Impact of routine preoperative 18 FDG PET/CT on the surgical management of primary colorectal cancer.

OBJECTIVES: Determine the usefulness of [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (18 FDG-PET/CT) in the preoperative setting of colorectal cancer (CRC), assessing its impact on changes in management strategy. METHODS: Retrospective study of CRC patients who underwent preoperative 18 FDG-PET/CT and CT staging scans in a single referral center. The agreement between 18 FDG-PET/CT, contrast-enhanced CT, and colonoscopy for the surgical location was compared using the κ coefficient. Maximum standardized uptake (SUVmax ) value was obtained. Univariate and multivariate analyses were conducted. RESULTS: One hundred ninety-five patients were included. 18 FDG-PET/CT improved tumor localization in 84.6% (165/195) of cases (κ value 0.798, p < 0.001), thus correcting endoscopic errors 69.7% (30/43) of the time. In patients with incomplete colonoscopies, 18 FDG-PET/CT detected synchronous tumors in 2.5% (5/195) patients, overlooked by CT staging scans. Based on extracolonic 18 FDG-uptake, the second primary malignancy was diagnosed in 7(3.6%,7/195) patients and total accuracy for lymph node and distant metastasis was 66.1% and 98.4%, respectively. The treatment plan was altered in 30 (15.4%, 30/196) patients. There was a significant association between the SUVmax and tumor size (odds ratio [OR] 4.254, p = 0.003) and the depth of tumor invasion (OR 1.696, p = 0.026). CONCLUSIONS: Based on its ability to aid in preoperative evaluation and definitively alter surgical treatment planning, 18 FDG-PET/CT should be further evaluated in primary CRC.

Autocrine/Paracrine Slit-Robo Signaling Controls Optic Lobe Development in Drosophila melanogaster.

Cell segregation mechanisms play essential roles during the development of the central nervous system (CNS) to support its organization into distinct compartments. The Slit protein is a secreted signal, classically considered a paracrine repellent for axonal growth through Robo receptors. However, its function in the compartmentalization of CNS is less explored. In this work, we show that Slit and Robo3 are expressed in the same neuronal population of the Drosophila optic lobe, where they are required for the correct compartmentalization of optic lobe neuropils by the action of an autocrine/paracrine mechanism. We characterize the endocytic route followed by the Slit/Robo3 complex and detected genetic interactions with genes involved in endocytosis and actin dynamics. Thus, we report that the Slit-Robo3 pathway regulates the morphogenesis of the optic lobe through an atypical autocrine/paracrine mechanism in addition to its role in axon guidance, and in association with proteins of the endocytic pathway and small GTPases.

Slit/Robo Signaling Regulates Multiple Stages of the Development of the Drosophila Motion Detection System.

Neurogenesis is achieved through a sequence of steps that include specification and differentiation of progenitors into mature neurons. Frequently, precursors migrate to distinct positions before terminal differentiation. The Slit-Robo pathway, formed by the secreted ligand Slit and its membrane bound receptor Robo, was first discovered as a regulator of axonal growth. However, today, it is accepted that this pathway can regulate different cellular processes even outside the nervous system. Since most of the studies performed in the nervous system have been focused on axonal and dendritic growth, it is less clear how versatile is this signaling pathway in the developing nervous system. Here we describe the participation of the Slit-Robo pathway in the development of motion sensitive neurons of the Drosophila visual system. We show that Slit and Robo receptors are expressed in different stages during the neurogenesis of motion sensitive neurons. Furthermore, we find that Slit and Robo regulate multiple aspects of their development including neuronal precursor migration, cell segregation between neural stem cells and daughter cells and formation of their connectivity pattern. Specifically, loss of function of slit or robo receptors in differentiated motion sensitive neurons impairs dendritic targeting, while knocking down robo receptors in migratory progenitors or neural stem cells leads to structural defects in the adult optic lobe neuropil, caused by migration and cell segregation defects during larval development. Thus, our work reveals the co-option of the Slit-Robo signaling pathway in distinct developmental stages of a neural lineage.

Cell segregation and boundary formation during nervous system development.

