Regional variations in management of rectal cancer in France

BACKGROUND: Population-based registries provide excellent data for drawing an accurate picture of disease management practices. The purpose of this study was to determine whether diagnostic and therapeutic management practices for rectal cancer vary in different geographic regions of France. METHODS: Data Issued from nine cancer registries covering 11% of the French population. The files of 683 patients with a rectal cancer diagnosed in 1995 were selected for analysis. RESULTS: Colonoscopy was performed in a mean of 91.6% of patients (range: 80.9%-98.2%) (P=0.01). The practice of colonoscopy concomitantly with barium enema varied greatly, ranging from 1.9%-57.7% of patients (P<0.001). Pretherapeutic work-up practices were significantly different depending on the region with respect to: abdominal CT scans (13.4%-69.2%), thoracic CT scans (0.9%-13.2%) and tumor markers (46.8%-80.8%). There were no significant differences between geographic regions concerning rate of resection, use of colostomy, or tumor stage at diagnosis. Administration of adjuvant radiotherapy (mean, 46.8%; range: 21.6%-70%; P<0.001) and adjuvant chemotherapy (mean, 24.1%; range: 10.3%-40.6%; P<0.05) varied significantly between regions. CONCLUSION: Diagnostic practices and administration of adjuvant treatments vary significantly between geographic regions in France. The recommendations of the French consensus guidelines are only partially adhered to. Practitioners and healthcare Authorities should be aware of these differences in order to provide more harmonious patient care.     

Paradoxic inhibition of human natural interferon-producing cells by the activating receptor NKp44

Natural killer (NK) cell-mediated cytotoxicity is triggered by multiple activating receptors associated with the signaling adaptor protein DNAX activation protein 12/killer cell-activating receptor-associated protein (DAP12/KARAP). Here, we show that one of these receptors, NKp44, is present on a subset of natural interferon-producing cells (IPCs) in tonsils. NKp44 expression can also be induced on blood IPCs after in vitro culture with interleukin 3 (IL-3). Crosslinking of NKp44 does not trigger IPC-mediated cytotoxicity but, paradoxically, inhibits interferon alpha (IFN-alpha) production by IPCs in response to cytosine-phosphate-guanosine (CpG) oligonucleotides. We find that IPCs in tonsils are in close contact with CD8+ T cells and demonstrate that a subset of memory CD8+ T cells produces IL-3. Therefore, IL-3-mediated induction of NKp44 on IPCs may be an important component of the ongoing crosstalk between the innate and adaptive immune response that allows memory CD8+ T cells to control the IPC response to virus.     

Triggering receptor expressed on myeloid cells: role in the diagnosis of lung infections.

The triggering receptor expressed on myeloid cells (TREM)-1 is a recently described molecule, which plays an important role in myeloid cell-activated inflammatory responses. TREM-1 is expressed on blood neutrophils and monocytes, and also on alveolar macrophages, thus suggesting a potential role in lung inflammatory responses against infections. To investigate the differential expression of TREM-1 in lung infections, its levels were assessed in bronchoalveolar lavage specimens from patients with community-acquired pneumonia or tuberculosis. TREM-1 was also investigated in patients with interstitial lung diseases, as a model of noninfectious inflammatory disease of the lung. TREM-1 expression was significantly increased in lung neutrophils and in lung macrophages of patients with pneumonia (n=7; 387.9+/-61.4 and 660.5+/-18.3, respectively) compared with patients with pulmonary tuberculosis (n=7; 59.2+/-13.1 and 80.6+/-291.2) and patients with interstitial lung diseases (n=10; 91.8+/-23.3 and 123.9+/-22.8). In contrast, TREM-1 expression on peripheral blood neutrophils was no different among the three groups. In conclusion, these data suggest that triggering receptor expressed on myeloid cells-1 is selectively expressed in the lungs of patients with pneumonia caused by extracellular bacteria and not in patients with tuberculosis, providing a potential marker for differential diagnosis.     

Porins from Salmonella typhimurium accelerate human blood coagulation in vitro by selective stimulation of thrombin activity: implications in septic shock DIC pathogenesis

The effect of porins, major hydrophobic outer membrane proteins purified from Salmonella typhimurium, on human blood coagulation was investigated. It was found that micromolar concentrations of porins accelerated markedly human blood coagulation in vitro. Using appropriate experiments, data were obtained showing that the main target of the porin-induced procoagulant effect was thrombin. A possible binding of porins with thrombin has been suggested to be the basis of this effect. The implications of this finding in the pathogenesis of the disseminated intravascular coagulation syndrome (DIC) occurring during the Gram-negative septic shock is discussed.     

