Search

// Sandra Dupouy 1 , * , Van Kien Doan 1 , * , Zherui Wu 1 , 2 , * , Najat Mourra 1 , 3 , Jin Liu 2 , Olivier De Wever 4 , Frederique Penault Llorca 5 , Anne Cayre 5 , Amal Kouchkar 6 , Anne Gompel 2 , 7 , Patricia Forgez 2 1 UMRS U938, Hopital Saint-Antoine, Paris, France 2 UMRS 1007 Universite Paris Descartes 45, Paris, France 3 Pathology Department Hopital Saint-Antoine, Paris, France 4 The Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium 5 Pathology Department, Jean Perrin Center, Clermont Ferrand, France 6 Pathology Department, Alger Pierre and Marie Curie Center, Algeria 7 Gynecology Unit, Universite Paris Descartes, APHP, Hopitaux Universitaires Cochin Hotel-Dieu Broca, Paris, France * SD, VKD, and ZW contributed equally to this work. Correspondence to: Patricia Forgez, e-mail: Patricia.forgez@inserm.fr Keywords: Cancer growth and metastasis, neurotensin, EGFR, HER2, HER3, EGF like ligands Received: Novermber 28, 2013 Accepted: May 7, 2014 Published: October 03, 2014 ABSTRACT A present challenge in breast oncology research is to identify therapeutical targets which could impact tumor progression. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 20% of breast cancers, and NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in invasive breast carcinomas. Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here, we depict the cellular mechanisms activated by NTS, and contributing to breast cancer cell aggressiveness. We show that neurotensin (NTS) and its high affinity receptor (NTSR1) contribute to the enhancement of experimental tumor growth and metastasis emergence in an experimental mice model. This effect ensued following EGFR, HER2, and HER3 over-expression and autocrine activation and was associated with an increase of metalloproteinase MMP9, HB-EGF and Neuregulin 2 in the culture media. EGFR over expression ensued in a more intense response to EGF on cellular migration and invasion. Accordingly, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, as well as metformin, reduced the tumor growth of cells overexpressing NTS and NTSR1. All cellular effects, such as adherence, migration, invasion, altered by NTS/NTSR1 were abolished by a specific NTSR1 antagonist. A strong statistical correlation between NTS-NTSR1-and HER3 (p< 0.0001) as well as NTS-NTSR1-and HER3- HER2 (p< 0.001) expression was found in human breast tumors. Expression of NTS/NTSR1 on breast tumoral cells creates a cellular context associated with cancer aggressiveness by enhancing epidermal growth factor receptor activity. We propose the use of labeled NTS/NTSR1 complexes to enlarge the population eligible for therapy targeting HERs tyrosine kinase inhibitor or HER2 overexpression.

Aims Clusterin (CLU) is a sulphated glycoprotein implicated in many physiological and pathological processes, including tumorigenesis. We have previously demonstrated that CLU is highly expressed in pancreatic neuroendocrine tumours (NETs). The aims of this study were: to investigate CLU expression in gastrointestinal NETs; the potential correlation between this expression and different clinicopathological parameters; and its usefulness in the differential diagnosis of liver metastases. Methods and results Immunohistochemistry using an anti-CLU antibody was performed on paraffin sections from 108 primary NETs [G3 (13 cases), G2 (18 cases), and G1 (77 cases), according to the 2010 WHO classification] and 60 metastases. Cytoplasmic positivity was scored qualitatively and quantitatively. The pattern of staining was also assessed. Two-step statistical analyses (univariate and multivariate logistic regression) were performed. More than 90% of small-intestine NETs were completely negative. The probability of obtaining a positive CLU score was higher for the appendix, the stomach, the duodenum and the rectum than for the small intestine and colon. All G3 NETs and most G2 NETs were negative as compared with G1. CLU expression in the metastatic foci was identical to that of the primary tumour. Conclusions Clusterin expression in gastrointestinal NETs is highly correlated with location and probably also with grading, in both the primary tumour and metastases. Underexpression of CLU in small-intestine NETs is helpful for identifying the origin of liver metastases: a strong CLU score in a liver biopsy makes the small intestine highly unlikely as a primary site.