The development of multicellular organisms involves three main events: differentiation, growth, and morphogenesis. These processes need to be coordinated for a correct developmental program to work. Mechanisms of cell segregation and the formation of boundaries during development play essential roles in this coordination, allowing the generation and maintenance of distinct regions in an organism. These mechanisms are also at work in the nervous system. The process of regionalization involves first the patterning of the developing organism through gradients and the expression of transcription factors in specific regions. Once different tissues have been induced, segregation mechanisms may operate to avoid cell mixing between different compartments. Three mechanisms have been proposed to achieve segregation: (1) differential affinity, which mainly involves the expression of distinct pools of adhesion molecules such as members of the cadherin superfamily; (2) contact inhibition, which is largely mediated by Eph-ephrin signaling; and (3) cortical tension, which involves the actomyosin cytoskeleton. In many instances, these mechanisms collaborate in cell segregation. In the last three decades, there have been several advances in our understanding of how cell segregation and boundaries participate in the development of the nervous system. Interestingly, as in other aspects of development, the molecular players are remarkably similar between vertebrates and invertebrates. Here we summarize the main concepts of cell segregation and boundary formation, focusing on the nervous system and highlighting the similarities between vertebrate and invertebrate model organisms.

Correction: Preoperative chemoradiotherapy for rectal cancer: the sensitizer role of the association between miR-375 and c-Myc.

[This corrects the article DOI: 10.18632/oncotarget.19393.].

Slit neuronal secretion coordinates optic lobe morphogenesis in Drosophila.

The complexity of the nervous system requires the coordination of multiple cellular processes during development. Among them, we find boundary formation, axon guidance, cell migration and cell segregation. Understanding how different cell populations such as glial cells, developing neurons and neural stem cells contribute to the formation of boundaries and morphogenesis in the nervous system is a critical question in neurobiology. Slit is an evolutionary conserved protein essential for the development of the nervous system. For signaling, Slit has to bind to its cognate receptor Robo, a single-pass transmembrane protein. Although the Slit/Robo signaling pathway is well known for its involvement in axon guidance, it has also been associated to boundary formation in the Drosophila visual system. In the optic lobe, Slit is expressed in glial cells, positioned at the boundaries between developing neuropils, and in neurons of the medulla ganglia. Although it has been assumed that glial cells provide Slit to the system, the contribution of the neuronal expression has not been tested. Here, we show that, contrary to what was previously thought, Slit protein provided by medulla neurons is also required for boundary formation and morphogenesis of the optic lobe. Furthermore, tissue specific rescue using modified versions of Slit demonstrates that this protein acts at long range and does not require processing by extracellular proteases. Our data shed new light on our understanding of the cellular mechanisms involved in Slit function in the fly visual system morphogenesis.

Preoperative chemoradiotherapy for rectal cancer: the sensitizer role of the association between miR-375 and c-Myc.

Administration of chemoradiation before tumor resection has revolutionized the management of locally advanced rectal cancer, but many patients have proven resistant to this preoperative therapy. Our group recently reported a negative correlation between c-Myc gene expression and this resistance. In the present study, integrated analysis of miRNA and mRNA expression profiles was conducted in 45 pre-treatment rectal tumors in order to analyze the expressions of miRNAs and c-Myc and their relationship with clinicopathological factors and patient survival. Twelve miRNAs were found to be differentially expressed by responders and non-responders to the chemoradiation. Functional classification revealed an association between the differentially expressed miRNAs and c-Myc. Quantitative real-time PCR results showed that miRNA-148 and miRNA-375 levels were both significantly lower in responders than in non-responders. Notably, a significant negative correlation was found between miRNA-375 expression and c-Myc expression. According to these findings, miRNA-375 and its targeted c-Myc may be useful as a predictive biomarker of the response to neoadjuvant treatment in patients with locally advanced rectal cancer.

Preventing parastomal hernias with systematic intraperitoneal specifically designed mesh.

BACKGROUND: Parastomal hernia is a very common complication after stoma formation. Current surgical techniques for repairing parastomal hernia have unsatisfactory results. We aim to assess our preliminary experience with prophylactic mesh placement at the time of stoma formation. METHODS: Data were prospectively recorded. A specifically designed mesh made of polyvinyl fluoride with central conduit (Dynamesh IPST®) was fixed using an intra-peritoneal onlay technique. Safety was evaluated by means of surgical data and frequency of mesh-related complications, efficacy by the rate of parastomal hernias. RESULTS: Thirty-four patients were included in the study. Three of them died before a year of follow up (not related to the stoma), so they were excluded. The other 31 patients (11 women and 20 men) were prospectively followed up after different pathologies resulting in a permanent colostomy. Twelve months after surgery CT-Scan imaging revealed two (6.4%) parastomal hernias, one of them already clinically suspected. During the follow up, 29% of the patients (n = 9) developed another type of hernia (incisional, inguinal or both). In five patients (16.1%) a light stomal retraction of the otherwise slightly prominent ostomy was observed. Median clinical follow-up was 17.5 months (range 12-34). CONCLUSION: Prophylactic parastomal mesh placement might be a safe and effective procedure with a potential to reduce the risk of parastomal hernia. Routine use of this technique should be further analysed.

