Citations

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the role of the nurse in preparation of esophageal resection (ER); the management of patients who develop high‐grade dysplasia after having undergone Nissen fundoplication; the trajectory of care for the patient with esophageal cancer; the influence of the site of tumor in the choice of treatment; the best location for esophagogastrostomy; management of chylous leak after esophagectomy; the optimal approach to manage thoracic esophageal leak after esophagectomy; the choice for operational approach in surgery of cardioesophageal crossing; the advantages of robot esophagectomy; the place of open esophagectomy; the advantages of esophagectomy compared to definitive chemoradiotherapy; the pathologist report in the resected specimen; the best way to manage patients with unsuspected positive microscopic margin after ER; enhanced recovery after surgery for ER: expedited care protocols; and long‐term quality of life in patients following esophagectomy.

Abstract Background An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. Methods Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web‐platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. Results The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001). Conclusions The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.

AbstractBackgroundA globally harmonized protocol (HarP) for manual hippocampal segmentation based on magnetic resonance has been recently developed by a task force from European Alzheimer's Disease Consortium (EADC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Our aim was to produce benchmark labels based on the HarP for manual segmentation.MethodsFive experts of manual hippocampal segmentation underwent specific training on the HarP and segmented 40 right and left hippocampi from 10 ADNI subjects on both 1.5 T and 3 T scans. An independent expert visually checked segmentations for compliance with the HarP. Descriptive measures of agreement between tracers were intraclass correlation coefficients (ICCs) of crude volumes and similarity coefficients of three‐dimensional volumes.ResultsTwo hundred labels have been provided for the 20 magnetic resonance images. Intra‐ and interrater ICCs were >0.94, and mean similarity coefficients were 1.5 T, 0.73 (95% confidence interval [CI], 0.71–0.75); 3 T, 0.75 (95% CI, 0.74–0.76).ConclusionCertified benchmark labels have been produced based on the HarP to be used for tracers' training and qualification.

Abstract Malignant transformation is commonly associated with dysregulated ribosome biogenesis and for more than 100 years, pathologist have utilized the increase in size and number of nucleoli, the site of ribosome biogenesis as a marker for aggressive malignancies. Recently we demonstrated that hyperactivated RNA Polymerase I (Pol I) transcription, a rate limiting step in ribosome biogenesis, can be specifically targeted by the small molecule inhibitor, CX-5461. When evaluated for its anti-proliferative activity against a panel of genetically diverse human cancer cell lines, those derived from p53 wild type haemotological malignancies were the most sensitive (Drygin et al., Cancer Research, 2011). Evaluation of whether Pol I transcription inhibition could serve as therapeutic strategy in vivo revealed that CX-5461 administration significantly prolongs the overall survival of Eμ-Myc lymphoma bearing mice (Bywater et al., Cancer Cell, 2012). This survival advantage was associated with rapid activation of the ribosomal protein (Rp)-MDM2-p53 nucleolar stress response (Deisenroth et al., Oncogene, 2010) and subsequent induction of tumour-specific p53-dependent apoptosis (Bywater et al. Cancer Cell, 2012). New data and future directions: To further explore the therapeutic potential of Pol I transcription inhibition in haemotological cancers that are refractory to standard therapy, we employed mouse models of MLL-driven Acute Myeloid Leukemia (AML) (MLL/AF9 + Nras and MLL/ENL + Nras) (Zuber et al., Genes Dev, 2009) and V*κ-Myc-driven Multiple Myeloma (MM) (Chesi et al. Cancer Cell, 2009). CX-5461 administration significantly increased the overall survival time of AML-bearing mice (MLL/ENL Nras 17 days for vehicle vs 36 days for drug, P&lt;0.0001; MLL/AF9 Nras 15 days for vehicle vs 23 days for drug, P 0.0009))without severe adverse effects. The extended survival of MLL-driven AML bearing mice was associated with acute activation of p53, an aberrant G2/M cell cycle progression and consequently a delay in tumour progression as monitored by bioluminescence-imaging. In contrast to CX-5461, treatment of AML -bearing mice with Cytarabine/Doxorubicin, a regime used as standard-therapy in the clinic failed to induce p53 in MLL-driven AML resulting in a significantly less survival time than for CX-5461. In ongoing experiments with MM-bearing mice, chronic CX-5461 administration robustly reduced the secretion of serum monoclonal Ig, as detected by serum protein electrophoresis (SPEP), and significantly prolonged survival time demonstrating that CX-5461 possess potent anti-tumour activity in this highly refractory MM model. Analysis of the molecular mechanism responsible for the therapeutic benefit of CX-5461 in MM is ongoing but appears to involve both p53 mediated apoptosis and aberrant cell cycle progression. Conclusion: These data demonstrate that hyperactivated Pol I transcription can be successfully targeted through small molecule inhibitors to therapeutically treat models of human AML and MM that are refractory to standard therapy.. Based on these and published results (Bywater et al., Cancer Cell 2012) and a favorable toxicology profile, we have launched a first-in-human clinical trial of this first in class drug, CX-5461 in patients with hematological malignancies. The outcomes of this trial will offer valuable insights as to whether inhibition of ribosome synthesis might offer a new non-genotoxic therapy approach in the fight against cancers, which are highly refractory to standard-therapies. Citation Format: Nadine Hein, Denis Drygin, Sean O'Brien, Carleen Cullinane, Geoff Matthews, Marta Chesi, Leif Bergsagel, Johannes Zuber, Scott Lowe, Ricky Johnstone, Rick Pearson, Grant McArthur, Ross Hannan. Inhibition of RNA Polymerase I transcription by CX-5461 as a therapeutic strategy for the cancer-specific activation of p53 in highly refractory haematological malignancies. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B16.

