SAR user guide to the rectal MR synoptic report (primary staging).

Rectal MR is the key diagnostic exam at initial presentation for rectal cancer patients. It is the primary determinant in establishing clinical stage for the patient and greatly impacts the clinical decision-making process. Consequently, structured reporting for MR is critically important to ensure that all required information is provided to the clinical care team. The SAR initial staging reporting template has been constructed to address these important items, including locoregional extent and factors impacting the surgical approach and management of the patient. Potential outputs to each item are defined, requiring the radiologist to commit to a result. This provides essential information to the surgeon or oncologist to make specific treatment deisions for the patient. The SAR Initial Staging MR reporting template has now been officially adopted by the NAPRC (National Accreditation Program for Rectal Cancer) under the American College of Surgery. With the recent revisions to the reporting template, this user guide has been revamped to improve its practicality and support to the radiologist to complete the structured report. Each line item of the report is supplemented with clinical perspectives, images, and illustrations to help the radiologist understand the potential implications for a given finding. Common errors and pitfalls to avoid are highlighted. Ideally, rectal MR interpretation should not occur in a vacuum but in the context of a multi-disciplinary tumor board to ensure that healthcare providers use common terminology and share a solid understanding of the strengths and weaknesses of MR.

Effects of preceding endoscopic mucosal resection on the efficacy and safety of radiofrequency ablation for treatment of Barrett's esophagus: results from the United States Radiofrequency Ablation Registry.

The effects of preceding endoscopic mucosal resection (EMR) on the efficacy and safety of radiofrequency ablation (RFA) for treatment of nodular Barrett's esophagus (BE) is poorly understood. Prior studies have been limited to case series from individual tertiary care centers. We report the results of a large, multicenter registry. We assessed the effects of preceding EMR on the efficacy and safety of RFA for nodular BE with advanced neoplasia (high-grade dysplasia or intramucosal carcinoma) using the US RFA Registry, a nationwide study of BE patients treated with RFA at 148 institutions. Safety outcomes included stricture, gastrointestinal bleeding, and hospitalization. Efficacy outcomes included complete eradication of intestinal metaplasia (CEIM), complete eradication of dysplasia (CED), and number of RFA treatments needed to achieve CEIM. Analyses comparing patients with EMR before RFA to patients undergoing RFA alone were performed with Student's t-test, Chi-square test, logistic regression, and Kaplan-Meier analysis. Four hundred six patients were treated with EMR before RFA for nodular BE, and 857 patients were treated with RFA only for non-nodular BE. The total complication rates were 8.4% in the EMR-before-RFA group and 7.2% in the RFA-only group (P = 0.48). Rates of stricture, bleeding, and hospitalization were not significantly different between patients treated with EMR before RFA and patients treated with RFA alone. CEIM was achieved in 84% of patients treated with EMR before RFA, and 84% of patients treated with RFA only (P = 0.96). CED was achieved in 94% and 92% of patients in EMR-before-RFA and RFA-only group, respectively (P = 0.17). Durability of eradication did not differ between the groups. EMR-before-RFA for nodular BE with advanced neoplasia is effective and safe. The preceding EMR neither diminished the efficacy nor increased complication rate of RFA treatment compared to patients with advanced neoplasia who had RFA with no preceding EMR. Preceding EMR is not associated with poorer outcomes in RFA.

CT colonography at low tube potential: using iterative reconstruction to decrease noise.

AIM: To determine the level of iterative reconstruction required to reduce increased image noise associated with low tube potential computed tomography (CT). MATERIALS AND METHODS: Fifty patients underwent CT colonography with a supine scan at 120 kVp and a prone scan at 100 kVp with other scan parameters unchanged. Both scans were reconstructed with filtered back projection (FBP) and increasing levels of adaptive statistical iterative reconstruction (ASiR) at 30%, 60%, and 90%. Mean noise, soft tissue and tagged fluid attenuation, contrast, and contrast-to-noise ratio (CNR) were collected from reconstructions at both 120 and 100 kVp and compared using a generalised linear mixed model. RESULTS: Decreasing tube potential from 120 to 100 kVp significantly increased image noise by 30-34% and tagged fluid attenuation by 120 HU at all ASiR levels (p<0.0001, all measures). Increasing ASiR from 0% (FBP) to 30%, 60%, and 90% resulted in significant decreases in noise and increases in CNR at both tube potentials (p<0.001, all comparisons). Compared to 120 kVp FBP, ASiR greater than 30% at 100 kVp yielded similar or lower image noise. CONCLUSIONS: Iterative reconstruction adequately compensates for increased image noise associated with low tube potential imaging while improving CNR. An ASiR level of approximately 50% at 100 kVp yields similar noise to 120 kVp without ASiR.

