Progastrin production transitions from Bmi1+/Prox1+ to Lgr5high cells during early intestinal tumorigenesis.

Progastrin is an unprocessed soluble peptide precursor with a well-described tumor-promoting role in colorectal cancer. It is expressed at small levels in the healthy intestinal mucosa, and its expression is enhanced at early stages of intestinal tumor development, with high levels of this peptide in hyperplastic intestinal polyps being associated with poor neoplasm-free survival in patients. Yet, the precise type of progastrin-producing cells in the healthy intestinal mucosa and in early adenomas remains unclear. Here, we used a combination of immunostaining, RNAscope labelling and retrospective analysis of single cell RNAseq results to demonstrate that progastrin is produced within intestinal crypts by a subset of Bmi1+/Prox1+/LGR5low endocrine cells, previously shown to act as replacement stem cells in case of mucosal injury. In contrast, our findings indicate that intestinal stem cells, specified by expression of the Wnt signaling target LGR5, become the main source of progastrin production in early mouse and human intestinal adenomas. Collectively our results suggest that the previously identified feed-forward mechanisms between progastrin and Wnt signaling is a hallmark of early neoplastic transformation in mouse and human colonic adenomas.

MiniSOX9, a dominant-negative variant in colon cancer cells.

Inherited and acquired changes in pre-mRNA processing have significant roles in human diseases, especially cancer. Characterization of aberrantly spliced mRNAs may thus contribute to understand malignant transformation. We recently reported an anti-oncogenic potential for the SOX9 transcription factor in the colon. For instance, the Sox9 gene knock out in the mouse intestine results in an excess of proliferation with appearance of hyperplasia. SOX9 is expressed in colon cancer cells but its endogenous activity is weak. We looked for SOX9 variants that may impair SOX9 activity in colon cancer cells and we discovered MiniSOX9, a truncated version of SOX9 devoid of transactivation domain as a result of retention of the second intron. A significant overexpression of MiniSOX9 mRNA in human tumor samples compared with their matched normal tissues was observed by real-time reverse transcriptase-PCR. Immunohistochemistry revealed that MiniSOX9 is expressed at high levels in human colon cancer samples whereas it is undetectable in the surrounding healthy tissues. Finally, we discovered that MiniSOX9 behaves as a SOX9 inhibitor, inhibits protein kinase Cα promoter activity and stimulates the canonical Wnt pathway. This potential oncogenic activity of the SOX9 locus gives new insights on its role in colon cancer.

[The lymph node of Mondor: myth or reality?]. / Le ganglion de Mondor : mythe ou réalité ?

AIM OF THE STUDY: Lymph node involvement is one of the most significant prognostic factors of patients with rectal cancer. Despite major advances in our understanding of the propagation of the rectal cancer, the lymphatic drainage of the rectum remains unclear. This study was designed to assess the number of lymph nodes located around the superior rectal artery and to assess the frequency of Mondor's lymph nodes. PATIENTS AND METHODS: Twenty-five anatomic subjects were studied. All resections were performed using total mesorectal excision. Lymph nodes were sought in the tissue surrounding the superior rectal artery up to 2 cm under the ending of the superior rectal artery by manual dissection and were submitted for histological examination. The correlation between the number of lymph nodes, and the volume and weight of the tissue surrounding the superior rectal artery was evaluated by non-parametric Spearman test. RESULTS: The mean number of lymph nodes per specimen was 2.7 +/- 1.4. The size of the lymph nodes varied between 1 and 7 mm. The lymph nodes were mostly smaller than 3 mm (56%). The number of lymph nodes in the superior rectal mesentery was independent of its volume and its weight. Seven subjects had a Mondor's lymph node. The mean size of Mondor's lymph node was 3.4 +/- 2.1 cm. CONCLUSIONS: The number of NL located around the superior rectal artery is small, varying between 1 and 5. The Mondor's lymph node is an inconstant rectal NL. Its only characteristic is its location in the bifurcation or trifurcation of the superior rectal artery.

The number of lymph nodes is correlated with mesorectal morphometry.

BACKGROUND: Lymph node involvement is one of the most significant prognostic factors of patients with rectal cancer. However, the distribution of mesorectal lymph nodes is not well known. This study was designed to assess lymph nodes in the mesorectum and to evaluate the correlation between the volume and weight of the mesorectum and the number of lymph nodes. METHODS: The mesorectums of 20 human cadavers were studied. The volume and weight of the superior rectal mesentery, superior mesorectum and inferior mesorectum were measured. Lymph nodes were sought by manual dissection and were submitted for histological examination. The correlation between the number of lymph nodes and the volume and weight of the mesorectum was evaluated by non-parametric Spearman test. RESULTS: A total of 178 lymph nodes were identified. The mean number of lymph nodes per specimen was 9.2 +/- 4.5. The lymph nodes were mostly smaller than 3 mm and located in the superior and posterior parts of the mesorectum. A positive correlation was found between the number of mesorectal lymph nodes and the volume and weight of the mesorectum. The number of lymph nodes in the superior rectal mesentery was independent of its volume and its weight. CONCLUSIONS: Mesorectal lymph nodes are mainly located above the peritoneal reflection within the posterior mesorectum. The positive correlation between the volume or the weight of the mesorectum and the number of mesorectal lymph nodes should be considered as a possible means to determine the minimum number of mesorectal lymph nodes required for histological examination.

