Metastatic tumors to the colon and rectum: a multi-institutional study.

Context.-Unlike the small bowel, the colorectal mucosa is seldom the site of metastatic disease. Objective.-To determine the incidence of truly colorectal metastases, and subsequent clinicopathologic findings, in a substantial colorectal cancer population collected from 7 European centers. Design.-During the last decade, 10 365 patients were identified as having colorectal malignant tumors, other than systemic diseases. Data collected included patient demographics, clinical symptoms, treatment, the presence of metastases in other sites, disease-free interval, follow-up, and overall survival. All secondary tumors resulting from direct invasion from malignant tumors of the contiguous organs were excluded, as well as those resulting from lymph node metastases or peritoneal seeding. Results.-Only 35 patients were included (10 men) with a median age of 59 years. They presented with obstruction, bleeding, abdominal pain, or perforation. The leading source of metastases was the breast, followed by melanoma. Metastases were synchronous in 3 cases. The mean disease-free interval for the remaining cases was 6.61 years. Surgical resection was performed in 28 cases. Follow-up was available for 26 patients; all had died, with a mean survival time of 10.67 months (range, 1-41 months). Conclusions.-Colorectal metastases are exceptional (0.338%) with the breast as a leading source of metastases; they still represent a late stage of disease and reflect a poor prognosis. Therefore, the pathologist should be alert for the possibility of secondary tumors when studying large bowel biopsies. Any therapy is usually palliative, but our results suggest that prolonged survival after surgery and complementary therapy can be obtained in some patients.

Gastric outlet obstruction by Brunner's gland hyperplasia in an 8-year-old child.

Several cases of Brunner's gland hyperplasia causing hemorrhage, obstruction, or intussusception have been published in the adult literature. Similar cases in the pediatric population are very rare and have only been described twice, always associated with chronic renal failure. We report the third and youngest case of gastric outlet obstruction because of Brunner's gland hyperplasia focusing on histopathologic condition and treatment based on a review of the literature.

Educational intervention on malignant hyperthermia with nursing professionals of the operating room

OBJECTIVE To evaluate the effectiveness of an educational intervention on malignant hyperthermia with operating room nurses. METHOD A quasi-experimental study, aimed at an educational intervention of short duration with the nursing staff in the operating room of the institution hosting the research in the city of São Paulo, with the participation of 96 professionals. Pre-intervention tests and post-intervention tests were applied, which consisted of a lecture followed by simulation. RESULTS Considering the overall results of the intervention, there was a statistically significant difference (p<0.00). After the educational intervention, there was an increase of the minimum and maximum scores, and average growth of 2.64 points in the knowledge of professionals when compared to the previous step. CONCLUSION The educational intervention strategy favors the concept of the content developed by everyone involved and qualifies professionals to work safely.

Mechanisms of proteasome inhibitor-induced cytotoxicity in malignant glioma.

The 26S proteasome constitutes an essential degradation apparatus involved in the consistent recycling of misfolded and damaged proteins inside cells. The aberrant activation of the proteasome has been widely observed in various types of cancers and implicated in the development and progression of carcinogenesis. In the era of targeted therapies, the clinical use of proteasome inhibitors necessitates a better understanding of the molecular mechanisms of cell death responsible for their cytotoxic action, which are reviewed here in the context of sensitization of malignant gliomas, a tumor type particularly refractory to conventional treatments.

Connexins 43 and 26 are differentially increased after rat bladder outlet obstruction.

To evaluate the regulation of connexin expression by fluid pressure, we have studied the effects of elevated transmural urine pressure on Connexin43 (Cx43) and Cx26. We chose to focus on these two proteins out of the five connexins (Cx26, 43, 40, 37, and 45) which we found by RT-PCR to be expressed in the rat bladder, since in situ hybridization and immunofluorescence showed that Cx43 is the predominant connexin expressed by smooth muscle cells (SMC), whereas Cx26 is abundantly expressed only in the latter cell type. To evaluate whether these connexins are affected by changes in transmural urine pressure, we used a rat model of bladder outlet obstruction, in which a ligature is placed around the urethra. Under conditions of increased fluid pressure due to urine retention, we observed that the expression of both Cx43 and Cx26 increased at both transcript and protein levels, reaching a maximum 7-9 h after the ligature. Further analysis revealed that these changes were accounted for by a fourfold increase in Cx43 mRNA of SMC but not urothelial cell and by a fivefold increase in Cx26 mRNA of urothelium. Scrape-loading of propidium iodide showed that the latter change was paralleled by a twofold increase in coupling between urothelial cells. The data show that Cx43 and Cx26 are differentially regulated during bladder outlet obstruction and contribute to the response of the bladder wall to increased voiding pressure, possibly to control its elasticity.