Expression of nerve growth factor, its TrkA receptor, and several neuropeptides in porcine esophagus. Implications for interactions between neural, vascular and epithelial components of the esophagus.

UNLABELLED: This study was aimed to determine the expression and localization of nerve growth factor (NGF) and several neural peptides in porcine esophagus. Transmural esophageal specimens were obtained from euthanized pigs. STUDIES: 1) histologic evaluation, 2) expressions of NGF and its tropomyosin receptor kinase A (TrkA) receptor, calcitonin generelated peptide (CGRP), neuronal nitric oxide synthase (nNOS), and neuronal enolase using immunostaining and quantification of signal distribution and intensity. Immunostaining for NGF, CGRP, nNOS and neuronal specific enolase (NSE) showed their strong and differential expression and localization in the neuronal network. NGF was strongly expressed in the majority of neurons and nerves, distribution of TrkA was complementary; its signal was 1.5-fold weaker P < 0.001 than NGF). Quantitatively the signal intensity was: CGRP > nNOS > NGF > NES > TrkA. In addition to neural structures, nNOS, NGF and TrkA were expressed in keratinocyte progenitor cells of esophageal mucosa and in endothelial cells of blood vessels. We conclude that a strong expression of NGF in majority of esophageal neurons and nerves indicates important, but previously unrecognized regulatory roles in the esophagus; 2) This study showed expression of NGF and some of the neuropeptides in neural elements, keratinocyte progenitor cells and endothelial cells of blood vessels, which indicates local interactions between neural, epithelial and endothelial cells.

MicroRNA-149 targets GIT1 to suppress integrin signaling and breast cancer metastasis.

Metastasis is the predominant cause of death in breast cancer patients. Several lines of evidence have shown that microRNAs (miRs) can have an important role in cancer metastasis. Using isogenic pairs of low and high metastatic lines derived from a human breast cancer line, we have identified miR-149 to be a suppressor of breast cancer cell invasion and metastasis. We also identified GIT1 (G-protein-coupled receptor kinase-interacting protein 1) as a direct target of miR-149. Knockdown of GIT1 reduced migration/invasion and metastasis of highly invasive cells. Re-expression of GIT1 significantly rescued miR-149-mediated inhibition of cell migration/invasion and metastasis. Expression of miR-149 impaired fibronectin-induced focal adhesion formation and reduced phosphorylation of focal adhesion kinase and paxillin, which could be restored by re-expression of GIT1. Inhibition of GIT1 led to enhanced protein degradation of paxillin and α5ß1 integrin via proteasome and lysosome pathways, respectively. Moreover, we found that GIT1 depletion in metastatic breast cancer cells greatly reduced α5ß1-integrin-mediated cell adhesion to fibronectin and collagen. Low level of miR-149 and high level of GIT1 was significantly associated with advanced stages of breast cancer, as well as with lymph node metastasis. We conclude that miR-149 suppresses breast cancer cell migration/invasion and metastasis by targeting GIT1, suggesting potential applications of the miR-149-GIT1 pathway in clinical diagnosis and therapeutics.

Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-κB-mediated antiapoptotic pathway.

