CARMN-NOTCH2 fusion transcript drives high NOTCH2 expression in glomus tumors of the upper digestive tract.

Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA-sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN-NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN-NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.

Predictive value of 18F-FDG PET and somatostatin receptor scintigraphy in patients with metastatic endocrine tumors.

UNLABELLED: The treatment of metastatic neuroendocrine tumors depends on the aggressiveness of the disease. We wanted to know whether (18)F-FDG PET and somatostatin receptor scintigraphy (SRS) can predict early disease progression and patient survival. METHODS: We undertook a prospective study of patients with metastatic neuroendocrine tumor diagnosed between September 2003 and January 2006. After obtaining signed informed consent from the patients, we performed CT, SRS, and (18)F-FDG PET and reviewed histologic data. CT was repeated every 3 mo to assess the risk of early progressive disease (first 6 mo), progression-free survival, and overall survival. RESULTS: Thirty-eight patients (mean age, 60 +/- 15 y) were included. Histologically, 4 patients had a high-grade and 34 a low-grade tumor. The results of (18)F-FDG PET and SRS were positive in 15 and 27 patients. The 2-y overall survival and progression-free survival were 73% and 45%; 16 patients had early progressive disease. Most (18)F-FDG PET-positive patients had early progressive disease (14/15, vs. 2/23 (18)F-FDG PET-negative patients), and most SRS-negative patients had early progressive disease (9/11, vs. 7/27 SRS-positive patients); (18)F-FDG PET gave excellent negative and positive predictive values of 91% and 93%; (18)F-FDG PET results correlated with progression-free survival (P < 0.001) and overall survival (P < 0.001) even when only low-grade tumors were considered. SRS was associated with progression-free survival (P < 0.001) and overall survival (P < 0.03). At multivariate analysis, only (18)F-FDG PET was predictive of progression-free survival. CONCLUSION: (18)F-FDG PET exhibits excellent predictive values for early tumor progression. (18)F-FDG PET and SRS results correlate with progression-free survival and overall survival even for histologically low-grade tumors. These explorations could be included in the initial work-up for metastatic neuroendocrine tumor.

UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan.

PURPOSE: Irinotecan (CPT-11) is approved in metastatic colorectal cancer treatment and can cause severe toxicity. The main purpose of our study was to assess the role of different polymorphisms on the occurrence of hematologic toxicities and disease-free survival in high-risk stage III colon cancer patients receiving 5-fluorouracil (5FU) and CPT-11 adjuvant chemotherapy regimen in a prospective randomized trial. EXPERIMENTAL DESIGN: Four hundred patients were randomized in a phase III trial comparing LV5FU2 to LV5FU2 + CPT-11. DNA from 184 patients was extracted and genotyped to detect nucleotide polymorphism: 3435C>T for ABCB1, 6986A>G for CYP3A5, UGT1A1*28 and -3156G>A for UGT1A1. RESULTS: Genotype frequencies were similar in both treatment arms. In the test arm, no significant difference was observed in toxicity or disease-free survival for ABCB1 and CYP3A5 polymorphisms. UGT1A1*28 homozygous patients showed more frequent severe hematologic toxicity (50%) than UGT1A1*1 homozygous patients (16.2%), P = 0.06. Moreover, patients homozygous for the mutant allele of -3156G>A UGT1A1 polymorphism showed more frequent severe hematologic toxicity (50%) than patients homozygous for wild-type allele (12.5%), P = 0.01. This toxicity occurred significantly earlier in homozygous mutant than wild-type homozygous patients (P = 0.043). In a Cox model, the hazard ratio for severe hematologic toxicity is significantly higher for patients with the A/A compared with the G/G genotype [hazard ratio, 8.4; 95% confidence interval, 1.9-37.2; P = 0.005]. CONCLUSIONS: This study supports the clinical utility of identification of UGT1A1 promoter polymorphisms before LV5FU2 + CPT-11 treatment to predict early hematologic toxicity. The -3156G>A polymorphism seems to be a better predictor than the UGT1A1 (TA)(6)TAA>(TA)(7)TAA polymorphism.

Type 1 and 2 gastric carcinoid tumors: long-term follow-up of the efficacy of treatment with a slow-release somatostatin analogue.