Inguinal endometriosis (IE) secondary to involvement of the extraperitoneal portion of the round ligament is a rare condition, occurring in

Glucocorticoids (GCs) regulate cell homeostasis and can affect carcinogenesis. An inherited germline mutation in the BRCA1 gene, a tumor suppressor gene, confers a predisposition to breast and ovarian cancers. BRCA1 participates in the maintenance of genome stability through DNA repair, in cellular homeostasis through gene transcription, and in signaling regulation. The interaction between BRCA1 and the glucocorticoid receptor (GR) signaling pathway was studied in normal breast tissues and triple-negative breast cancers from BRCA1 mutation carriers. A loss of the active Ser211 phosphorylated form of GR was found in the mutant as compared to the non-mutant. In in vitro studies, the BRCA1 status in breast cancer cell lines regulates GC-dependent proliferation/apoptosis and impacts GC-dependent gene expression. The lack of BRCA1 inhibited dexamethasone actions on its target genes' expression and the opposite effect was seen with BRCA1 overexpression. BRCA1 overexpression enhances MAPK p38 phosphorylation, resulting in an amplification of GR phosphorylation on Ser 211 and GR basal expression. Our results indicate that BRCA1 is essential to develop an efficient GC signalization. GR P-Ser211 levels may constitute an important diagnostic factor for screening BRCA1 loss of expression in tumors from BRCA1 mutation carriers as well as in sporadic BRCAness tumors. This marker may help to optimize therapeutic strategies.

Clusterin (CLU) is a sulfated glycoprotein implicated in many physiological and pathological processes, including tumorigenesis. Several studies have reported the overexpression of CLU in human neoplasm, examined by immunohistochemistry. However, there are no extensive data on its role in the thyroid. Here we investigate CLU expression in thyroid tumors, and the potential correlation between this expression and clinicopathological parameters. Immunohistochemistry with anti-CLU was performed on paraffin sections from 39 thyroid tumors. Only medullary thyroid carcinomas (MTCs) were positive (n = 5). To confirm these results, 130 further cases (including 4 C-cell hyperplasia), their matched lymph node metastases (46 cases), and lymph node recurrences (10 cases) were analyzed. All MTCs were subdivided according to World Health Organization classification. Cytoplasmic positivity was scored qualitatively (weak, moderate, strong) and quantitatively on a 5-tier scale from 0, 1+ (10% of cells positive) to 5+ (75%). Statistical analysis was performed. CLU was expressed in normal C cells, C-cell hyperplasia, all MTCs, their lymph node metastases, and recurrences. There was a strong association between CLU score and the cellular type (P.004). CLU score was inversely correlated with the presence of lymph node metastases (P.0001). There were no differences between primary and metastatic or recurrent tumors. CLU expression is related to the cellular type and inversely correlated with the presence of lymph node metastases, which could represent a new positive prognostic factor.

// Laudine Communal 1 , Myriam Vilasco 1, * , Justine Hugon-Rodin 1, 2, * , Aurelie Courtin 1 , Najat Mourra 3 , Najiba Lahlou 4 , Morwenna Le Guillou 5 , Muriel Perrault de Jotemps 6 , Marie-Pierre Chauvet 7 , Marc Chaouat 8 , Pascal Pujol 9 , Jean Feunteun 5 , Suzette Delaloge 10 , Patricia Forgez 1 , Anne Gompel 1, 2 1 UMRS 1007, Saints Peres, Paris Descartes University, Paris, France 2 UF de Gynecologie-Endocrinienne, Paris Descartes University, AP-HP, Hopital Cochin, Paris, France 3 Service d’Anatomie et Cytologie Pathologiques, AP-HP, Hopital Saint-Antoine, Paris, France 4 Service de Biologie Hormonale, Paris Descartes University, AP-HP, Hopital Cochin, Paris, France 5 CNRS UMR8200 Gustave Roussy, Stabilite genetique et Oncogenese, Paris-Saclay University, Villejuif, France 6 Service de Chirurgie Plastique et Reconstructrice, Clinique Hartmann, Neuilly sur Seine, France 7 Departement de Senologie, Centre Oscar Lambret, Lille, France 8 Service de Chirurgie Plastique Reconstructrice et Esthetique et Chirurgie des Brules, Denis Diderot University, AP-HP, Hopital Saint-Louis, Paris 9 Centre Hospitalier Universitaire, Montpellier University, Montpellier, France 10 Breast Cancer Group, Gustave Roussy Cancer Campus, Villejuif, France * These authors have contributed equally to this work Correspondence to: Patricia Forgez, email: patricia.forgez@inserm.fr Anne Gompel, email: anne.gompel@cch.aphp.fr Keywords: BRCA1, breast cancer, ovarian hormones, prevention, ulipristal acetate Received: January 25, 2016 Accepted: May 09, 2016 Published: May 26, 2016 ABSTRACT Women with inherited BRCA1 mutations have an elevated risk (40-80%) for developing breast and ovarian cancers. Reproductive history has been reported to alter this risk, suggesting a relationship between ovarian hormone signaling and BRCA1 -related tumor development. BRCA1 interactions with estrogen receptor (ER) and progesterone receptor (PR) signaling were previously described in human breast cancer cell lines and mouse models. However, few studies have examined the effect of ovarian hormone regulation in normal human breast tissues bearing a heterozygous BRCA1 mutation. This study compares the proliferation level (Ki67) and the expression of ER, PR, and of the PR target gene, fatty acid synthase (FASN), in histologically normal breast tissues from women with BRCA1 mutations ( BRCA1 +/mut , n=23) or without BRCA1 mutations ( BRCA1 +/+ , n=28). BRCA1 +/mut tissues showed an increased proliferation and impaired hormone receptor expression with a marked loss of the PR isoform, PR-B. Responses to estradiol and progesterone treatments in BRCA1 +/mut and BRCA1 +/+ breast tissues were studied in a mouse xenograft model, and showed that PR and FASN expression were deregulated in BRCA1 +/mut breast tissues. Progesterone added to estradiol treatment increased the proliferation in a subset of BRCA1 +/mut breast tissues. The PR inhibitor, ulipristal acetate (UPA), was able to reverse this aberrant progesterone-induced proliferation. This study suggests that a subset of women with BRCA1 mutations could be candidates for a UPA treatment as a preventive breast cancer strategy.