Gain of function of membrane receptor was a good strategy exploited by cancer cells to benefit own growth and survival. Overexpression of HER2 has been found to serve as a target for developing trastuzumab to treat 20-25% of breast cancer. However, little or none of the other membrane receptor was found to be useful as a potential target for breast cancer treatment since then. Here, we showed that amplified signaling of interleukin-17 receptor B (IL-17RB) and its ligand IL-17B promoted tumorigenicity in breast cancer cells and impeded acinus formation in immortalized normal mammary epithelial cells. External signal transmitted through IL-17RB activated nuclear factor-κB to upregulate antiapoptotic factor Bcl-2 and induced etoposide resistance. Elevated expression of IL-17RB had a stronger correlation with poor prognosis than HER2 in breast cancer patients. Interestingly, breast cancer patients with high expression of IL-17RB and HER2 had the shortest survival rate. Depletion of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumorigenic activity, suggesting that IL-17RB and HER2 have an independent role in breast carcinogenesis. Furthermore, treatment with antibodies specifically against IL-17RB or IL-17B effectively attenuated tumorigenicity of breast cancer cells. These results suggest that the amplified IL-17RB/IL-17B signaling pathways may serve as a therapeutic target for developing treatment to manage IL-17RB-associated breast cancer.

Molecular imaging of epidermal growth factor-receptor and survivin in vivo in porcine esophageal and gastric mucosae using probe-based confocal laser-induced endomicroscopy: proof of concept.

UNLABELLED: Confocal laser-induced endomicroscopy (CLE) enables in vivo, real time visualization of the subsurface cells and tissue structures in gastrointestinal mucosa at a subcellular resolution of ≈1000x magnification. The aims of this pilot study were to establish a principle of molecular imaging and determine in vivo expression of epidermal growth factor receptor (EGF-R) and survivin in porcine esophageal and gastric mucosa using probe-based CLE (pCLE) and topically applied FITC-labeled antibodies. Studies were performed in anesthetized pigs. During endoscopy FITC-labeled antibodies against EGF-R and survivin were either sprayed onto esophageal and gastric mucosa in preselected areas or administered via submucosal injection. Thirty minutes later pCLE was performed using a through-the-scope probe (GastroFlex UHD, Cellvizio, Mauna Kea Technologies, Paris, France) to determine cellular and tissue localization of EGF-R and survivin. Then the pigs were euthanized and esophageal and gastric walls from the areas sprayed or injected with antibodies were collected for histologic examination under epifluorescence microscopy. RESULTS: CLE enabled visualization of EGF-R and survivin in esophageal and gastric mucosa and this was confirmed by histology. In the esophagus both EGF-R and survivin were localized predominantly to the keratinocyte progenitor cells. In the stomach, EGF-R was localized to progenitor zone cells and some epithelial cells. Localization of survivin was similar, but involved more surface epithelial cells. This study demonstrated feasibility of using CLE and topical administration of FITC labeled antibodies for in vivo localization of EGF-R and survivin in esophageal and gastric mucosa.

In vivo visualization of epidermal growth factor receptor and survivin expression in porcine pancreas using endoscopic ultrasound guided fine needle imaging with confocal laser-induced endomicroscopy.

UNLABELLED: The aims of this pilot study were to establish a principle of molecular imaging of the pancreas and determine in vivo expression of epidermal growth factor receptor (EGF-R) and survivin using a novel endoscopic ultrasound-guided fine needle imaging (EUS-FNI) technique, which incorporates needle based confocal laser-induced endomicroscopy (nCLE) after intrapancreatic injection of FTIC-labeled antibodies. Studies were performed in anesthetized pigs. FITC-labeled specific antibodies against EGF-R and survivin were injected into the tail and neck of the pancreas using a 19 gauge needle introduced under EUS guidance. Thirty minutes later, nCLE was performed using a prototype needle-based confocal laser-induced endomicroscopy probe (Cellvizio AQ-Flex-19, Mauna Kea Technologies, Paris, France) to determine cellular and tissue localization of EGF-R and survivin in the pancreas. Then pigs were euthanized and specimens of pancreas from areas injected with antibodies were obtained for histologic examination under epifluorescence microscope. RESULTS: EUS-guided nCLE enabled visualization of EGF-R and survivin in pancreatic tissue. Expression of EGF-R and survivin in pancreas was confirmed by histology. EGF-R immunoreactivity was localized to majority of duct-lining cells and to the surface and cytoplasm of many acinar cells. Survivin was localized mainly to the acinar cells. This study demonstrated the feasibility of in vivo, real time visualization of EGF-R and survivin in the pancreas by local injection of FITC-labeled antibodies via EUS-guided fine needle injection, followed by EUS-guided needle based confocal laser-induced endomicroscopy.