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile. Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either up-front or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

Epithelial to mesenchymal transition in the pathogenesis of uterine malignant mixed Müllerian tumours: the role of ubiquitin proteasome system and therapeutic opportunities.

Malignant mixed Müllerian tumours (malignant mixed mesodermal tumours, MMMT) of the uterus are metaplastic carcinomas with a sarcomatous component and thus they are also called carcinosarcomas. It has now been accepted that the sarcomatous component is derived from epithelial elements that have undergone metaplasia. The process that produces this metaplasia is epithelial to mesenchymal transition (EMT), which has recently been described as a neoplasia-associated programme shared with embryonic development and enabling neoplastic cells to move and metastasise. The ubiquitin proteasome system (UPS) regulates the turnover and functions of hundreds of cellular proteins. It plays important roles in EMT by being involved in the regulation of several pathways participating in the execution of this metastasis-associated programme. In this review the specifi c role of UPS in EMT of MMMT is discussed and therapeutic opportunities from UPS manipulations are proposed.

Preclinical comparison of mTHPC and verteporfin for intracavitary photodynamic therapy of malignant pleural mesothelioma.

Efficacy and tumour selectivity of photodynamic therapy with two clinically approved sensitizers (mTHPC, verteporfin) were assessed for focal intracavitary photodynamic therapy (PDT) in rodents with malignant pleural mesothelioma (MPM) at recommended drug-light conditions and at escalating sensitizer dosages. MPM tumours were generated in 15 Fischer rats by subpleural mediastinal tumour cell injection followed after 5 days by intracavitary PDT with light delivery monitored by in situ dosimetry. Animals were intravenously sensitized either with mTHPC (0.1 mg/kg, n = 3; 0.2 mg/kg, n = 3) followed after 4 days by illumination with 20 J/cm(2) at 652 nm, or with verteporfin (0.6 mg/kg, n = 3; 1.2 mg/kg, n = 3) followed after 20 min by illumination with 100 J/cm(2) at 689 nm. Three untreated tumour-bearing animals served as controls. Histological evaluation of the treated tumour and of adjacent normal organs was performed 10 days after tumour implantation. The extent of PDT-induced tumour necrosis was compared to the non-necrosed area and expressed in percentage. A locally invasive growing MPM tumour (3.1 +/- 1 mm diameter) without spontaneous necrosis diameter was found in all animals. For both sensitizers, focal intracavitary PDT was well tolerated at drug-light conditions recommended for clinical applications. Mediastinal organs were spared for both sensitizers but verteporfin resulted in a higher extent of tumour necrosis (80%) than mTHPC (50%). Drug dose escalation revealed a higher extent of PDT-related tumour necrosis for both sensitizers (mTHPC 55%, verteporfin 88%), however, verteporfin-PDT was associated with a higher toxicity than mTHPC-PDT.

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.

Expression of common acute lymphoblastic leukemia antigen (CALLA) on human malignant melanoma cell lines.

Fifteen human melanoma cells lines were tested by an antibody-binding radioimmunoassay using a monoclonal antibody (A12) directed against the common acute lymphoblastic leukemia antigen (CALLA). Cells from six melanoma lines were found to react with this antibody. The level of antigen and the percentage of positive cells in these six melanoma lines showed wide variation, as demonstrated by analysis in the fluorescence-activated cell sorter (FACS). Immunoprecipitation of solubilized 125I-labeled membrane proteins from CALLA positive melanoma cells with A12 monoclonal antibody revealed a major polypeptide chain with an apparent m.w. of 100,000 daltons, characteristic for CALLA as determined on SDS-polyacrylamide gel electrophoresis. The expression of CALLA on MP-6 melanoma cells was modulated when the cells were cultured in the presence of A12 antibody. Reexpression of CALLA on these cells occurred within 5 days after transfer of the modulated cells into medium devoid of monoclonal antibody.

Establishment of the epithelial-specific transcriptome of normal and malignant human breast cells based on MPSS and array expression data.