background: Antiprogestins are of growing interest for the development of new treatments in the gynecological field. Ulipristal acetate (UPA) is a progesterone receptor (PR) modulator considered for long-term administration in contraception and is currently being registered for the treatment of uterine fibroids. In light of the influences of hormonal dysfunction in breast pathologies, the secondary consequences of chronic UPA therapy need to be established. The aim of this study was to determine UPA actions mediated by PR and glucocorticoid receptor (GR) in normal and transformed breast. methods: UPA, progesterone (P) and dexamethasone (DEX) effects were observed on PR and GR responsive genes and on proliferation and apoptosis of normal human breast epithelial (HBE) and breast cancer cells. Human normal breast tissue samples were xenografted in athymic mice and treated with estradiol (E2), or E2 + P, or E2 + P + UPA. results: Analysis of PR and GR reporter gene transactivation and their respective endogenous target genes indicated that UPA exerted anti-progestational and anti-glucocorticoid activity in both types of cells with a more pronounced effect in cancer cells. When combined with P or DEX, UPA limits the proliferation of HBE cells but increases growth in breast cancer cell lines. UPA administration had no impact on the mitotic index on xenografted human breast tissue exposed to gonadal hormones at similar concentrations to those present in normal women. conclusions: Although further clinical trials are required to confirm that the results from our experimental models can be extrapolated to women treated with UPA, they suggest that such treatment would not be deleterious to normal breast tissue at least for a cycle (28 days) of continuous administration.

At the time of EGD, a 2-cm, yellowish, soft, mobile, subepithelial lesion was seen at the distal end of D2, suspected to be a lipoma (Figure A). Upon biopsy attempt using cold forceps, the polypoid structure ruptured and white serous fluid gushed out of the lesion (Figure B) until it completely flattened (Figure C). The procedure was well-tolerated. The biopsy specimen was sent for pathologic ssessment. Look on page 1533 for the answer and see the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information n submitting your favorite image to Clinical Challenges and Images in GI. Conflicts of interest: The authors disclose no conflicts. © 2011 by the AGA Institute 0016-5085/$36.00 doi:10.1053/j.gastro.2010.07.054

A growing challenge in medicine today, is the need to improve the suitability of drug treatments for cancer patients. In this field, biomarkers have become the "flags" to provide additional information in tumor biology. They are a relay between the patient and practitioner and consequently, aid in the diagnosis, providing information for prognosis, or in some cases predicting the response to specific therapies. In addition to being markers, these tumor "flags" can also be major participants in the process of carcinogenesis. Neurotensin receptor 1 (NTSR1) was recently identified as a prognosis marker in breast, lung, and head and neck squamous carcinomas. Neurotensin (NTS) was also shown to exert numerous oncogenic effects involved in tumor growth and metastatic spread. These effects were mostly mediated by NTSR1, making the NTS/NTSR1 complex an actor in cancer progression. In this review, we gather information on the oncogenic effects of the NTS/NTSR1 complex and its associated signaling pathways in order to illuminate its significant role in tumor progression and its potential as a biomarker and a therapeutic target in some tumors.