Predictive Biomarkers to Chemoradiation in Locally Advanced Rectal Cancer.

There has been a high local recurrence rate in rectal cancer. Besides improvements in surgical techniques, both neoadjuvant short-course radiotherapy and long-course chemoradiation improve oncological results. Approximately 40-60% of rectal cancer patients treated with neoadjuvant chemoradiation achieve some degree of pathologic response. However, there is no effective method of predicting which patients will respond to neoadjuvant treatment. Recent studies have evaluated the potential of genetic biomarkers to predict outcome in locally advanced rectal adenocarcinoma treated with neoadjuvant chemoradiation. The articles produced by the PubMed search were reviewed for those specifically addressing a genetic profile's ability to predict response to neoadjuvant treatment in rectal cancer. Although tissue gene microarray profiling has led to promising data in cancer, to date, none of the identified signatures or molecular markers in locally advanced rectal cancer has been successfully validated as a diagnostic or prognostic tool applicable to routine clinical practice.

Expression profiling of rectal tumors defines response to neoadjuvant treatment related genes.

To date, no effective method exists that predicts the response to preoperative chemoradiation (CRT) in locally advanced rectal cancer (LARC). Nevertheless, identification of patients who have a higher likelihood of responding to preoperative CRT could be crucial in decreasing treatment morbidity and avoiding expensive and time-consuming treatments. The aim of this study was to identify signatures or molecular markers related to response to pre-operative CRT in LARC. We analyzed the gene expression profiles of 26 pre-treatment biopsies of LARC (10 responders and 16 non-responders) without metastasis using Human WG CodeLink microarray platform. Two hundred and fifty seven genes were differentially over-expressed in the responder patient subgroup. Ingenuity Pathway Analysis revealed a significant ratio of differentially expressed genes related to cancer, cellular growth and proliferation pathways, and c-Myc network. We demonstrated that high Gng4, c-Myc, Pola1, and Rrm1 mRNA expression levels was a significant prognostic factor for response to treatment in LARC patients (p<0.05). Using this gene set, we were able to establish a new model for predicting the response to CRT in rectal cancer with a sensitivity of 60% and 100% specificity. Our results reflect the value of gene expression profiling to gain insight about the molecular pathways involved in the response to treatment of LARC patients. These findings could be clinically relevant and support the use of mRNA levels when aiming to identify patients who respond to CRT therapy.

Ileal carcinoid tumor within Crohn’s disease / Tumor carcinoide ileal en la enfermedad de Crohn

No disponible

Antiretroviral therapy as a factor protective against anal dysplasia in HIV-infected males who have sex with males.

OBJECTIVES: Chronic infection with oncogenic HPV genotype is associated with the development of anal dysplasia. Antiretroviral therapy (ART) has been shown to decrease the incidence of cervical carcinoma in women with HIV. We sought to: 1) describe the prevalence and grade of anal dysplasia and HPV infection in our study subjects; 2) analyze the grade of correlation between anal cytology, PCR of high-risk HPV, and histology; 3) identify the factors associated with the appearance of ≥ AIN2 lesions. DESIGN: Cross-sectional, prospective study. METHODS: A cohort of HIV-positive males (n = 140, mean age  = 37 years) who have sex with males (MSM) had epidemiological, clinical and analytical data collected. Anal mucosa samples were taken for cytology, HPV PCR genotyping, and anoscopy for histological analysis. RESULTS: Within the cohort, 77.1% were being treated with ART, 8.5% anoscopy findings were AIN2, and 11.4% carcinoma in situ; 74.2% had high-risk (HR), 59.7% low-risk (LR) HPV genotypes and 46.8% had both. The combination of cytology with PCR identifying HR-HPV better predicts the histology findings than either of these factors alone. Logistic regression highlighted ART as a protective factor against ≥ AIN2 lesions (OR: 0.214; 95%CI: 0.054-0.84). Anal/genital condylomas (OR: 4.26; 95%CI: 1.27-14.3), and HPV68 genotype (OR: 10.6; 95%CI: 1.23-91.47) were identified as risk factors. CONCLUSIONS: In our cohort, ART has a protective effect against dysplastic anal lesions. Anal/genital warts and HPV68 genotype are predictors of ≥ AIN2 lesions. Introducing PCR HPV genotype evaluation improves screening success over that of cytology alone.