Little is known about the long-term results of treating gastric carcinoid tumors with a slow-release somatostatin analogue. We report three patients with type 1 and 2 gastric carcinoid tumors who were treated in the above mentioned way and followed for 27-50 months. In all cases, alternative endoscopic or surgical management was considered but deemed inappropriate. Treatment with a slow-release somatostatin analogue was begun in light of a favorable recent report. The result was regression or complete disappearance of macroscopic fundal tumors. No side-effects were reported and, most notably, none of the patients developed gallstones. This small study may help define the optimal duration, dose, and administration interval of the treatment. Slow-release somatostatin analogue is a safe and efficacious treatment for type 1 and 2 gastric carcinoid tumors, and can be used when tumors are growing rapidly. Slow-release somatostatin analogue represents an alternative to repeated endoscopic treatment or high-risk surgery.

[Subcutaneous emphysema, pneumomediastinum, pneumoperitoneum and retropneumoperitoneum following a colonoscopy with mucosectomy]. / Emphysème sous-cutané, pneumomédiastin, pneumopéritoine et rétropneumopéritoine dans les suites d'une coloscopie avec mucosectomie.

The occurrence of associated intraperitoneal and retroperitoneal colonic perforation is uncommon after colonoscopy. We report a case of this complication revealed by subcutaneous emphysema, pneumomediastinum, pneumoperitoneum and retro-pneumoperitoneum after colonic mucosectomy.

[A method for segmental gross examination of the liver]. / Technique de découpe segmentaire des pièces d'hépatectomie, basée sur la vascularisation hépatique.

Segmental localization of hepatic tumours by the pathologists is often approximate. However this information is essential to analyze the impact of preoperative treatments. We describe a new technique for gross examination of the liver, based on hepatic segmental anatomy. After segment I has been resected, sagittal sectioning along the umbilical scissure splits the liver into the left and right lobes. On the left lobe, parenchymal sectioning along the plane of the left hepatic vein separates segment II from segment III. On the right lobe, parenchymal sectioning along the median hepatic vein separates segment IV from the right liver. The right liver is then separated into its four segments once the parenchyma has been cut along the plane of the right hepatic vein and the right portal axis, respectively. We used this technique to examine 387 explanted livers, 214 of wich contained tumors. In 49 cases, pathologic location of the lesions concorded with radiological findings in 92% of cases.

Resection of hepatocellular carcinoma in noncirrhotic liver: analysis of risk factors for survival.

BACKGROUND: The aim of this study was to identify factors predictive of survival after curative resection of hepatocellular carcinoma (HCC) in noncirrhotic liver. STUDY DESIGN: Eighty-four patients underwent resection of HCC in noncirrhotic liver between January 1998 and December 2003. Univariate and multivariable analyses were used to retrospectively identify factors associated with overall survival and disease-free survival when resection was curative for the primary tumor. RESULTS: Overall 1-, 3-, and 5-year survival rates were 77.8%, 55.0%, and 44.4%, respectively, and 84.0%, 62.0%, and 50.0% when resection was curative for the primary tumor. HCC recurred in 27 patients (39.1%). Recurrence was intrahepatic in 14 patients (51.9%), extrahepatic in 3 patients (11.1%), and both intra- and extrahepatic in the remaining 10 patients (37.0%). In multivariable analysis, three independent factors were associated with poorer overall survival and recurrence-free survival, namely multiple tumors, macroscopic vascular invasion, and nonuse of adjuvant iodine-131-iodized oil. CONCLUSIONS: Aggressive operation is an effective treatment for HCC in noncirrhotic patients, whatever the degree of liver fibrosis. Multiple tumors and macroscopic vascular invasion are poor prognostic factors. Postoperative iodine-131-iodized oil injection appears to prevent recurrence and improve overall survival, although this needs to be confirmed in a prospective randomized trial.

[Liver transplantation for hepatocellular carcinoma]. / Transplantation hépatique pour carcinome hépatocellulaire.

Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver. It mostly develops on cirrhotic livers. Orthotopic liver transplantation is the only treatment that definitively addresses both the metachronous occurrence risk of HCC and the underlying disease. Under Milan criteria, i.e. less than 3 nodules of 3 cm max in diameter, or 1 nodule of 5 cm maximum, OLT has been shown effective and provides with survival rates almost equal to those obtained with HCC free cirrhotic patients. In Rennes, 195 patients with early HCC on cirrhotic livers have been transplanted from January 1995 to June 2005. Global and disease free 8 years patient survival rates were 73 and 70%, respectively. These results were significantly altered when the recipient was female, the cirrhosis due to C virus and the patient of B blood group. Despite these excellent results, the principal limit to the application of transplantation for HCC remains the long period of time patients have to wait for a graft. During this period of time, growth of the tumour may drop the patient out of Milan criteria and subsequently from the waiting list. The role of chemoembolisation, liver resection and thermal ablation while the patient is waiting for a graft remains debatable.

Tonsillar metastasis revealing signet-ring cell carcinoma of the rectum.

A 45-year-old man presented with a tonsillar tumor and rectal syndrome. Histology specimens revealed signet-cell adenocarcinoma of both the tonsils and rectum. The clinical course was rapidly degenerated with multiple metastases in the skin and bones. Tonsil metastasis is rare and generally develops from primary gastric or colorectal cancer, predominantly poorly-differentiated or signet-ring cell adenocarcinomas.

Adenocarcinoma of the upper esophagus arising in heterotopic gastric mucosa: common pathogenesis with Barrett's adenocarcinoma?

Adenocarcinoma of the upper esophagus arising in heterotopic gastric mucosa is a rare tumor, with only 15 cases reported to date. We report a case in a 61-year-old man complaining of dysphagia. The upper endoscopy revealed that the tumor measured 3 cm and was 22 cm distant from the incisivors. A hiatal hernia with erosive esophagitis of the distal esophagus was present. On microscopic examination the tumor corresponded to a poorly differentiated adenocarcinoma immunoreactive for cytokeratin (CK) 7 and p53. The surrounding heterotopic gastric mucosa contained foci of intestinal metaplasia immunoreactive for CK7 in the surface epithelium and the entire glands and CK20 in the superficial epithelium and superficial glands. The CK7 and p53 positivity that we observed is very common in Barrett's adenocarcinomas. Moreover, intestinal metaplasia in heterotopic gastric mucosa shows the same CK7/CK20 pattern as specialized Barrett's mucosa. These common features shared by adenocarcinomas of the upper esophagus arising in heterotopic gastric mucosa and adenocarcinoma of the lower esophagus developing on Barrett's mucosa suggest that those two types of cancer have a common pathogenesis, related to gastroesophageal reflux disease.

Squamous cell carcinoma arising in a hepatic forgut cyst.

We report the second case of squamous cell carcinoma arising in a hepatic foregut cyst (CHFC) in a 40-year-old woman. Microscopically, the lining of the cyst was composed of ciliated columnar epithelium, gastric and squamous epithelium. The squamous epithelium showed areas with dysplastic changes and other areas with carcinomatous transformation. In this congenital lesion, it was not surprising to find squamous and gastric mucosa because oesophagus, stomach, and tracheobronchic tree derive from the embryologic foregut. Squamous carcinoma might develop in a context of inflammation as in biliary cyst. In agreement with the first case described in the literature, this report also suggests that a large-sized symptomatic hepatic cyst should be excised.

[Paroxysmal nocturnal hemoglobinuria associated with intestinal ischemia leading to small bowel perforation]. / Hémoglobinurie paroxystique nocturne avec ischémie digestive compliquée de perforation de l'intestin grêle.

Paroxysmal nocturnal hemoglobinuria is rarely associated with intestinal complications. We report a case of paroxysmal nocturnal hemoglobinuria with small bowel ischemia leading to ileal perforation. In the literature, an ulcerative jejuno-ileitis has been reported in 6 cases of intestinal ischemia, due to thrombosis of mucosal small vessels. This disease is usually revealed by abdominal pain. Based on published cases and our observation of intestinal ischemia leading to small bowel perforation, surgery should be considered as the first-line treatment, especially when small bowel lesions are limited.

[Neuroendocrine differentiation of bladder tumors]. / Différenciation neuro-endocrine des tumeurs de vessie.