AbstractGhrelin is a gut hormone processed from the proghrelin peptide acting as the endogenous ligand of the GH secretagogue receptor 1a. The regulatory role of endogenous ghrelin on pulsatile GH secretion and linear growth had to be established. The aim of the present study was to delineate the endogenous actions of preproghrelin on peripheral and central components of the GH axis. Accordingly, the ultradian pattern of GH secretion was measured in young and old preproghrelin-deficient males. Blood samples were collected by tail bleeding every 10 minutes over a period of 6 hours. Analysis of the GH pulsatile pattern by deconvolution showed that GH was secreted in an ultradian manner in all genotypes, with major secretory peaks occurring at about 3-hour intervals. In older mice, the peak number was reduced and secretion was less irregular compared with younger animals. Remarkably, in young Ghrl−/− mice, the amplitude of GH secretory bursts was significantly reduced. In older mice, however, genotype differences were less significant. Changes in GH pulsatility in young Ghrl−/− mice were associated with a tendency for reduced GH pituitary contents and plasma IGF-I concentrations, but with only a minor impact on linear growth. In Ghrl+/− mice, despite reduced Acyl ghrelin to des-acyl ghrelin ratio, GH secretion was not impaired. Ghrelin deficiency was not associated with a reduction in hypothalamic GHRH content or altered response to GHRH stimulation. Therefore, reduction in GHRH production and/or sensitivity do not primarily account for the altered GH pulsatile secretion of young Ghrl−/− mice. Instead, GHRH expression was elevated in young but not old Ghrl−/− mice, suggesting that differential compensatory responses resulting from the absence of endogenous ghrelin is occurring according to age. These results show that endogenous ghrelin is a regulator of GH pulse amplitude in growing mice but does not significantly modulate linear growth.

Abstract Purpose: Recurrence risk assessment to make treatment decisions for early-stage colon cancer patients is a major unmet medical need. The aim of this retrospective multicenter study was to evaluate the clinical utility of guanylyl cyclase C (GCC) mRNA levels in lymph nodes on colon cancer recurrence. Methods: The proportion of lymph nodes with GCC-positive mRNA (LNR) was evaluated in 463 untreated T3N0 patients, blinded to clinical outcomes. One site's (n = 97) tissue grossing method precluded appropriate lymph node assessment resulting in post hoc exclusion. Cox regression models tested the relationship between GCC and the primary endpoint of time to recurrence. Assay methods, primary analyses, and cut points were all prespecified. Results: Final dataset contained 366 patients, 38 (10%) of whom had recurrence. Presence of four or more GCC-positive lymph nodes was significantly associated with risk of recurrence [hazard ratio (HR) = 2.46, 95% confidence interval (CI), 1.07–5.69, P = 0.035], whereas binary GCC LNR risk class (HR = 1.87, 95% CI, 0.99–3.54, P = 0.054) and mismatch repair (MMR) status (HR = 0.77, 95% CI, 0.36–1.62, P = 0.49) were not. In a secondary analysis using a 3-level GCC LNR risk group classification of high (LNR &gt; 0.20), intermediate (0.10 &lt; LNR ≤ 0.20), and low (LNR ≤ 0.10), high-risk patients had a 2.5 times higher recurrence risk compared with low-risk patients (HR = 2.53, 95% CI, 1.24–5.17, P = 0.011). Conclusions: GCC status is a promising prognostic factor independent of traditional histopathology risk factors in a contemporary population of patients with stage IIa colon cancer not treated with adjuvant therapy, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique. Clin Cancer Res; 20(16); 4361–9. ©2014 AACR.