Microarray profiling of mononuclear peripheral blood cells identifies novel candidate genes related to chemoradiation response in rectal cancer.

Preoperative chemoradiation significantly improves oncological outcome in locally advanced rectal cancer. However there is no effective method of predicting tumor response to chemoradiation in these patients. Peripheral blood mononuclear cells have emerged recently as pathology markers of cancer and other diseases, making possible their use as therapy predictors. Furthermore, the importance of the immune response in radiosensivity of solid organs led us to hypothesized that microarray gene expression profiling of peripheral blood mononuclear cells could identify patients with response to chemoradiation in rectal cancer. Thirty five 35 patients with locally advanced rectal cancer were recruited initially to perform the study. Peripheral blood samples were obtained before neaodjuvant treatment. RNA was extracted and purified to obtain cDNA and cRNA for hybridization of microarrays included in Human WG CodeLink bioarrays. Quantitative real time PCR was used to validate microarray experiment data. Results were correlated with pathological response, according to Mandard´s criteria and final UICC Stage (patients with tumor regression grade 1-2 and downstaging being defined as responders and patients with grade 3-5 and no downstaging as non-responders). Twenty seven out of 35 patients were finally included in the study. We performed a multiple t-test using Significance Analysis of Microarrays, to find those genes differing significantly in expression, between responders (n = 11) and non-responders (n = 16) to CRT. The differently expressed genes were: BC 035656.1, CIR, PRDM2, CAPG, FALZ, HLA-DPB2, NUPL2, and ZFP36. The measurement of FALZ (p = 0.029) gene expression level determined by qRT-PCR, showed statistically significant differences between the two groups. Gene expression profiling reveals novel genes in peripheral blood samples of mononuclear cells that could predict responders and non-responders to chemoradiation in patients with locally advanced rectal cancer. Moreover, our investigation added further evidence to the importance of mononuclear cells' mediated response in the neoadjuvant treatment of rectal cancer.

The value of metabolic imaging to predict tumour response after chemoradiation in locally advanced rectal cancer.

BACKGROUND: We aim to investigate the possibility of using 18F-positron emission tomography/computer tomography (PET-CT) to predict the histopathologic response in locally advanced rectal cancer (LARC) treated with preoperative chemoradiation (CRT). METHODS: The study included 50 patients with LARC treated with preoperative CRT. All patients were evaluated by PET-CT before and after CRT, and results were compared to histopathologic response quantified by tumour regression grade (patients with TRG 1-2 being defined as responders and patients with grade 3-5 as non-responders). Furthermore, the predictive value of metabolic imaging for pathologic complete response (ypCR) was investigated. RESULTS: Responders and non-responders showed statistically significant differences according to Mandard's criteria for maximum standardized uptake value (SUVmax) before and after CRT with a specificity of 76,6% and a positive predictive value of 66,7%. Furthermore, SUVmax values after CRT were able to differentiate patients with ypCR with a sensitivity of 63% and a specificity of 74,4% (positive predictive value 41,2% and negative predictive value 87,9%); This rather low sensitivity and specificity determined that PET-CT was only able to distinguish 7 cases of ypCR from a total of 11 patients. CONCLUSIONS: We conclude that 18-F PET-CT performed five to seven weeks after the end of CRT can visualise functional tumour response in LARC. In contrast, metabolic imaging with 18-F PET-CT is not able to predict patients with ypCR accurately.

Enhanced iNOS gene expression in the steatotic rat liver after normothermic ischemia.