Neuroendocrine bladder tumours (NET) constitute a group of various tumours with a common neuroendocrine phenotype. This is a very well defined entity (morphological, immunohistochemical, and ultrastructural). The great majority of bladder NETs reported in the literature are high-grade small cell carcinomas, but large cell carcinoma are probably underestimated due to the lack of systematic investigation. This paper reviews these rare, poorly known tumours, which require specific management. All bladder NETs are described. The frequency and diagnostic and therapeutic strategy of neuroendocrine bladder tumours are described.

Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C.

BACKGROUND/AIMS: Patients with chronic hepatitis C have frequently mild to moderate liver iron overload which increases with fibrosis stage. Thus, it has been postulated that iron could enhance the progression of fibrosis. However, the real impact of iron is still controversial. The study was undertaken to determine the effect of confounding variables. All factors known to influence both iron overload and fibrosis were taken into account. METHODS: Five hundred and eighty-six patients, who had liver biopsy performed prior to antiviral treatment, were included. Serum ferritin and liver iron were correlated with clinical, biological and histological variables in univariate and multivariate analysis. The impact of iron on fibrosis was evaluated in multivariate analysis in the whole group and in the subgroup of 380 patients with available date of infection. RESULTS: Hyperferritinemia, encountered in 27%, was associated with liver iron deposits in only 46% of cases. Liver iron was elevated in 17%, and correlated with age, male sex, and alcohol intake. The univariate strong link which existed between liver iron and fibrosis disappeared after adjustment for confounding variables. CONCLUSIONS: According to the results of this study, liver iron should be considered more as a surrogate marker for disease severity than as a fibrogenic factor per se.

Cytotoxic effector cells with antitumor activity can be amplified ex vivo from biopsies or blood of patients with renal cell carcinoma for cell therapy use.

Adoptive immunotherapy with antitumor effector cells is an attractive therapeutic approach in metastatic renal cell carcinoma (RCC). The aim of the work was to enhance in vitro activation of lymphocytes with optimal cytotoxic activity against tumor cells. We evaluated a procedure based on the use of dendritic cells (DCs) loaded with irradiated tumor cells (DC-Tu) to stimulate lymphocytes. Experimental conditions were established with cells from healthy donors and melanoma cell lines. Procedures were then applied to cells from RCC patients. A total of 30 tumor biopsies, 14 proximal lymph nodes, and 17 peripheral blood samples from 30 patients were used. When lymphocytes were stimulated in vitro with DC-Tu, they responded to tumor cells with an increased cytolytic activity for all the assays with donor cells (n=18). For RCC patients, DC-Tu stimulation improved the final cytotoxic activity in only half of the assays (16/31). When significantly enhanced (>10%, n=8), responder cells resulted in a final 43% cytotoxicity against autologous RCC cells. Mechanism of lysis was at least in part class I mediated. Effector cells have no lytic activity against normal renal cells. Percentage of cells with regulatory T-cell phenotype was not found to be enhanced in the DC-Tu stimulated lymphocytes. Individual differences were observed in the characteristics of DCs generated from RCC patients in contrast to that observed in donors and could explain why lymphocyte stimulation was not improved by DC-Tu in half of the RCC assays. T-cell spreading was suitable for a therapeutic use (>10(9) cells) irrespective of the procedure (with or without DC-Tu stimulation) or the tissular origin of lymphocytes from patients. Data show that precursors of selective antitumor effector cells are present in patients with RCC and can be amplified in vitro either with or without DC-Tu stimulation. One of these populations could be chosen for an adoptive transfer immunotherapy.

Novel mutation in ferroportin 1 gene is associated with autosomal dominant iron overload.

We report a family affected with dominant autosomal iron overload related to a new mutation in ferroportin 1, a transmembrane protein involved in the export of iron from duodenal enterocytes and likely from macrophages. The originality of this family is represented by the nature of the mutation consisting in the replacement of glycine 490 with aspartate. Clinicians should be aware of this novel iron overload entity, which corresponds to a particular phenotypic expression (high serum ferritin values contrasting with relatively low transferring saturation, and important Kupffer cell iron deposition as compared to hepatocytic iron excess) with poor tolerance of venesection therapy and a dominant pattern of inheritance. Given this dominant transmission, the mixed Causasian-Asian origin of our Asian proband leaves open the issue of the ethnic origin of the new mutation.