Endoscopic ultrasound-guided rendezvous for biliary access after failed cannulation.

INTRODUCTION: Selective cannulation fails in approximately 3 % of endoscopic retrograde cholangiography (ERC) procedures. An endoscopic ultrasound-guided rendezvous technique (EUS - RV) may salvage failed cannulation. The aims of the current study were to determine the safety and efficacy of EUS - RV. METHODS: A total of 40 patients underwent salvage EUS - RV. EUS - RV was attempted immediately after failed biliary cannulation. A dilated intra- or extra-hepatic biliary duct (IHBD or EHBD) was punctured from the stomach or the small intestine under EUS guidance followed by cholangiography and antegrade manipulation of the guide wire into the small intestine. Finally, the echoendoscope was exchanged for an appropriate endoscope and biliary cannulation was achieved over or adjacent to the guide wire. RESULT: EUS-RV appears safe and effective and may be considered as a primary salvage technique after failed cannulation. Antegrade manipulation of the guide wire into the small intestine was achieved in 29 of 40 patients (73 %; EHBD 25 /31 and IHBD 4/9). The reasons for failure were inability to advance the guide wire through an obstruction or a native ampulla. Re-attempt at ERC immediately after failed EUS - RV was made in seven of the 11 patients, and was successful in four. The remaining seven patients underwent percutaneous drainage within 3 days. Complications occurred in five patients (13 %), including pancreatitis, abdominal pain, pneumoperitoneum, and sepsis/death, which was unlikely to be related to the procedure. CONCLUSION: EUS - RV is safe and effective and should be considered as a primary salvage technique after failed cannulation. Immediate re-attempt at ERC after failed EUS - RV is warranted, as EUS-guided cholangiogram can facilitate biliary cannulation in some cases. Finally, prompt alternative biliary drainage should be available.

miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1.

MicroRNAs (miRNAs) are involved in tumorigenecity by regulating specific oncogenes and tumor suppressor genes, and their roles in breast cancer stem cells (BCSCs) are becoming apparent. Distinct from the CD44(+)/CD24(-/low) sub-population, we have isolated a novel PROCR(+)/ESA(+) BCSC sub-population. To explore miRNA-regulatory mechanisms in this sub-population, we performed miRNA expression profiling and found miR-495 as the most highly upegulated miRNA in PROCR(+)/ESA(+) cells. Coincidently, high upregulation of miR-495 was also found in CD44(+)/CD24(-/low) BCSCs, reflecting its potential importance in maintaining common BCSC properties. Ectopic expression of miR-495 in breast cancer cells promoted their colony formation in vitro and tumorigenesis in mice. miR-495 directly suppressed E-cadherin expression to promote cell invasion and inhibited REDD1 expression to enhance cell proliferation in hypoxia through post-transcriptional mechanism. miR-495 expression was directly modulated by transcription factor E12/E47, which itself is highly expressed in BCSCs. These findings reveal a novel regulatory pathway centered on miR-495 that contributes to BCSC properties and hypoxia resistance.

Endoscopic radiofrequency ablation for Barrett's esophagus: 5-year outcomes from a prospective multicenter trial.