Stress enhances glucocorticoid (GC) synthesis, which alters inflammation and immune responses, as well as cellular proliferation and apoptosis in a number of tissues. Increasingly, stress has been associated with cancer progression, and in particular in breast cancer. Consequently, an operational glucocorticoid receptor system in breast tissue influences breast cancer development. In this review, we summarize the data on the GC/GR system in normal and tumoral breast tissue. We also review the molecular mechanisms by which GCs control apoptosis and proliferation in breast cancer models and how GCs alter the chemotherapy of breast cancer treatment when used in combination. Finally, we discuss the participation of GR in breast tumorigenesis under hormone replacement therapy.

The purpose of this article is to determine the tumorigenic potential of estradiol treatment (E2) when combined with either progesterone (P4) or medroxyprogesterone acetate (MPA) in normal luminal human breast cells (HBE) and in human breast cancer cells (T47-D, MCF-7). Proliferation profiles were evaluated, along with the gene transactivation activity between the progesterone and glucocorticoid receptors (PR, GR) in HBE, T47-D, and MCF-7 cells treated by E2 + P4 or E2 + MPA. High throughput transcriptome analysis was performed on RNA from HBE cells treated by E2, E2 + MPA and E2 + P4. GR content was analyzed in normal breast cells as well. In HBE cells, E2 + P4 treatment was antiproliferative and promoted cellular differentiation. In contrast, E2 + MPA displayed mitogenic, antiapoptotic effects in HBE cells and did not influence cellular differentiation. The effect of P4 and MPA on cell proliferation was, however, variable in breast cancer cells. In cells containing GR or/and PR, MPA decreased proliferation whereas P4 antiproliferative effect needed the presence of PR. In HBE cells, the regulation of genes by E2 + P4, and E2 + MPA was significantly different, particularly in cell proliferation and cell death gene families. Further analysis revealed a modulation of the glucocorticoid receptor gene expression pathway by E2 + MPA. Predominant MPA glucocorticoid activity in normal and breast cancer cells was demonstrated using a glucocorticoid antagonist and the down-regulation of the GR by RNA interference. In normal luminal breast cells and in breast cancer cells, P4 and MPA combined with E2 treatment have opposing mitogenic effects due to GR. The consequences of MPA glucocorticoid potencies as well as the importance of GR in breast tissue merit a reappraisal.

Objectives Metastatic tumors to the pancreas are rare and usually present a part of an advanced metastatic disease. Isolated metastasis is even rarer and may be difficult to differentiate from primary pancreatic neoplasm. The leading sources of metastases are breast, lung, kidney, and skin (melanoma). We present our experience with 12 cases of isolated pancreatic metastasis. Methods We made a retrospective review from a series of pancreatic resections for metastatic disease, which occurred during the last decade. Results The sites of origin were as follows: kidney (8 cases), lung (2 cases), bone (1 case), and breast (1 case). Only 4 patients were symptomatic (abdominal pain, 3 cases; melena, 1 case). The metastasis was metachronous in 11 cases, with mean disease-free interval of 9 years. The preoperative diagnosis was endocrine tumor in 4 cases. All patients underwent complete extirpation. At the time of follow-up, 3 patients had died of malignancy and 9 were still alive and free of disease, with a mean follow-up of 3 years. Conclusions Isolated metastatic tumors to the pancreas may be detected decades after the initial diagnosis and can be asymptomatic, emphasizing the need for lifelong surveillance in this population. Surgical extirpation of these lesions may offer the chance of long-term survival.

Acute lower gastrointestinal hemorrhage is an uncommon and severe symptom. The overall mortality rate ranges from 5 to 12 percent and can approach 40 percent for persistent or recurring bleedings. We report a case of a patient with severe recurrent lower bleeding in whom, despite several repeated explorations and a blind subtotal colectomy, no lesion could be found. Multiple (n = 4) leveled stomas of the small bowel with succus entericus reinfusion were required to localize and treat the cause of the bleeding. This case report is followed by a review of the literature of the management of lower gastrointestinal bleeding.

Magnetic resonance imaging (MRI) features of 11 surgically resected pelvic tailgut cysts were analyzed with reference to histopathologic and clinical data. Homogeneity, size, location, signal intensity, appearance and presence of septa and/or nodules and/or peripheral rim and involvement of surrounding structures were studied. Histological examination demonstrated 11 tailgut cysts (TGC), including one infected TGC and one TGC with a component of adenocarcinoma. Lesions (3-8 cm in diameter) were exclusively or partly retrorectal in all cases but one, with an extension down the anal canal in five cases. Lesions were multicystic in all patients but one. On T1-weighted MR images, all cystic lesions contained at least one hyperintense cyst. The peripheral rim of the cystic lesion was regular and non or moderately enhancing in all cases but the two complicated TGC. Nodular peripheral rim and irregular septa were seen in the degenerated TGC. Marked enhancement of the peripheral structures was noted in the two complicated TGC. Pelvic MRI is a valuable tool in the preoperative evaluation of TGC.

