.78) as it was found in virtually all PTC specimens. A matching analysis in fresh PTC specimens (n = 13) confirmed that PDGFR-α expression was strongly linked to metastatic spread (p = 0.0047). PDGFR-α and -β were not found in normal thyroid tissue (p0.0001). PTC cell lines selectively expressing PDGFR-α or -β were assessed for invasive potential and activation of downstream signal transduction pathways. PTC cell lines expressing PDGFR-α responded to PDGF-BB stimulation with increased invasive potential and this process can be blocked by the tyrosine kinase receptor inhibitor sunitinib (p0.009). Cell lines with only PDGFR-β, or no PDGFR, did not show significant changes in invasive potential. Activation of PDGFR-α led to downstream up-regulation of both the MAPK/ERK and PI3K/Akt pathways and disruption of either pathway is sufficient to block PDGFR-mediated increases in invasive potential. Thus, PDGFR-α is associated with lymph node metastases in papillary thyroid carcinoma and PDGFR-α promotes increased invasive potential in PTC cell lines. PDGFR-α is a strong candidate for a diagnostic biomarker to identify patients at risk of nodal metastases. Our results also strengthen the rationale for selection of tyrosine kinase receptor inhibitors that target PDGFR in the treatment of progressive, metastatic PTC.

Papillary thyroid cancer (PTC) has an impressive propensity for lymphatic spread. Signal transducers and activators of transcription 3 (STAT3), constitutively activated in many different cancers, may play a role in PTC lymphatic metastases. We examined 49 patients with PTC, 22 with and 27 without lymphatic metastases. All patients had a total thyroidectomy with lymph node dissection to document true node negative cases. The level of STAT3 expression in benign, non-neoplastic thyroid tissue is barely detectable by immunohistochemistry. Only 11 of the 35 (31%) specimens exhibited weak immunostainingfor STAT3 and pSTAT3 was found weakly positive in 3 of 35 (9%) benign specimens. Expression of STAT3 in all PTC primary tumors was 98% (40/41) and thus significantly higher than corresponding benign thyroid tissue (p=0.0001). pSTAT3 was found in 37% of primary tumors (15/41) and this was significantly higher than pSTAT3 expression in benign tissue (p=0.006). Comparing node-positive and node-negative primary tumors, there was no difference in staining intensity for STAT3 where strong (2+) staining was seen 12/19 node-positive tumors and 13/22 node-negative tumors (p=1). Regarding pSTAT3 expression in primary PTC tumors, node negative cases (n=22) exhibited significantly less staining compared to node positive cases (n=19). Only 4 of 22 (18%) cases in the node-negative group were weakly (1+) positive for pSTAT3 while 12 of 19 (58%) cases in the node-positive group were positive (p=0.011) with 45% of these specimens exhibiting strong (2+) staining. Lymphatic metastases were highly positive (>93%) for both STAT3 and pSTAT3. The STAT3 pathway is ubiquitous in PTC and activated pSTAT3 is significantly upregulated in PTC tumors with metastatic disease. This study is the first to suggest a potential role for activated pSTAT3 in lymphatic metastases in thyroid cancer.

Background: While the increased risk to parathyroid gland preservation has long been recognized during surgery for thyroid cancer, the effect of different benign pathological conditions on parathyroid preservation has not previously been reported. The aim of this study was to examine parathyroid viability in relation to autoimmune thyroid disease. Methods: This is a retrospective cohort study including all patients having an initial total thyroidectomy (TT) performed by this unit during the period 2004–2005. Results: A total of 628 patients underwent TT in the study period. For the Graves' disease cases, 45 (62.5%) required the autotransplantation of one or less parathyroid gland, whereas 27 (37.5%) required two or more glands to be autotransplanted. This was significantly higher than for the benign thyroid disease group in which the respective figures were 242 (77.6%) and 70 (22.4%) (P= 0.01). Of the lymphocytic thyroiditis cases, 61 (65.5%) required the autotransplantation of one or less gland, whereas 32 (34.4%) required the autotransplantation of two or more glands. This was also significantly higher (P= 0.03). Temporary hypocalcaemia was significantly higher when two or more glands were autotransplanted (23 out of 177, 13.2%) than one or less gland autotransplanted (18 out of 451, 4.0%, P < 0.01). However, the overall incidence of permanent hypoparathyroidism was 1.0%, and there was no significant difference between the groups. Conclusion: TT performed for Graves' disease and lymphocytic thyroiditis results in the autotransplantation of more parathyroid glands, leading to a higher incidence of temporary hypocalcaemia post-operatively. Despite this, the incidence of permanent hypoparathyroidism remains low at 1%.