Dissociated overexpression of cathepsin D and estrogen receptor alpha in preinvasive mammary tumors.

The role of estrogen as a promoter agent of sporadic breast cancer has been considered by assaying, in benign breast disease (BBD) and in situ carcinomas (CIS), 2 markers, the estrogen receptor alpha (ERalpha) and cathepsin D (cath-D) involved in estrogen action on mammary tissue. ERalpha and cath-D were assayed by quantitative immunohistochemistry using an image analyzer in 170 lesions of varying histological risk (94 BBD and 76 CIS), and in "normal" glands close to these lesions. The ERalpha level increased significantly in proliferative BBD with atypia (P < .001), in non-high-grade CIS (P < .001), and in adjacent "normal" glands. ERalpha level was decreased in high-grade ductal CIS (DCIS) and also in adjacent "normal" glands. Cath-D level increased in ductal proliferative BBD (P < or = .01) and in high-grade DCIS (P < or = .003), but not in the other lesions. After menopause, ERalpha level was increased (P = .012) but not cath-D level. According to Mac Neman test, the high-grade DCIS were predominantly ERalpha negative and cath-D positive (P = .0017), and the other CIS were predominantly ERalpha positive and cath-D negative (P = .0002). The 2 markers are overexpressed early in premalignant lesions, but independently. This dissociation suggests a branched model of mammary carcinogenesis involving 1 estrogen-independent pathway with high cath-D and low ERalpha levels (including high-grade DCIS) and 1 estrogen-dependent pathway, with high ERalpha level (including proliferative BBD with atypia and low-grade DCIS). We propose that ERalpha-negative breast cancers may develop directly from high-grade DCIS and that ERalpha assay in preinvasive lesions should be considered in prevention trials with antiestrogens.

[Vestigial retrorectal cyst in adults]. / Kyste vestigial rétrorectal de l'adulte.

STUDY AIM: The aim of this retrospective study was to report three cases of retrorectal vestigial cyst in adults. PATIENTS AND METHOD: From 1977 to 1999 retrorectal vestigial cyst (RVC) was diagnosed in our department in three women who were 28, 57 and 53 years of age, respectively. RVC was revealed by either pain (n = 2) that occurred in one case in a pregnant woman, or acute intestinal obstruction (n = 1). The patients were operated on using a perineal approach in two cases and an abdominal approach in one case. RESULTS: One epidermoid cyst and two mixed cysts without any sign of malignancy were observed. Postoperative follow-up was simple in two patients, while complications occurred in the third one via an uretero-vaginal fistula which required uretero-vesical reimplantation. The first two patients, reviewed after a 1-year follow-up, had no functional trouble and no sign of recurrence. CONCLUSION: Retrorectal vestigial cysts are very rare tumors with a risk for degeneration. Computerized tomography on nuclear magnetic resonance and endorectal ultrasonography allow detection of their structure and topography and help guide their surgical approach. In the absence of malignancy, wide excision, if possible without opening of the cystic wall, leads to good results.

Mechanisms of ventricular arrhythmias induced by myocardial contusion: a high-resolution mapping study in left ventricular rabbit heart.

BACKGROUND: The aims of the Langendorff-perfused rabbit heart study were to evaluate the arrhythmogenic consequences of myocardial contusion and to determine the mechanism of arrhythmia. METHODS: Six hearts were in the control group, and 24 hearts (intact heart protocol) were submitted to one of four different contusion kinetic energies (75, 100, 150, or 200 millijoules [mJ]; n = 6). Occurrence of arrhythmia, of an electrically silent area (i.e., area with no electrical activity), and of line of fixed conduction block were reported before and for 1 h after contusion. In 16 hearts (frozen hearts) submitted to cryoprocedure and contusion impact of 100 or 200 mJ, ventricular conduction velocities, anisotropic ratio, wavelengths, ventricular effective refractory period, and its dispersion were measured before and for 1 h after contusion. Using high-resolution mapping, arrhythmias were recorded and analyzed. RESULTS: The intact heart study showed that the number and seriousness of contusion-induced arrhythmias increased with increasing contusion kinetic energy, as did the number of electrically silent areas (five of six ventricular fibrillations and five of six electrically silent areas at 200 mJ). In the frozen heart study, immediately after contusion ventricular effective refractory periods were shortened and dispersed, and wavelengths were also shortened. The arrhythmia analysis showed that all ventricular tachycardias but one were based on reentry developed around an electrically silent area or a line of fixed conduction block. CONCLUSIONS: Myocardial contusion has direct arrhythmogenic effects, and the seriousness of arrhythmia increases with the level of contusion kinetic energy. The mechanism of arrhythmia was mainly based on reentrant circuit around a fixed obstacle.