Resume La pancreatite auto-immune (PAI), aujourd’hui mieux definie, est une affection dont le nombre de cas rapportes augmente. Elle peut etre associee a un diabete ou a d’autres maladies auto-immunes, a des lesions biliaires repondant comme les lesions pancreatiques a la corticotherapie. Nous rapportons le cas d’un homme de 34 ans, opere d’une rectocolite hemorragique, chez qui une premiere poussee de pancreatite aigue etait attribuee a une probable tumeur intracanalaire papillaire et mucineuse du pancreas (TIPMP) segmentaire du canal principal. Aucune lesion biliaire n’etait detectee par l’imagerie. L’examen anatomopathologique de la splenopancreatectomie gauche infirmait ce diagnostic et revelait une PAI. Une corticotherapie etait instituee. Il s’agit, a notre connaissance, du premier cas rapporte de PAI mimant une TIPMP du canal principal.

Several genes have been recognized, when mutated in the germline, to highly predispose to colorectal cancer, impairing the DNA mismatch repair system in hereditary nonpolyposis colon cancer syndrome, or APC/MYH in adenomatous polyposis. However, 10 percent of microsatellite stable colorectal cancer is reported to develop in an unexplained context of genetic predisposition. This study was designed to depict the genetic mechanisms underlying early-onset microsatellite stable colon cancers. Patients younger than aged 50 years undergoing primary surgical resection for colon carcinoma were collected prospectively between 1993 and 2003. A first series of 8 samples has been allelotyped using 361 poly–CA polymorphisms distributed on the 39 autosomal arms within a larger set of 166 sporadic tumors. Genotyping of 24 poly–CA polymorphisms distributed on the 8 chromosomes exhibiting allelic losses in more than 30 percent of the previous cases was then applied to an independent series of 40 tumors. A third series of 70 tumors has been genotyped on chromosome 14 only. Comparison of genomic profile from patients younger and older than aged 50 years at the 8 most frequently lost chromosomes allowed, identify chromosome 14 as showing a significant difference between the two groups. Dense chromosome 14 genotyping detected two partial deletions in a general background of 57 percent allelic loss, pointing at a region located between D14S63 and D14S292. These observations suggest that a tumor-suppressor gene located on chromosome 14 might have an important role in microsatellite stable colon carcinogenesis. Because it seems to be more frequently involved in early-onset cases, it could be a good candidate in inherited conditions.

Background Hereditary non-polyposis colorectal cancer (HNPCC) arises mostly from germline mutations of the mismatch repair genes MSH2 and MLH1. The diagnosis of HNPCC is based on a set of clinical criteria that may be too restrictive to identify all affected patients. Immunohistochemical staining (IHC) for the mismatch repair proteins, MutS homologue 2 (MSH2) and MutL homologue 1 (MLH1), reliably identifies the microsatellite instability phenotype. This study evaluated the ability of IHC to detect germline mutations in an unselected group of patients with colorectal cancer (CRC). Methods All patients with CRC operated on between July 2000 and March 2003, and demonstrating a loss of protein, were contacted. Following informed consent, searchs for germline mutation and methylation of the promoter were performed on normal and tumoral DNA. Results Thirty patients agreed to participate, four of whom fulfilled the Amsterdam II criteria. Loss of expression of MLH1 was found in 20 patients, and loss of expression of MSH2 in ten patients. Four of the MLH1-deficient patients had a germline MLH1 point mutation (positive predictive value (PPV) 20 (95 per cent confidence interval (c.i.) 2 to 38 per cent) and 11 had promoter methylation. Seven of the MSH2-deficient patients had a germline MSH2 point mutation (PPV 70 (95 per cent c.i. 54 to 96 per cent), and none showed promoter methylation. Conclusion MLH1-deficient patients who are young or have a positive family history of cancer should be referred for genetic testing and counselling, whereas MSH2-deficient patients should be counselled in the same way as patients with HNPCC.

Diagnosis of incidental adrenal masses is a real challenge to radiologists. The most common incidental tumors of the adrenal gland are adenomas and metastases. This article presents our experience with uncommon adrenal incidentalomas. Most of the magnetic resonance imaging characteristic features are demonstrated. When possible, they are correlated with the findings at gross and microscopic analysis, to help in understanding the mechanisms by which magnetic resonance imaging may aid in the characterization of the incidental adrenal mass.