INTRODUCTION: Diverse microarray and sequencing technologies have been widely used to characterise the molecular changes in malignant epithelial cells in breast cancers. Such gene expression studies to identify markers and targets in tumour cells are, however, compromised by the cellular heterogeneity of solid breast tumours and by the lack of appropriate counterparts representing normal breast epithelial cells. METHODS: Malignant neoplastic epithelial cells from primary breast cancers and luminal and myoepithelial cells isolated from normal human breast tissue were isolated by immunomagnetic separation methods. Pools of RNA from highly enriched preparations of these cell types were subjected to expression profiling using massively parallel signature sequencing (MPSS) and four different genome wide microarray platforms. Functional related transcripts of the differential tumour epithelial transcriptome were used for gene set enrichment analysis to identify enrichment of luminal and myoepithelial type genes. Clinical pathological validation of a small number of genes was performed on tissue microarrays. RESULTS: MPSS identified 6,553 differentially expressed genes between the pool of normal luminal cells and that of primary tumours substantially enriched for epithelial cells, of which 98% were represented and 60% were confirmed by microarray profiling. Significant expression level changes between these two samples detected only by microarray technology were shown by 4,149 transcripts, resulting in a combined differential tumour epithelial transcriptome of 8,051 genes. Microarray gene signatures identified a comprehensive list of 907 and 955 transcripts whose expression differed between luminal epithelial cells and myoepithelial cells, respectively. Functional annotation and gene set enrichment analysis highlighted a group of genes related to skeletal development that were associated with the myoepithelial/basal cells and upregulated in the tumour sample. One of the most highly overexpressed genes in this category, that encoding periostin, was analysed immunohistochemically on breast cancer tissue microarrays and its expression in neoplastic cells correlated with poor outcome in a cohort of poor prognosis estrogen receptor-positive tumours. CONCLUSION: Using highly enriched cell populations in combination with multiplatform gene expression profiling studies, a comprehensive analysis of molecular changes between the normal and malignant breast tissue was established. This study provides a basis for the identification of novel and potentially important targets for diagnosis, prognosis and therapy in breast cancer.

Targeting integrins in malignant glioma.

The integrin family of cell adhesion receptors is emerging as a promising target of anticancer therapy. AlphaVbeta3 and alphaVbeta5 integrins are overexpressed on both glioma cells and tumor vasculature. Cilengitide, the most advanced specific integrin inhibitor in oncology, has shown antitumor activity against glioma in early clinical trials. Durable remissions have been observed in phase I and phase II trials for recurrent glioblastoma (GBM) with both lower and higher doses of cilengitide. Pilot trials in newly diagnosed glioblastoma in conjunction with standard chemoradiotherapy have been encouraging. Preclinical data suggest synergy with concomitant chemo- and radiation therapy. A pivotal phase III study (CENTRIC) in newly diagnosed GBM patients is currently recruiting. This paper summarizes the current understanding of the role of integrins and their inhibition in gliomagenesis. The background and design of ongoing trials are outlined.

Dramatic malignant progression of a pigmented villonodular synovitis of the knee after 27 years of multimodality treatment

Introduction: Pigmented villonodular synovitis (PVNS) is a rare benign tumour of the synovium, most commonly arising around the knee. Resection remains the treatment of choice. The diffuse variant of the disease is prone to local recurrence (30-50%). However distant dissemination is extremely rare. We report the case of a patient with massive loco-regional and late distant spread to the lungs of PVNS originating in the knee. Case report: A 69 yo women presented to our service 27 years ago with PVNS in her knee. Despite multible surgical resections, synoviorthesis and external beam radiotherapy, no local control was achieved. The disease spread in all thigh compartments. Due to the resistance to all convetional treatment modalities, isolated limb perfusion with TNFα and Melphalan was performed, without any effect on local control. After the disease was diagnosed in iliac lymph nodes, the patient was subjected to a systemic chemotherapy protocol with imitamib, which had to be abandoned, due to intolerance. Due to a giant lymphoedema of the entire limb, making up for a considerable part of the patient's body weight and in view of significant skin invasion, a hip disarticulation was performed. Finally, rapidly growing lung metastases appeared on CT scan, confirmed by core-needle biopsy. Palliative chemotherapy was initiated. Interestingly, histological analysis of the disease throughout the years remained consistent with classic benign PVNS. No sarcomatous dedifferentiation was observed, not even in the pulmonary lesions. Conclusion: PVNS is a benign tumour, with a high risk of local recurrence. Malignant behaviour, with loco-regional and distant metastases remains extremely rare. A histologically benign appearance does not exclude a clinically malignant behaviour with systemic spread.