Effectiveness of the treatment of arterial hypertension in a specialized service. An audit using the automatic measurement of arterial blood pressure

The ineluctable fade out of mercury sphingomanometer pressure device involve the necessity in using automatic blood pressure systems. In parallel the recent PHARE II study witness of a lack in the control of hypertension in general practice. In the basis of an automatic blood pressure device measure, we had try to know the efficiency of blood pressure contr?l (BPC) in a specialised consultation. METHOD: 100 patients with essential systolo-diastolic hypertension (HTA) were screened. An independent physician measured the blood pressure level with an OMRON 705 CP device 3 times. The acceptable BPC was considered less than 160/95 mmHg and the optimal BPC less than 140/90 mmHg. There was 70 man, 30 female (mean age = 67 year old). The initial mean blood pressure was 169/104 mmHg. RESULTS: The final blood pressure measured was 137/80 mmHg. The percentage of patients who have an acceptable contr?l (< 160/95) was 91% and an optimal contr?l (< 140/90) 66%. 12% of these 66 maintain a height cardio-vascular risk. The mean number of medication used was 2 and it's paradoxally not differ between the optimal blood pressure control group and the other patients who need probably an intensive medication. In conclusion these study shows us the importance in understanding our patients particularity in order to increase the treatment efficiency.     

HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells.

Natural killer (NK) cells recognize alloantigens on normal cells. One of these alloantigens correlates with homozygosity for a dimorphism of HLA-C at positions 77-80, which is shared by a number of HLA-C alleles. A second allelic alloantigen correlates with homozygosity for the alternative HLA-C dimorphism, which is shared by the remaining HLA-C alleles. Moreover, NK1- and NK2-specific NK cell lines can be generated by mixed leukocyte cultures in which donor and stimulator are homozygous for the alternative dimorphisms at positions 77-80 of HLA-C. In the present work, the role of HLA-C in NK cell-mediated allorecognition was directly investigated by analyzing the effects produced by transfection of several HLA-C alleles on NK sensitivity of class I-deleted mutant cell lines. Transfection of cells with HLA-C alleles encoding Asn-77-Lys-80 (including HLA-Cw4, -Cw5, and -Cw6) inhibited the lysis of the targets by NK1-specific NK cells, whereas HLA-C alleles encoding Ser-77-Asn-80 (including HLA-Cw1, -Cw7, and -Cw13) protected the targets from NK2-specific NK cells. Thus, HLA-C alleles are the dominant inhibitory ligands that protect targets from lysis by these allospecific NK cells.     

CRTAM controls residency of gut CD4+CD8+ T cells in the steady state and maintenance of gut CD4+ Th17 during parasitic infection