Pelvic magnetic resonance (MR) imaging is useful for identification of postoperative changes, complications, and disease recurrence in patients who have undergone surgery for primary or recurrent anorectal disease. Commonly used interventions include treatment for anorectal carcinoma: anterior rectal resection with or without creation of different colic anastomoses and abdominoperineal excision with or without pelvic reconstruction (omentoplasty, placement of myocutaneous flaps). Other common interventions include treatment for inflammatory bowel disease (coloproctectomy with or without creation of an ileoanal anastomosis and ileal pouch) and treatment for fistulas (placement of flaps or setons). Postoperative anatomic changes and formation of scar tissue can usually be identified with consecutive MR imaging examinations. Pelvic MR imaging is an accurate technique for assessment of complications including anastomotic leakage, septic complications such as fistulas and abscesses, neoplastic recurrence, and other less common complications (perineal hernia, peritoneal pseudocyst). The sophisticated surgical procedures used in rectal surgery can alter normal anatomy and make image interpretation difficult. Thus, familiarity with the appearances of postoperative anatomic changes, complications, and tumor recurrence is essential for accurate MR imaging evaluation after surgery for anorectal disease.

Sentinel lymph node mapping has been used in clinical work in malignant melanoma and breast cancer and shown an advantage over routine regional lymphadenectomy. The technique has been applied to colorectal cancer, but concerns over accuracy and high false-negative rates have restricted its use in the routine clinical setting. Most published series have used the in vivo technique and only three studies have been published in which the ex vivo technique was used. The aim of this study was to report the results of a larger study of ex vivo sentinel node mapping. All patients with colorectal cancer were considered for the trial, except patients who received preoperative radiotherapy for rectal cancer. All specimens were examined in the operating room within 30 minutes of resection. After opening the bowel, 0.5 ml of patent blue dye was injected submucosally at four sites immediately adjacent to the tumor (2 ml). The pathologic examination of the sentinel nodes and of an equal number of nonsentinel nodes consisted of standard hematoxylin and eosin sectioning, followed by multiple sectioning for further hematoxylin and eosin staining and immunohistochemistry if initial samples did not show tumor metastases. A total of 58 tumors in 57 patients were studied. One or more sentinel nodes were found in relation to 56 tumors, with one of the two failures being attributed to gross mesenteric metastases obstructing lymphatic flow. A mean of 2.93 (0–8) sentinel nodes were found per patient. There was concordance between the sentinel nodes and nonsentinel nodes in 43 patients (76.8 percent). There were nine false-negative sentinel nodes (16 percent). Two patients were upstaged by detailed pathologic examination of the sentinel nodes (micrometastases), and in a further two patients the sentinel node was the only positive node on simple hematoxylin and eosin sectioning. The technique of ex vivo sentinel node mapping is feasible and accurate in defining sentinel nodes in colorectal cancer. There is, however, a significant false-negative rate making the sentinel nodes not representative of the lymph node basin. This precludes the use of this technique in routine clinical practice. There may be a role in a research setting to help define the prognostic significance of micrometastases.

Erratum to: Breast Cancer Res Treat (2013),142:283–296,DOI 10.1007/s10549-013-2722-8. In the original publication of the article, the blot corresponding to the total P38 protein content for the conditions siCtl and siBRCA1 in Fig. 7a was incorrectly laid out. The corrected Fig. 7a is given in this erratum.The

Background: Primary adenocarcinomas of the small intestine are rare, and the genetic mechanisms involved in their carcinogenesis remain unclear. Aim: To examine the expression of candidate proteins in small intestinal adenocarcinomas by immunohistochemistry performed on tissue microarrays (TMAs). Methods: Twenty seven primary sporadic small intestinal adenocarcinomas were analysed. The TMA technique was validated by comparing immunohistochemical labelling of hMLH1 and hMSH2 on TMAs and the tissue sections they derived from. The expression of Smad4, hMSH6, β catenin, and p53 was investigated and results compared with those obtained in 14 malignant ampullary tumours. Results: TMA technology with threefold redundancy adequately represented the immunohistochemical pattern of small intestinal adenocarcinomas. Loss of hMLH1 expression, but not hMSH2 or hMSH6, was seen in two of 27 small intestinal adenocarcinomas. All ampullary tumours showed nuclear staining for hMSH2 and hMSH6. One case showed lack of immunostaining for hMLH1. Smad4 expression was absent in five small intestinal adenocarcinomas and two ampullary tumours. Overexpression of p53 was detected in the nuclei of 14 of the 27 small intestinal adenocarcinomas, and five of the 14 ampullary tumours. Nuclear or cytoplasmic expression of β catenin was present in all specimens. Conclusion: Inactivation of the SMAD4/DPC4 gene seems to be involved in small intestinal adenocarcinoma tumorigenesis. Overexpression of p53 and abnormal expression of β catenin are two common events, unlike the loss of expression of the DNA mismatch repair proteins (hMLH1, hMSH2, and hMSH6). The carcinogenetic process appears to be similar in small intestinal adenocarcinomas and malignant ampullary tumours.