BACKGROUND AND STUDY AIMS: The AIM-II Trial included patients with nondysplastic Barrett's esophagus (NDBE) treated with radiofrequency ablation (RFA). Complete eradication of NDBE (complete response-intestinal metaplasia [CR-IM]) was achieved in 98.4 % of patients at 2.5 years. We report the proportion of patients demonstrating CR-IM at 5-year follow-up. PATIENTS AND METHODS: Prospective, multicenter US trial (NCT00489268). After endoscopic RFA of NDBE up to 6 cm, patients with CR-IM at 2.5 years were eligible for longer-term follow-up. At 5 years, we obtained four-quadrant biopsies from every 1 cm of the original extent of Barrett's esophagus. All specimens were reviewed by one expert gastrointestinal pathologist, followed by focal RFA and repeat biopsy if NDBE was identified. Primary outcomes were (i) proportion of patients demonstrating CR-IM at 5-year biopsy, and (ii) proportion of patients demonstrating CR-IM at 5-year biopsy or after the single-session focal RFA. RESULTS: Of 60 eligible patients, 50 consented to participate. Of 1473 esophageal specimens obtained at 5 years 85 % contained lamina propria or deeper tissue (per patient, mean 30 , standard deviation [SD] 13). CR-IM was demonstrated in 92 % (46 / 50) of patients, while 8 % (4 / 50) had focal NDBE; focal RFA converted all these to CR-IM. There were no buried glands, dysplasia, strictures, or serious adverse events. Kaplan-Meier CR-IM survival analysis showed probability of maintaining CR-IM for at least 4 years after first durable CR-IM was 0.91 (95 % confidence interval [CI] 0.77 - 0.97) and mean duration of CR-IM was 4.22 years (standard error [SE] 0.12). CONCLUSIONS: In patients with NDBE treated with RFA, CR-IM was demonstrated in the majority of patients (92 %) at 5-year follow-up, biopsy depth was adequate to detect recurrence, and all failures (4 / 4, 100 %) were converted to CR-IM with single-session focal RFA.

Defects responsible for the hole gas in Ge/Si core-shell nanowires.

The origin of the ballistic hole gas recently observed in Ge/Si core-shell nanowires has not been clearly resolved yet, although it is thought to be the result of the band offset at the radial interface. Here we perform spin-polarized density-functional calculations to investigate the defect levels of surface dangling bonds and Au impurities in the Si shell. Without any doping strategy, we find that Si dangling bond and substitutional Au defects behave as charge traps, generating hole carriers in the Ge core, while their defect levels are very deep in one-component Si nanowires. The defect levels lie to within 10 meV from or below the valence band edge for nanowires with diameters larger than 33 A and the Ge fractions above 30%. As carriers are spatially separated from charge traps, scattering is greatly suppressed, leading to the ballistic conduction, in good agreement with experiments.

Cumulative survival in early-onset unilateral and bilateral breast cancer: an analysis of 1907 Taiwanese women.

As the epidemiological pattern of breast cancer in modernising Asian countries differs greatly from that in Western countries, it is worthwhile to investigate the long-term prognoses of unilateral and bilateral breast cancer in these nations. A retrospective cohort study composed of 1907 Taiwanese women was conducted to follow 1863 unilateral and 44 bilateral cases of breast cancer. Time-dependent Cox regression was used to assess the risk of breast cancer death by considering the time course of unilateral and bilateral tumour development. The 15-year survival rates were 68.37, 62.63, and 26.42% for unilateral, synchronous bilateral, and metachronous bilateral breast cancer, respectively. Differences among types were most apparent after 5 years of follow-up. After adjusting for significant prognostic factors, the risk of death for overall bilateral breast cancer was 2.50-fold greater (95% CI, 1.43-4.37) compared to unilateral breast cancer. The corresponding figures were 1.12-fold (95% CI, 0.42-3.02) and 6.11-fold (95% CI, 3.14-11.89) for synchronous and metachronous bilateral breast cancer, respectively. Taiwanese women, who are frequently diagnosed with breast cancer before 50 years of age, showed poorer survival for metachronous bilateral than for synchronous bilateral or unilateral breast cancer. Survival was markedly poorer compared to recent data from Sweden.

Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial-mesenchymal transition.

