Citations

Consensus abstract Background The management of primary rectal cancer beyond total mesorectal excision planes (PRC-bTME) and recurrent rectal cancer (RRC) is challenging. There is global variation in standards and no guidelines exist. To achieve cure most patients require extended, multivisceral, exenterative surgery, beyond conventional total mesorectal excision planes. The aim of the Beyond TME Group was to achieve consensus on the definitions and principles of management, and to identify areas of research priority. Methods Delphi methodology was used to achieve consensus. The Group consisted of invited experts from surgery, radiology, oncology and pathology. The process included two international dedicated discussion conferences, formal feedback, three rounds of editing and two rounds of anonymized web-based voting. Consensus was achieved with more than 80 per cent agreement; less than 80 per cent agreement indicated low consensus. During conferences held in September 2011 and March 2012, open discussion took place on areas in which there is a low level of consensus. Results The final consensus document included 51 voted statements, making recommendations on ten key areas of PRC-bTME and RRC. Consensus agreement was achieved on the recommendations of 49 statements, with 34 achieving consensus in over 95 per cent. The lowest level of consensus obtained was 76 per cent. There was clear identification of the need for referral to a specialist multidisciplinary team for diagnosis, assessment and further management. Conclusion The consensus process has provided guidance for the management of patients with PRC-bTME or RRC, taking into account global variations in surgical techniques and technology. It has further identified areas of research priority.

Abstract The selective estrogen receptor modulators (SERM) tamoxifen and raloxifene can reduce the occurrence of breast cancer in high-risk women by 50%, but this U.S. Food and Drug Administration-approved prevention therapy is not often used. We attempted to identify genetic factors that contribute to variation in SERM breast cancer prevention, using DNA from the NSABP P-1 and P-2 breast cancer prevention trials. An initial discovery genome-wide association study identified common single-nucleotide polymorphisms (SNP) in or near the ZNF423 and CTSO genes that were associated with breast cancer risk during SERM therapy. We then showed that both ZNF423 and CTSO participated in the estrogen-dependent induction of BRCA1 expression, in both cases with SNP-dependent variation in induction. ZNF423 appeared to be an estrogen-inducible BRCA1 transcription factor. The OR for differences in breast cancer risk during SERM therapy for subjects homozygous for both protective or both risk alleles for ZNF423 and CTSO was 5.71. Significance: This study identified novel, functionally polymorphic genes involved in the estrogen-dependent regulation of BRCA1 expression, as well as a novel mechanism for genetic variation in SERM therapeutic effect. These observations, and definition of their underlying mechanisms, represent steps toward pharmacogenomically individualized SERM breast cancer prevention. Cancer Discov; 3(7); 812–25. ©2013 AACR. See related commentary by Machiela and Chanock, p. 728 This article is highlighted in the In This Issue feature, p. 705

Consensus abstract Background The management of primary rectal cancer beyond total mesorectal excision planes (PRC-bTME) and recurrent rectal cancer (RRC) is challenging. There is global variation in standards and no guidelines exist. To achieve cure most patients require extended, multivisceral, exenterative surgery, beyond conventional total mesorectal excision planes. The aim of the Beyond TME Group was to achieve consensus on the definitions and principles of management, and to identify areas of research priority. Methods Delphi methodology was used to achieve consensus. The Group consisted of invited experts from surgery, radiology, oncology and pathology. The process included two international dedicated discussion conferences, formal feedback, three rounds of editing and two rounds of anonymized web-based voting. Consensus was achieved with more than 80 per cent agreement; less than 80 per cent agreement indicated low consensus. During conferences held in September 2011 and March 2012, open discussion took place on areas in which there is a low level of consensus. Results The final consensus document included 51 voted statements, making recommendations on ten key areas of PRC-bTME and RRC. Consensus agreement was achieved on the recommendations of 49 statements, with 34 achieving consensus in over 95 per cent. The lowest level of consensus obtained was 76 per cent. There was clear identification of the need for referral to a specialist multidisciplinary team for diagnosis, assessment and further management. Conclusion The consensus process has provided guidance for the management of patients with PRC-bTME or RRC, taking into account global variations in surgical techniques and technology. It has further identified areas of research priority.

Heme oxygenase-2 (HO-2), the constitutive isoform of the heme-degrading enzyme heme oxygenase, may serve as an anti-inflammatory vasorelaxant, in part, by generating carbon monoxide. Arteriovenous fistulas (AVFs) are employed as hemodialysis vascular accesses because they provide an accessible, high-blood-flow vascular segment. We examined the role of vascular expression of HO-2 in AVF function. An AVF was created in mice by anastomosing the carotid artery to the jugular vein. HO-2 expression was detected by immunohistochemistry in the intact carotid artery, mainly in endothelial cells and smooth muscle cells; expression of HO-2 protein and mRNA was modestly increased in the artery of the AVF. Creating an AVF in HO-2−/−mice compared with an AVF in HO-2+/+mice led to markedly reduced AVF blood flow and increased numbers of nonfunctioning AVFs. The impairment of AVF function in the setting of HO-2 deficiency could not be ascribed to either preexisting intrinsic abnormalities in endothelium-dependent and endothelium-independent relaxation of the carotid artery in HO-2-deficient mice or to impaired vasorelaxant responses in the intact carotid artery in vivo. HO-1 mRNA was comparably induced in the AVF in HO-2+/+and HO-2−/−mice, whereas the AVF in HO-2−/−mice compared with that in HO-2+/+mice exhibited exaggerated induction of matrix metalloproteinase (MMP)-9 but similar induction of MMP-2. HO-2 deficiency also led to lower AVF blood flow when AVFs were created in uremia, the latter induced by subtotal nephrectomy. We conclude that HO-2 critically contributes to the adequacy of AVF blood flow and function.

