Tumor-reactive, SSX-2-specific CD8+ T cells are selectively expanded during immune responses to antigen-expressing tumors in melanoma patients.

The SSX-2 gene encodes a tumor-specific antigen expressed in neoplasms of various histological types. By analyzing a tumor-infiltrated lymph node of a melanoma patient bearing an SSX-2-expressing tumor, we have recently identified the first SSX-2-derived CD8(+) T-cell epitope, that corresponds to peptide SSX-2(41-49), and is recognized by specific CTL in an HLA-A2 restricted fashion. Here, we have used fluorescent HLA-A2/SSX-2(41-49) peptide multimeric complexes to analyze the response to SSX-2(41-49) in melanoma patients and healthy donors. Multimer(+) CD8(+) T cells were readily detected in the majority of patients bearing SSX-2-expressing tumors and, at lower proportions, in patients with nonexpressing tumors and healthy donors. Importantly, isolated A2/SSX-2(41-49) multimer(+) CD8(+) T cells exhibited a large functional heterogeneity in terms of antigen recognition and tumor reactivity. SSX-2-specific CTLs isolated from tumor-infiltrated lymph node of antigen-expressing patients as well as from the corresponding peripheral blood mononuclear cells exhibited high functional avidity of antigen recognition and efficiently recognized antigen-expressing tumors. In contrast, SSX-2-specific CTLs isolated from patients with undetectable responses in the tumor-infiltrated lymph node, as well as from healthy donors, recognized the antigen with decreased functional avidity and were not tumor reactive. Together, these data indicate that CD8(+) T-cell responses to SSX-2(41-49) frequently occur in SSX-2-expressing melanoma patients and suggest that SSX-2(41-49)-specific CTLs of high avidity and tumor reactivity are selectively expanded during immune responses to SSX-2-expressing tumors in vivo.

Congenital tumors: imaging when life just begins.

BACKGROUND: The technical developments of imaging methods over the last 2 decades are changing our knowledge of perinatal oncology. Fetal ultrasound is usually the first imaging method used and thus constitutes the reference prenatal study, but MRI seems to be an excellent complementary method for evaluating the fetus. The widespread use of both techniques has increased the diagnosis rates of congenital tumors. During pregnancy and after birth, an accurate knowledge of the possibilities and limits of the different imaging techniques available would improve the information obtainable, thus helping the medical team to make the most appropriate decisions about therapy and to inform the family about the prognosis. CONCLUSION: In this review article, we describe the main congenital neoplasms, their prognosis and their imaging characteristics with the different pre- and postnatal imaging methods available.

Immunonutrition in gastrointestinal surgery.

Background: Patients undergoing major gastrointestinal surgery are at increased risk of developing complications. The use of immunonutrition (IN) in such patients is not widespread because the available data are heterogeneous, and some show contradictory results with regard to complications, mortality and length of hospital stay. Methods: Randomized controlled trials (RCTs) published between January 1985 and September 2009 that assessed the clinical impact of perioperative enteral IN in major gastrointestinal elective surgery were included in a meta-analysis. Results: Twenty-one RCTs enrolling a total of 2730 patients were included in the meta-analysis. Twelve were considered as high-quality studies. The included studies showed significant heterogeneity with respect to patients, control groups, timing and duration of IN, which limited group analysis. IN significantly reduced overall complications when used before surgery (odds ratio (OR) 0.48, 95 per cent confidence interval (c.i.) 0.34 to 0.69), both before and after operation (OR 0.39, 0.28 to 0.54) or after surgery (OR 0.46, 0.25 to 0.84). For these three timings of IN administration, ORs of postoperative infection were 0.36 (0.24 to 0.56), 0.41 (0.28 to 0.58) and 0.53 (0.40 to 0.71) respectively. Use of IN led to a shorter hospital stay: mean difference -2.12 (95 per cent c.i. -2.97 to -1.26) days. Beneficial effects of IN were confirmed when low-quality trials were excluded. Perioperative IN had no influence on mortality (OR 0.90, 0.46 to 1.76). Conclusion: Perioperative enteral IN decreases morbidity and hospital stay but not mortality after major gastrointestinal surgery; its routine use can be recommended.

MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951.