Retention of lymphocytes in the intestinal mucosa requires specialized chemokine receptors and adhesion molecules. We find that both CD4⁺CD8⁺ and CD4⁺ T cells in the intestinal epithelium, as well as CD8⁺ T cells in the intestinal mucosa and mesenteric lymph nodes, express the cell adhesion molecule class I–restricted T cell–associated molecule (Crtam) upon activation, whereas the ligand of Crtam, cell adhesion molecule 1 (Cadm1), is expressed on gut CD103⁺DCs. Lack of Crtam–Cadm1 interactions in Crtam^−/− and Cadm1^−/− mice results in loss of CD4⁺CD8⁺ T cells, which arise from mucosal CD4⁺ T cells that acquire a CD8 lineage expression profile. After acute oral infection with Toxoplasma gondii, both WT and Crtam^−/− mice mounted a robust TH1 response, but markedly fewer TH17 cells were present in the intestinal mucosa of Crtam^−/− mice. The almost exclusive TH1 response in Crtam^−/− mice resulted in more efficient control of intestinal T. gondii infection. Thus, Crtam–Cadm1 interactions have a major impact on the residency and maintenance of CD4⁺CD8⁺ T cells in the gut mucosa in the steady state. During pathogenic infection, Crtam–Cadm1 interactions regulate the dynamic equilibrium between newly formed CD4⁺ T cells and their retention in the gut, thereby shaping representation of disparate CD4⁺ T cell subsets and the overall quality of the CD4⁺ T cell response.Class I–restricted T cell–associated molecule (Crtam) is an Ig-like cell surface protein that was originally found on activated NKT cells (Kennedy et al., 2000), NK cells, and CD8⁺ T cells (Arase et al., 2005; Boles et al., 2005; Galibert et al., 2005) and shown to bind the cell adhesion molecule 1 (Cadm1, also known as Nectin like [Necl] 2; Arase et al., 2005; Boles et al., 2005; Galibert et al., 2005). Cadm1 is a cell surface molecule of the nectin and Necl families that is expressed on CD8α DCs (Galibert et al., 2005; Poulin et al., 2010), epithelial cells, neurons, and tumor cells (Sakisaka and Takai, 2004; Mizutani et al., 2011). Crtam–Cadm1 interactions strengthen NK cell and CD8⁺ T cell effector functions (Arase et al., 2005; Boles et al., 2005; Galibert et al., 2005; Murakami, 2005) and promote the retention of virus-specific CD8⁺ T cells within LNs (Takeuchi et al., 2009). One report proposed that Crtam is essential for the establishment of CD4⁺ T cell polarization after TCR engagement, a process which blocks CD4⁺ T cell division and induces the capacity to secrete IFN-γ, IL-17, and IL-22 (Yeh et al., 2008).The immune system associated with the gastrointestinal mucosa comprises large numbers of dispersed lymphoid cells that reside in the epithelium and the underlying lamina propria. Intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) include antigen-experienced CD8⁺ and CD4⁺ T cells, γδ T cells, various subsets of innate lymphoid cells (ILCs), and IgA-secreting plasma cells (Jabri and Ebert, 2007; Cerutti, 2008; Cheroutre et al., 2011; Sheridan and Lefrançois, 2011; Spits et al., 2013). Homing and residency of IELs and LPLs in the mucosa requires specialized chemokine receptors, such as CCR9, CCR6, and CXCR6, which detect chemokines released by gut epithelial cells (CCL25, CCL20, and CXCL16, respectively; Johansson-Lindbom and Agace, 2007). Integrins, like CD103 (α_E) and α₄β₇, also play an essential role in promoting homing and retention of IELs and LPLs in the mucosa by binding E-cadherin and MAdCAM-1 on epithelial cells and vascular endothelial cells, respectively (Johansson-Lindbom and Agace, 2007).T cell acquisition of homing and adhesion molecules is induced by T cell interaction with DCs (Mora et al., 2008; Villablanca et al., 2011). Among the disparate subsets of DC in the intestinal lamina propria and mesenteric LNs (mLN), the CD103⁺ DC subset produces retinoic acid (RA), which induces the gut homing receptors CCR9 and α₄β₇ on lymphocytes (Coombes et al., 2007; Mora et al., 2008; Villablanca et al., 2011). Gut-associated CD103⁺ DCs also produce TGF-β, which induces the expression of CD103 on T cells (Coombes et al., 2007; Mora et al., 2008; Villablanca et al., 2011). In addition to imprinting gut-homing capacity on T cells, gut CD103⁺ DCs control the differentiation of CD4⁺ T cells by priming regulatory CD4⁺ T cells during the steady state (Mucida et al., 2007) and TH1 and TH17 cells during inflammation (DePaolo et al., 2011; Hall et al., 2011).Here, we investigated the impact of Crtam–Cadm1 interaction in the intestinal immune system. We find that Crtam is expressed upon activation on all CD8⁺ T cells of the intestinal mucosa and mLN, intraepithelial CD4⁺ T cells, and intraepithelial CD4⁺CD8⁺ T cells, whereas Cadm1 is expressed on gut CD103⁺ DCs. Crtam–Cadm1 interactions have a major impact on the maintenance of intraepithelial CD4⁺CD8⁺ T cells and a limited influence on the presence of mucosal CD4⁺ and CD8⁺ T cells. Crtam^−/− and Cadm1^−/− mice almost completely lacked CD4⁺CD8⁺ T cells in the intestinal epithelium under steady-state conditions and had fewer CD4⁺ and CD8⁺ T cells in the intestinal mucosa than WT mice. CD4⁺CD8⁺ T cells arise from CD4⁺ T cells that acquire a CD8 T cell lineage gene expression profile upon reaching the intestinal mucosa (Mucida et al., 2013; Reis et al., 2013). Therefore, we further investigated the role of Crtam–Cadm1 interactions in governing CD4⁺ T cell homing and maintenance in the intestinal mucosa, and found that Crtam^−/− CD4⁺ T cells reconstituted the intestinal CD4⁺ T cell and CD4⁺CD8⁺ T cell subsets less effectively than did WT CD4⁺ T cells after transfer into Rag1^−/− mice. Moreover, fewer intestinal CD4⁺ T cells in Crtam^−/− mice expressed gut homing, adhesion, and retention molecules typical of their counterparts in WT mice (including CCR9, CD103, and CD69), and hence adhered less firmly to the intestinal mucosa.Crtam deficiency did not affect the intrinsic capacity of naive CD4⁺ T cells to differentiate into IFN-γ– or IL-17–producing CD4⁺ T cells in vitro. After acute oral infection with Toxoplasma gondii, both WT and Crtam^−/− mice mounted a robust TH1 response and cleared the intestinal infection. However, a preferential reduction of TH17 cells was evident within the intestinal mucosa CD4⁺ T cells in the Crtam^−/− mice. The almost exclusive TH1 response in Crtam^−/− mice resulted in more efficient clearance of intestinal infection. Antibody blockade of IL-17 in WT mice orally infected with T. gondii recapitulated the enhanced host response of Crtam^−/− mice. Thus, the defects in T cell gut homing and maintenance in Crtam^−/− mice preferentially affected TH17, whereas TH1 were relatively unaffected. Because the differentiation of CD4⁺CD8⁺ T cells from CD4⁺ T cells skews CD4⁺ T cell cytokine production toward IFN-γ at the expenses of IL-17 production (Mucida et al., 2013; Reis et al., 2013), the need for continuous replacement of lost CD4⁺CD8⁺ T cells in Crtam^−/− mice may result in a relative depletion of TH17 cells. Together, these results demonstrate that Crtam–Cadm1 interactions have a major impact on the residency and maintenance of CD4⁺CD8⁺ T cells in the gut mucosa in the steady-state. During mucosal responses against pathogenic infection, Crtam–Cadm1 interactions may be required to retain a balanced representation of disparate CD4⁺ T cell subsets, thereby influencing the overall quality of the CD4⁺ T cell response.