· Background:We set out to evaluate the influence of fetal calf serum, acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) on three- dimensional cultures of human keratocytes in type I collagen gel matrix. · Methods: Polymerized gels were cultured at 37°C for 35 days. Gel contraction and integrated optical density were assessed 3 times weekly for 5 weeks using an image analysis system. Gels were studied at the end of the culture period by means of transmission electron microscopy (TEM) and immunochemistry. · Results: Serum significantly increased gel contraction and decreased gel optical transmittance. Keratocyte density was significantly increased by serum and HGF. In TEM, collagen density was higher with serum-supplemented media than with serum-free media, and higher with HGF-supplemented media than with HGF-free media. Immunoperoxidase staining of keratocyte-populated gels showed positive staining for vimentin, connexin 43, and type I, type V, and type VI human collagen, whereas no expression of desmin, alpha smooth muscle actin, and type IV collagen was observed. Expression of type I collagen was significantly increased by aFGF and HGF, expression of type VI collagen by serum and bFGF. · Conclusion: Serum and HGF improve ultrastructural and immunochemical features of human keratocyte-populated collagen gels.

Question: A 20-year-old woman presented with a 1-month history of epigastric pain. She denied melena, fever, or weight loss. Her medical history was remarkable for a Crohn’s disease, first manifested during childhood age and treated medically (immunosuppression) and surgically (ileocolecteomy, 5 years earlier). Preliminary laboratory analyses revealed an elevation of serum lipase (2200 U/L). Contrast-enhanced CT scan (Figure A) showed a large hypodense mass, embedded within the pancreatic body with a 0.8-cm cyst (not shown). T2-weighted magnetic resonance imaging demonstrated a high signal intensity of this mass (Figure B), with delayed enhancement after gadolinium injection (not shown). Owing to her age, sex, and the cystic component, the patient was referred to surgery with a preoperative diagnosis of solid and pseudopapillary neoplasm. She underwent splenopancreatectomy with en bloc resection of the left colonic flexure, a part of the jejunum, and posterior gastric wall. Digestive tract reconstruction was performed. Figure C shows a gross section of this pancreatic mass, Figures D and E show a hematoxylin and eosin stained microscopic section, and Figure F shows an immunohistochemical study. Her postoperative recovery was uneventful and there was no evidence of recurrence after 15 months of follow-up. What is the diagnosis? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

Pancreatic perivascular epithelioid cell tumors (PEComas) are exceedingly rare neoplasms

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.

Biliary papillomatosis is a rare entity characterized by multiple papillary adenomas involving extensive areas of the biliary tract with a great potential for recurrence and malignant transformation. It has been reported in association with Caroli disease and a choledochal cyst. We report herein a case of malignant intrahepatic biliary papillomatosis associated with cirrhosis secondary to hepatitis C. To the best of our knowledge, this is the first report of this association.

Intraductal papillary mucinous neoplasm (IPMN) is a rare pancreatic tumor defined as intraductal mucin-producting neoplasm with tall, columnar, mucin-containing epithelium. IPMN have already been described in association with inherited genetic disorder including familial adenomatous polyposis and Peutz-Jeghers syndrome. However, there is no reported description of familial history of IPMN. We reported in this case-report IPMN in the first-degree relatives without familial history of colorectal polyposis or previous extra-pancreatic cancer. The rarety of IPMN suggests that the coexistence of this tumor in two first-degree relatives is probably due to a genetic inherited factor that remains to be elucidated.

Summary Purpose Mucinous cystadenomas are tumors arising mostly from the ovaries and pancreas. They can also arise from the kidneys, lungs, liver and appendix, but are rarely seen in the mesocolon. Recently, they have been included in an updated classification of mesenteric cysts and cystic tumors. The WHO classification (ICD 10) divides them into three subcategories according to their malignant behavior. Methods This report of two cases of mucinous cystadenoma of the mesocolon discusses the diagnostic and therapeutic modalities as well as the pathophysiological pathway(s) of development of these neoplasms. Results and conclusion The diagnosis of mucinous cystadenomas of the mesocolon is challenging due to the absence of specific clinical, biological and radiological features, and is often made during or after laparotomy. Preoperative biopsy is not useful and may even lead to misdiagnosis or peritoneal spillage. Surgery is the only curative treatment, but the modalities of resection are still a subject of debate.