PURPOSE: O6-methylguanine-methyltransferase (MGMT) promoter methylation has been shown to predict survival of patients with glioblastomas if temozolomide is added to radiotherapy (RT). It is unknown if MGMT promoter methylation is also predictive to outcome to RT followed by adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in patients with anaplastic oligodendroglial tumors (AOT). PATIENTS AND METHODS: In the European Organisation for the Research and Treatment of Cancer study 26951, 368 patients with AOT were randomly assigned to either RT alone or to RT followed by adjuvant PCV. From 165 patients of this study, formalin-fixed, paraffin-embedded tumor tissue was available for MGMT promoter methylation analysis. This was investigated with methylation specific multiplex ligation-dependent probe amplification. RESULTS: In 152 cases, an MGMT result was obtained, in 121 (80%) cases MGMT promoter methylation was observed. Methylation strongly correlated with combined loss of chromosome 1p and 19q loss (P = .00043). In multivariate analysis, MGMT promoter methylation, 1p/19q codeletion, tumor necrosis, and extent of resection were independent prognostic factors. The prognostic significance of MGMT promoter methylation was equally strong in the RT arm and the RT/PCV arm for both progression-free survival and overall survival. In tumors diagnosed at central pathology review as glioblastoma, no prognostic effect of MGMT promoter methylation was observed. CONCLUSION: In this study, on patients with AOT MGMT promoter methylation was of prognostic significance and did not have predictive significance for outcome to adjuvant PCV chemotherapy. The biologic effect of MGMT promoter methylation or pathogenetic features associated with MGMT promoter methylation may be different for AOT compared with glioblastoma.

Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study.

BACKGROUND: The quality of colon cleansing is a major determinant of quality of colonoscopy. To our knowledge, the impact of bowel preparation on the quality of colonoscopy has not been assessed prospectively in a large multicenter study. Therefore, this study assessed the factors that determine colon-cleansing quality and the impact of cleansing quality on the technical performance and diagnostic yield of colonoscopy. METHODS: Twenty-one centers from 11 countries participated in this prospective observational study. Colon-cleansing quality was assessed on a 5-point scale and was categorized on 3 levels. The clinical indication for colonoscopy, diagnoses, and technical parameters related to colonoscopy were recorded. RESULTS: A total of 5832 patients were included in the study (48.7% men, mean age 57.6 [15.9] years). Cleansing quality was lower in elderly patients and in patients in the hospital. Procedures in poorly prepared patients were longer, more difficult, and more often incomplete. The detection of polyps of any size depended on cleansing quality: odds ratio (OR) 1.73: 95% confidence interval (CI)[1.28, 2.36] for intermediate-quality compared with low-quality preparation; and OR 1.46: 95% CI[1.11, 1.93] for high-quality compared with low-quality preparation. For polyps >10 mm in size, corresponding ORs were 1.0 for low-quality cleansing, OR 1.83: 95% CI[1.11, 3.05] for intermediate-quality cleansing, and OR 1.72: 95% CI[1.11, 2.67] for high-quality cleansing. Cancers were not detected less frequently in the case of poor preparation. CONCLUSIONS: Cleansing quality critically determines quality, difficulty, speed, and completeness of colonoscopy, and is lower in hospitalized patients and patients with higher levels of comorbid conditions. The proportion of patients who undergo polypectomy increases with higher cleansing quality, whereas colon cancer detection does not seem to critically depend on the quality of bowel preparation.

Modulation of angiogenic and inflammatory response in glioblastoma by hypoxia.

Glioblastoma are rapidly proliferating brain tumors in which hypoxia is readily recognizable, as indicated by focal or extensive necrosis and vascular proliferation, two independent diagnostic criteria for glioblastoma. Gene expression profiling of glioblastoma revealed a gene expression signature associated with hypoxia-regulated genes. The correlated gene set emerging from unsupervised analysis comprised known hypoxia-inducible genes involved in angiogenesis and inflammation such as VEGF and BIRC3, respectively. The relationship between hypoxia-modulated angiogenic genes and inflammatory genes was associated with outcome in our cohort of glioblastoma patients treated within prospective clinical trials of combined chemoradiotherapy. The hypoxia regulation of several new genes comprised in this cluster including ZNF395, TNFAIP3, and TREM1 was experimentally confirmed in glioma cell lines and primary monocytes exposed to hypoxia in vitro. Interestingly, the cluster seems to characterize differential response of tumor cells, stromal cells and the macrophage/microglia compartment to hypoxic conditions. Most genes classically associated with the inflammatory compartment are part of the NF-kappaB signaling pathway including TNFAIP3 and BIRC3 that have been shown to be involved in resistance to chemotherapy.Our results associate hypoxia-driven tumor response with inflammation in glioblastoma, hence underlining the importance of tumor-host interaction involving the inflammatory compartment.