Metaplastic carcinoma of the breast (MCB) is a poorly understood subtype of breast cancer. It is generally characterized by the coexistence of ductal carcinomatous and transdifferentiated sarcomatous components, but the underlying molecular alterations, possibly related to epithelial-mesenchymal transition (EMT), remain elusive. We performed transcriptional profiling using half-a-genome oligonucleotide microarrays to elucidate genetic profiles of MCBs and their differences to those of ductal carcinoma of breasts (DCBs) using discarded specimens of four MCBs and 34 DCBs. Unsupervised clustering disclosed distinctive expression profiles between MCBs and DCBs. Supervised analysis identified gene signatures discriminating MCBs from DCBs and between MCB subclasses. Notably, many of the discriminator genes were associated with downregulation of epithelial phenotypes and with synthesis, remodeling and adhesion of extracellular matrix, with some of them have known or inferred roles related to EMT. Importantly, several of the discriminator genes were upregulated in a mutant Snail-transfected MCF7 cell known to exhibit features of EMT, thereby indicating a crucial role for EMT in the pathogenesis of MCBs. Finally, the identification of SPARC and vimentin as poor prognostic factors reinforced the role of EMT in cancer progression. These data advance our understanding of MCB and offer clues to the molecular alterations underlying EMT.

Differential expression of glucocorticoid receptor in human breast tissues and related neoplasms.

Glucocorticoid receptor (GR) is a steroid hormone receptor that has been shown to play important roles in mammary development and differentiation, and has been implicated in breast tumourigenesis, but its precise biological significance in mammary pathophysiology remains unclear. In order to generate a comprehensive expression profile for GR in normal versus neoplastic breast tissues, GR expression was investigated in situ in 400 human breast tissue samples, comprising normal tissue and a range of benign, pre-invasive, and invasive lesions, using immunohistochemical assays. The novel expression of GR in myoepithelium, not observed in luminal epithelium, not only demonstrates expression patterns exclusive to the alpha form of oestrogen receptor and progesterone receptor and suggests distinctive functions between GR and these two important steroid hormone receptors in the breast, but may also indicate unique physiological and perhaps pathological roles for the myoepithelium in mediating the effects of glucocorticoid hormones in the breast. The strong expression of GR in metaplastic carcinomas (94.4%) and malignant phyllodes tumours (92.3%) suggests a pathogenetic role for GR, and implies that targeting GR in these tumours may have potential therapeutic application. However, studies on the roles of GR in mammary carcinogenesis should be interpreted with great caution, based on the lack of GR expression in cancer cells in the great majority (98.2%) of non-metaplastic carcinomas, which has gone unnoticed in previous studies. This marked discrepancy warrants a re-examination of the biological roles of GR in the pathophysiology of breast malignancy. The lack of methylation in the promoter region of the GR gene in all 118 non-metaplastic carcinomas, as demonstrated by methylation-specific PCR and bisulphite DNA sequencing analysis, indicates that methylation is less likely to play a role in the reduction of GR expression in non-metaplastic carcinoma of the breast.

Proliferative activity, apoptosis and expression of oestrogen receptor and Bcl-2 oncoprotein in canine mammary gland tumours.

Samples of 39 canine mammary gland tumours (MGTs) were examined immunohistochemically for oestrogen receptor (ER-alpha), Bcl-2 protein and Ki67 antigen, and by TUNEL assay for apoptosis. ER-alpha was expressed by 80% (31/39) of the tumours, including all of the 15 benign tumours and 67% (16/42) of the malignant tumours. ER-alpha expression was greater in the benign than in the malignant tumours (P<0.01). Bcl-2 protein was detected in 62% (24/39) of the MGTs, of which 67% (10/15) were benign and 58% (14/24) malignant. No significant difference in Bcl-2 expression between benign and malignant tumours was detected. The Ki67 and TUNEL indices were greater in malignant than in benign tumours (P<0.01). Correlation analysis suggested that ER-alpha and Bcl-2 expression were related, but this observation lacked statistical significance. The levels of cell proliferation and apoptosis did not appear to be significantly correlated with the expression of Bcl-2. A positive relationship was apparent between cell proliferation and apoptosis, whilst a negative correlation between ER-alpha and cell proliferation was demonstrated. In conclusion, the suggestion of a positive correlation between ER-alpha and Bcl-2 in canine MGTs indicates that ER may be the regulator of Bcl-2 protein, as in human breast cancer. In contrast to cell proliferation and apoptosis, ER-alpha and Bcl-2 expression were greater in benign MGTs than in their malignant counterparts.