MYH associated polyposis is a hereditary syndrome responsible for early colorectal cancer with a distinct genetic pathway from the Familial Adenomatous Polyposis or the Hereditary Non Polyposis Colorectal Cancer syndrome. We have studied a family with three members bearing a biallelic mutation in MYH at c.1185_1186dup. One patient who developed colon cancer had loss of expression of MLH1 on tumoral tissue and microsatellite instability (MSI) phenotype. Analysis of MLH1 based on his blood sample revealed no germline mutation or large genomic deletion. No methylation of the promoter was identified in tumoral DNA. No transversion mutations were identified in APC or KRAS in tumor DNA of this patient. Loss of expression of MLH1 was due to a transversion in intron 7 at position +5 (c.588 + 5G > T) leading to a complete deletion of exon 7 at the RNA level. This observation demonstrates that MLH1 can be a target of MYH transversions leading to MSI phenotype.

Background Gastrointestinal duplications are uncommon congenital abnormalities, usually recognised before the age of 2 (80%). Colorectal duplications (CDDs) occur in only 6.8% of cases, rarely in adults, and are revealed by abdominal pain and intestinal obstruction. Malignant changes are uncommon, but are most often found in the colon. Methods and results During the last 7 years, the authors have observed seven cases of CDD (three men) with mean age 50.7 years (range 32–73). Four cases were revealed by abdominal pain, and three by intestinal obstruction. Five duplications were located in the caecum, one in the transverse colon, and one in the sigmoid colon. All CDDs were of the cystic type (4.42 cm, range 2–7.5), and three had a communication with the intestinal lumen. All patients except one underwent ‘en bloc’ resection of the cyst with the adjacent colon. On microscopic examination, CDDs contained multiple layers of the bowel wall, including colonic or small intestinal mucosa. Heterotopic gastric mucosa was observed in only one case, high-grade dysplasia in one case, and low-grade dysplasia in another. No invasive carcinoma was found. Conclusion Although uncommon, CDDs should be included in the differential diagnosis of all abdominal masses. The treatment approach is excision, in order to avoid any complication. En bloc resection of the colon with CDD may be necessary, because of the intimate attachments of the common wall. Thorough sampling of the specimen is mandatory in order to detect any malignant changes.

In colon cancer, the occurrence of metastases is associated with microsatellite stability. As metastatic cells derive from a clonal expansion of primary tumor cells, specific genomic alterations are expected in addition to the common genomic profile.Genome-wide allelotyping was performed on 75 liver metastases samples from sporadic colon cancer.No microsatellite instability was observed. Allelic loss on 5q in metastases was significantly different from that of non metastatic primary tumors (16/58 vs. 43/75, p=0.0008). Four additional chromosomes, 4, 7, 8 and 19, were more frequently lost in liver metastases, but statistical significance was reached only for 19q (14/63 versus 2/68 in primary tumors; p=0.033 after Dunn-Sidak adjustment).This study confirms that liver metastasis is rather restricted to patients with microsatellite stable colon cancer and these retain the 5q arm with high frequency. In addition, it suggests that loss of 19q may be critical for one of the steps involved in the development of liver metastases.

The prognosis of patients with colorectal cancer is largely determined by the tumor stage. In this respect, colorectal cancer with lymph node metastases has the worst prognosis. Accordingly, there is considerable clinical interest in understanding the genetic mechanisms underlying metastasis formation. The short arm of chromosome 8 is often lost in colorectal cancer and has been associated with the advanced stages. A common region of deletion has been identified in 8p21, and we investigate here the localization of the putative tumor suppressor gene. A series of 683 sporadic microsatellite stability colorectal tumor samples has been genotyped on 12 microsatellite loci encompassing the common deleted region. Allelic losses were identified in 50% of the cases and 10 break points have been evidenced between D8S1734 and D8S1810, reducing the region of interest to D8S1771-D8S131. Among the 21 genes mapped in this interval, 14 candidate genes have been retained for the sequencing analysis of 48 tumors with 8p allelic loss. No mutation was found, suggesting more complex mechanisms of inactivation or side effects of chromosome arm 8q duplication, which might be up-regulating oncogenes not located within the deleted region.