Transcription factors link mouse WAP-T mammary tumors with human breast cancer.

Mouse models are important tools to decipher the molecular mechanisms of mammary carcinogenesis and to mimic the respective human disease. Despite sharing common phenotypic and genetic features, the proper translation of murine models to human breast cancer remains a challenging task. In a previous study we showed that in the SV40 transgenic WAP-T mice an active Met-pathway and epithelial-mesenchymal characteristics distinguish low- and high-grade mammary carcinoma. To assign these murine tumors to corresponding human tumors we here incorporated the analysis of expression of transcription factor (TF) coding genes and show that thereby a more accurate interspecies translation can be achieved. We describe a novel cross-species translation procedure and demonstrate that expression of unsupervised selected TFs, such as ELF5, HOXA5 and TFCP2L1, can clearly distinguish between the human molecular breast cancer subtypes-or as, for example, expression of TFAP2B between yet unclassified subgroups. By integrating different levels of information like histology, gene set enrichment, expression of differentiation markers and TFs we conclude that tumors in WAP-T mice exhibit similarities to both, human basal-like and non-basal-like subtypes. We furthermore suggest that the low- and high-grade WAP-T tumor phenotypes might arise from distinct cells of tumor origin. Our results underscore the importance of TFs as common cross-species denominators in the regulatory networks underlying mammary carcinogenesis.

Pial and arachnoid welding for restoration of normal cord anatomy after excision of intramedullary spinal cord tumors.

A significant postoperative problem in patients undergoing excision of intramedullary tumors is painful dysesthesiae, attributed to various causes, including edema, arachnoid scarring and cord tethering. The authors describe a technique of welding the pia and arachnoid after the excision of intramedullary spinal cord tumors used in seven cases. Using a fine bipolar forcep and a low current, the pial edges of the myelotomy were brought together and welded under saline irrigation. A similar method was used for closing the arachnoid while the dura was closed with a running 5-0 vicryl suture. Closing the pia and arachnoid restores normal cord anatomy after tumor excision and may reduce the incidence of postoperative painful dysesthesiae.

Levetiracetam and pregabalin for antiepileptic monotherapy in patients with primary brain tumors. A phase II randomized study.

BACKGROUND: In patients with brain tumors, the choice of antiepileptic medication is guided by tolerability and pharmacokinetic interactions. This study investigated the effectiveness of levetiracetam (LEV) and pregabalin (PGB), 2 non-enzyme-inducing agents, in this setting. METHODS: In this pragmatic, randomized, unblinded phase II trial (NCT00629889), patients with primary brain tumors and epilepsy were titrated to a monotherapy of LEV or PGB. Efficacy and tolerability were assessed using structured questionnaires. The primary composite endpoint was the need to discontinue the study drug, add-on of a further antiepileptic treatment, or occurrence of at least 2 seizures with impaired consciousness during 1 year follow-up. RESULTS: Over 40 months, 25 patients were randomized to LEV, and 27 to PGB. Most were middle-aged men, with a high-grade tumor and at least one generalized convulsion. Mean daily doses were 1125 mg (LEV) and 294 mg (PGB). Retention rates were 59% in the LEV group, and 41% in the PGB group. The composite endpoint was reached in 9 LEV and 12 PGB patients-need to discontinue: side effects, 6 LEV, 3 PGB; lack of efficacy, 1 and 2; impaired oral administration, 0 and 2; add-on of another agent: 1 LEV, 4 PGB; and seizures impairing consciousness: 1 in each. Seven LEV and 5 PGB subjects died of tumor progression. CONCLUSIONS: This study shows that LEV and PGB represent valuable monotherapy options in this setting, with very good antiepileptic efficacy and an acceptable tolerability profile, and provides important data for the design of a phase III trial.