Abstract Intraluminal airway pressure and pharyngeal muscle activity are widely recognized as major determinants of the size and collapsibility of the upper airway. In addition, changes in the volume or pressure of tissue surrounding the pharyngeal airway may significantly influence its size. The present study used fast computed tomography (CT) to determine the effects of changes in central venous pressure (CVP) on upper airway size. Ten awake male patients with obstructive sleep apnea (OSA) were studied. Scans were performed at functional residual capacity (FRC) and at the end of a tidal inspiration (VTei) under three conditions of CVP: (1) at baseline (CVP nl) with patients lying supine; (2) at decreased CVP (CVP-) by inflating blood pressure cuffs to 40 mm Hg on both legs; and (3) at increased CVP (CVP+) by elevating both legs to 33 degrees. At FRC, changes in CVP had no significant effect on either mean or minimum cross-sectional area (CSA) of the upper airway. In contrast, an analysis of variance (ANOVA) indicated that alterations in CVP were associated with changes in mean CSA (p = 0.03) and to a lesser extent in minimum CSA (p = 0.07) at VTei. With the legs elevated (CVP+), neither mean nor minimum CSA showed any significant change with tidal breathing. However, after leg-cuff inflation (CVP-), highly significant increases in both mean (163 +/- 22 to 218 +/- 19 mm2, p = 0.001) and minimum (48 +/- 8 to 85 +/- 12 mm2, p = 0.02) CSA were detected. Changes in mean and minimum CSA with tidal breathing at baseline (CVP nl) were intermediate. These results indicate that changes in CVP significantly alter the response of the upper airway to tidal breathing. They further suggest that increases in upper airway size with tidal breathing may be related to reduction in venous blood volume in pharyngeal and neck tissues as the generation of negative intrathoracic pressure during inspiration increases venous return to the chest.

Abstract Fast-CT scanning was used to study the effects of changes in body position on upper airway (UA) size and shape in 11 awake subjects with obstructive sleep apnea (OSA). Six patients with position (P)-dependent OSA were compared with five patients with nonposition (NP)-dependent OSA. Scans were repeated in the prone (PRN), right side (RS), and supine (SUP) body positions at both functional residual capacity and end-inspiratory tidal volume. Significant group, group by position, and borderline group by respiration effects were detected for minimum but not mean UA dimension data. Significant differences between groups were noted in minimum cross-sectional area and minimum lateral distance but not in minimum anteroposterior distance in the RS and SUP positions. Turning from the PRN to the RS or SUP position tended to decrease UA size in the NP group by decreasing the lateral distance, while the opposite effect was found in the P group. The results indicate that changes in body position during wakefulness affect the lateral but not the anteroposterior dimensions of the UA, and the UA behaves differently in patients with NP and P OSA in response to changes in body position.

Abstract The effects of an anti-CD23 monoclonal antibody (B3B4) in CD23-deficient and CD23-overexpressing mice were compared in a murine model of allergic sensitization. After sensitization and challenge with OA, mice developed increased serum levels of OA-specific IgE and IgG1 with airway eosinophilia and AHR when compared with nonsensitized animals. Anti-CD23 treatment was studied under two protocols: 10-d OA aerosol exposure and intraperitoneal sensitization followed by aerosol challenge. In both protocols anti-CD23 significantly reduced IgE and IgG1 levels, abolished eosinophilia, and normalized AHR in BALB/c and wild-type CD23+ / + mice but not in CD23− / − mice. These changes were associated with increases in IFN- γ and decreases in IL-4 production, suggesting that CD23 binding may affect not only IgE production but also the Th1/Th2 imbalance during the development of allergic AHR. Absence of CD23 in gene-deficient mice significantly enhanced OA-specific IgE and IgG1 levels, airway eosinophilia, and AHR when compared with CD23+ / + wild-type littermates after sensitization and airway challenge. Sensitized and challenged CD23 transgenic mice also developed eosinophilic airway inflammation and methacholine hyperresponsiveness. However, the extent of AHR, BAL, and tissue eosinophilia in these animals showed a significant negative correlation with levels of CD23 expression on splenic T and B cells, demonstrating a limiting role of CD23 in the development of allergic AHR. Haczku A, Takeda K, Hamelmann E, Loader J, Joetham A, Redai I, Irvin CG, Lee JJ, Kikutani H, Conrad D, Gelfand EW. CD23 exhibits negative regulatory effects on allergic sensitization and airway hyperresponsiveness.