BACKGROUND: Impaired hepatic microcirculation in the steatotic liver has been identified as a considerable factor for increased vulnerability after ischemia/reperfusion (I/R). Changes in regulation and synthesis of vasoactive mediators, such as nitric oxide (NO) and endothelin (ET-1), may result in functional impairment of postischemic sinusoidal perfusion. The aim of the current study was to assess the impact of I/R injury on postischemic gene expression of NO and ET-1 in steatotic livers. MATERIALS AND METHODS: Male Sprague-Dawley rats with or without hepatic steatosis (induced by carbon tetrachloride treatment) were subjected to normothermic I/R injury. Steady-state mRNA levels were assessed using RT-PCR to study the expression of genes encoding ET-1, NO synthase (endothelial cell NO synthase and inducible NO synthase, iNOS). Immunohistochemistry was performed for detection of iNOS. RESULTS: I/R injury was followed by increased iNOS gene expression (RT-PCR/immunohistochemistry) in animals with hepatic steatosis, predominately in hepatocytes with fatty degeneration. A mild increase in mRNA levels for ET-1 was found in steatotic rat livers. I/R induced a further increase in ET-1 gene expression in some but not all reperfused steatotic livers. CONCLUSIONS: We show an enhanced gene expression of iNOS in postischemic steatotic rat livers. Hepatocytes with fatty degeneration appear to be the major source for NO generation. Furthermore, I/R may also induce ET-1 gene expression. Dysregulation of sinusoidal perfusion by NO and ET-1 is therefore likely to contribute to I/R injury of the steatotic liver.

Intestinal barrier dysfunction in developing liver cirrhosis: An in vivo analysis of bacterial translocation.

AIM: Transmucosal passage of bacteria across the intestine, the essential step for bacterial translocation, has been identified as a key event in the pathogenesis of life-threatening infections in cirrhosis. Existing animal models of liver cirrhosis only provide indirect information about the pathogenesis of such infections. The aim of this study has been to assess transmucosal passage and bacterial translocation directly in vivo using a rat model of developing liver cirrhosis. METHODS: Male Sprague Dawley rats were randomly assigned to two groups: controls and animals with developing liver cirrhosis induced by s.c. injection of carbon tetrachloride. In anesthetized animals a suspension of green fluorescent protein (GFP)-tagged E. coli was administered into the terminal ileum. Time intervals necessary for translocation of E. coli into the mucosa and muscularis were assessed by intravital microscopy and translocation of E. coli in mesentery, liver and spleen was determined microbiologically. RESULTS: Bacterial kinetics at the level of the mucosa and muscularis showed significant enhancement in cirrhotic rats compared to the controls (P < 0.001). GFP-expressing E. coli were detected in the mesentery, liver and spleen of animals with cirrhosis taken one hour after E. coli administration. However, cultures of control animals remained sterile. CONCLUSION: Intravital microscopy of fluorescent bacteria represents a novel approach to studying bacterial translocation in vivo. Here we report that this technique can be used to visualize bacterial transit in in vivo and gives further support to the transmucosal passage of bacteria across the intestine correlating with bacterial translocation in CCl(4)-induced liver cirrhosis.

HIV-related and Epstein-Barr virus-associated anal Burkitt's lymphoma: report of a case.

PURPOSE: This article describes and discusses primary Burkitt's lymphoma of the anus which is an extremely rare site of origin. METHODS AND RESULTS: A 38-year-old HIV+ Rwandan farmer had an 8-cm x 13-cm anal tumor. Histopathology and immunohistology provided evidence of an Epstein-Barr virus-associated Burkitt's lymphoma. Chemotherapy in combination of virostatic therapy is the gold standard for treatment, but because of economic constraints surgical treatment was the only practicable intervention and an abdominoperineal resection of the anorectum was performed. CONCLUSIONS: Because of the AIDS epidemic and the increase of anal malignant pathologies, anal Burkitt's lymphoma may appear more frequently. Adequate treatment is available for only a small percentage of patients.

Case report: late perianal mucinous adenocarcinoma after Crohn's disease proctectomy: an oncological rarity.

BACKGROUND: As in ulcerative colitis, there is an increased incidence of colorectal carcinoma in Crohn's disease. While carcinoma formation originating from ano-rectal fistulas is generally considered as a rare event there are different publications reporting on mucinous adenocarcinoma formation in association with a neovagina and rectovaginal fistulas. To the best of our knowledge this is the first description of a perianal mucinous adenocarcinoma arising in a patient after Crohn's disease proctocolectomy. CASE PRESENTATION: We report the case of a 50-year old female with a mucinous adenocarcinoma forming in the perineum eleven years after proctocolectomy for Crohn's disease. The patient was readmitted with perineal pain, leucocytosis and a perineal mass highly suspicious of abscess formation in the MRI-Scan. Histological examination revealed a mucinous adenocarcinoma. Exenteration including vagina, uterus and ovaries together with the coccygeal-bone was performed. CONCLUSION: Mucinous adenocarcinoma formation is a rare complication of Crohn's disease and so far unreported after proctocolectomy.