Traitement chirurgical des tumeurs palpebrales. [Surgical treatment of eyelid tumors]

After reviewing the general principles of eyelid reconstruction, the authors present reconstruction techniques with regard to the location and size of the eyelid defect. When the defect is less than one-quarter of lid length, direct suture is possible. When the defect is larger, reconstruction techniques differ for the upper and lower lid.

Involvement of the CXCR7/CXCR4/CXCL12 Axis in the Malignant Progression of Human Neuroblastoma.

Neuroblastoma (NB) is a typical childhood and heterogeneous neoplasm for which efficient targeted therapies for high-risk tumors are not yet identified. The chemokine CXCL12, and its receptors CXCR4 and CXCR7 have been involved in tumor progression and dissemination. While CXCR4 expression is associated to undifferentiated tumors and poor prognosis, the role of CXCR7, the recently identified second CXCL12 receptor, has not yet been elucidated in NB. In this report, CXCR7 and CXCL12 expressions were evaluated using a tissue micro-array including 156 primary and 56 metastatic NB tissues. CXCL12 was found to be highly associated to NB vascular and stromal structures. In contrast to CXCR4, CXCR7 expression was low in undifferentiated tumors, while its expression was stronger in matured tissues and specifically associated to differentiated neural tumor cells. As determined by RT-PCR, CXCR7 expression was mainly detected in N-and S-type NB cell lines, and was slightly induced upon NB cell differentiation in vitro. The relative roles of the two CXCL12 receptors were further assessed by overexpressing CXCR7 or CXCR4 receptor alone, or in combination, in the IGR-NB8 and the SH-SY5Y NB cell lines. In vitro functional analyses indicated that, in response to their common ligand, both receptors induced activation of ERK1/2 cascade, but not Akt pathway. CXCR7 strongly reduced in vitro growth, in contrast to CXCR4, and impaired CXCR4/CXCL12-mediated chemotaxis. Subcutaneous implantation of CXCR7-expressing NB cells showed that CXCR7 also significantly reduced in vivo growth. Moreover, CXCR7 affected CXCR4-mediated orthotopic growth in a CXCL12-producing environment. In such model, CXCR7, in association with CXCR4, did not induce NB cell metastatic dissemination. In conclusion, the CXCR7 and CXCR4 receptors revealed specific expression patterns and distinct functional roles in NB. Our data suggest that CXCR7 elicits anti-tumorigenic functions, and may act as a regulator of CXCR4/CXCL12-mediated signaling in NB.

Radiolabeled fragments of monoclonal antibodies against carcinoembryonic antigen for localization of human colon carcinoma grafted into nude mice.

Four monoclonal antibodies against carcinoembryonic antigen (CEA) have been selected from 32 hybrids that produce antibodies against this antigen, by the criteria of high affinity for CEA and low cross-reactivity with granulocyte glycoprotein(s). The specificity of tumor localization in vivo of the four MAb, and their F(ab')2 and Fab fragments was compared in nude mice bearing grafts of a serially transplanted, CEA-producing, human colon carcinoma. The distribution of radiolabeled MAb and their fragments after intravenous injection was analyzed by direct measurement of radioactivity in tumor and normal organs, as well as by whole-body scanning and by autoradiography of tumor sections. Paired labeling experiments, in which 131I-labeled antibody or fragments and 125I-labeled control IgG are injected simultaneously, were undertaken to determine the relative tumor uptakes of each labeled protein. The tumor antibody uptake divided by that of control IgG defines the specificity index of localization. Tumor antibody uptakes (as compared with the whole mouse), ranging between 7 and 15, and specificity indices ranging between 3.4 and 6.8, were obtained with the four intact MAb at day 4-5 after injection. With F(ab')2 fragments of the four MAb, at day 3, the tumor antibody uptakes ranged between 12 and 24 and the specificity indices between 5.3 and 8.2. With the Fab fragments prepared from the two most promising MAb, the antibody uptakes reached values of 34 and 82 at day 2-3 and the specificity indices were as high as 12 and 19. The scanning results paralleled those obtained by direct measurement of radioactivity. With intact MAb, tumor grafts of 0.5-1 g gave very contrasted positive scans 3 d after injection. Using MAb fragments, tumors of smaller size were detectable earlier. The best results were obtained with Fab fragments of MAb 35, which gave clear detections of tumors weighing only 0.1 g as early as 48 h after injection. Autoradiographs of tumor sections from mice injected with 125I-labeled MAb demonstrated that the radioactivity was localized in the tumor tissues and not in the stromal connective tissue of mouse origin. The highest radioactivity concentration was localized in areas known to contain CEA such as the pseudolumen of glands and the apical side of carcinoma cells. The penetration of radioactivity in the central part of tumor nodules and the pseudolumen appeared to be increased with the use of MAb fragments.

Overuse of upper gastrointestinal endoscopy in a country with open-access endoscopy: a prospective study in primary care.

BACKGROUND: This prospective observational study was aimed at evaluating the appropriateness of use of upper gastrointestinal endoscopy (UGE) in primary care in a country with open access to and high availability of the procedure. METHODS: Outpatients were consecutively included in two clinical settings: Setting A (20 primary care physicians during 4 weeks) and B (university-based outpatient clinic during 3 weeks). In patients undergoing UGE, appropriateness of referral was judged by explicit Swiss criteria developed by the RAND/UCLA panel method. RESULTS: Patient visits (8135) were assessed. Six hundred eleven patients complained of upper gastrointestinal symptoms. Physicians decided to perform UGE in 63 of these patients. Twenty-five (40%) of the endoscopies were rated appropriate, 7 (11%) equivocal, and 31 (49%) inappropriate. Overuse of UGE occurred in 5.1% (setting A: 4.7%; setting B:6.5%; p = 0.39) of the patients who presented with upper gastrointestinal symptoms. The decision to perform UGE in previously untreated dyspeptic patients was the most common clinical situation resulting in overuse. CONCLUSIONS: Inappropriate use of UGE is high in Switzerland. However, to better reflect primary care decision making, overuse should be related not only to patients referred for a medical test, but also to the number of patients who complain of the symptoms that would be investigated by the procedure.

Cavernomas and brain cysts as treatment-related sequelae in survivors of pediatric brain tumors

Cavernomas after radiotherapy, developing in irradiated children treated for malignant brain tumors, are capillary malformations that are frquently asymptomatic and benign in their evolution. However, in some children this can lead to haemorrhage, which can cause symptoms and need a surgical intervention. Although there is increasing evidence of cavernoma as a possible long term sequelae after radiotherapy, there is still information needed concerning very long follow-up. Different groups studied this problem focusing on incidence and the lag time radiotherapy and the appearance of cavernomas. Results showed that the period can last a long time and the cumulative incidence increases over the years, but the numbers vary between the different publications. More recently researchers tried to compare several predictive factors with the incidence of cavernomas, such as age at radiotherapy, gender, kind of cancer and chemotherapy. No relation has been recorded except a growing incidence when the radiotherapy was started before the age of ten. Reason of the study : The observations reported until now comprised a very heterogenous cohort of patients. No study has ever been made with patients affected only by malignant brain tumors which are typical in a children. As for the studied predictive factors, no publication described the technical aspect of radiotherapy. Objectives: To study a population of pediatric patients children with only malignant brain tumors in order tp calculate the incidence of cavernomas after radiotherapy and their evolution over a longer period compared to so far published researches. To analyse known predictive factors such as age of children at the moment of the radiotherapy, gender, and kind of cancer. To study extensively the role technical aspects of radiotherapy in the occurrence of cavernomas. Methodology: Retrospective study of a group of 62 children irradiated at the CHUV (Lausanne, Switzerland) between 1975 and 2010 due to the following malignant brain cancers: medulloblastoma, ependymoma, PNET. The images of IRM post radiotherapy will be analysed by a neuroradiologist and a radiotherapist will interpret the radiotherapy data. Expected results: We expect to find relations between the incidence of cavernomas post radiotherapy and the predictive factors including different techniques of radiotherapy and consequently to define the best long-term follow up of the children at risk.