Release kinetics of cardiac troponin I and cardiac troponin T in effluents from isolated perfused rabbit hearts after graded experimental myocardial contusion.

BACKGROUND: Few experimental studies report effects of direct contusion on cardiac enzyme release. Cardiac troponins I (cTnI) and T (cTnT) have been shown to be highly sensitive and specific markers of myocardial cell injury. This investigation was designed to determine and compare the acute effects of quantified magnitudes of blunt cardiac trauma upon release of cTnI and cTnT in comparison with creatine kinase (CK) and lactate dehydrogenase (LD). METHODS: In 24 rabbit hearts prepared on a standard Langendorff apparatus, myocardial contusion (MC) was produced by a single blow with a ball falling from a predefined height, delivered directly to the surface of the heart. Hearts were divided into control (n = 6) and various quantified impacts: 75 mJoules (mJ) (n = 6), 100 mJ (n = 6), 200 mJ (n = 6). Coronary effluent samples for cTnI, cTnT, CK, and LD were collected at baseline, immediately after MC and 5, 15, 30, 45, and 60 minutes after MC. At the end of experiment, histologic condition was evaluated. RESULTS: The anti-cTnI and cTnT MAbs used in the cTnI (Access) and cTnT (Elecsys) assays cross-react with cTnI and cTnT of the rabbit. The time-courses of cTnI, cTnT, CK, and LD were monophasic in form. After MC, all parameters rose significantly compared with baseline and with control group. The maximal release occurred immediately after MC. The area under the cTnI curve and the maximal cTnI concentration were linked to the contusion energy when increased at 200 mJ. Maximal concentrations and areas under cTnT, CK, LD time activity curve were not linked to the contusion energy level and showed no between-energy group differences. The correlation found between maximal cTnI and maximal cTnT concentrations was 0.70 (p = 0.0001). Histologic examination showed cellular disruption and after the more severe impact, the extent of pathologic changes was more extensive. CONCLUSION: After graded experimental MC, maximal cTnI concentration and area under cTnI curve increase with the power of impact kinetic energy. Levels of cTnI allow a much higher accuracy in detecting the extent of myocardial injury postMC in comparison with cTnT, CK, and LD in this experimental study. These results should be consistent with the more extensive cTnI release with more severe impact in patients with blunt chest trauma. Furthermore, because specificity and time-course of release, both cTnI and cTnT should have a role in the diagnosis and evaluation of such patients.

p53 and follow-up of colorectal adenocarcinomas.

Circulating p53 antibodies (ELISA method), p53 genetic alterations (SSCP), and protein overexpression (immunohistochemistry) were studied in 41 patients with colorectal adenocarcinomas and 10 control patients. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA 19-9) were evaluated in parallel. Ten patients with p53 antibodies and p53 overexpression were selected. Tumor DNA extracts from these 10 patients were analyzed by SSCP. Of all 41 patients, 10 (24%) showed significant levels of p53 antibodies, and p53 accumulation was detected in 20 (48%) patients. In six patients, p53 antibody concentrations decreased rapidly after surgery; in two patients, these levels returned to normal values. Of the 10 selected tumors, eight revealed TP53 gene mutations. Only two patients with high values of both CEA and CA 19-9 developed p53 antibodies. In conclusion, beside classical tumor markers, circulating p53 antibodies may be considered as additional markers for the management of patients with colorectal adenocarcinomas.

Differential responsiveness to contractile agents of isolated smooth muscle cells from human colons as a function of age and inflammation.

To study the involvement of age and inflammation in motor colonic activity in man, contractile responses to CCK, carbachol, and KCl of isolated colonic smooth muscle cells (SMC) from normal and inflamed human colons were evaluated; the incidence of sex and smoking on contraction was also analyzed. Contractile responses to the three agonists were significantly lower in tissues with a low degree of inflammation than in tissues with high level of inflammation or normal tissues. This reduction in cell responsiveness appears to be nonspecific and nonreceptor mediated. A positive correlation of the contractile responses to the three stimulants with the age of patients was observed. In contrast, no association was found between sex, smoking, and cell contraction. In conclusion, contractions of SMC due to CCK, carbachol, and KCl were significantly modified during life; inflammation of the colon led to a loss of SMC responsiveness.

Primary sinusoidal lymphoma of the liver revealed by autoimmune hemolytic anemia.

Primary liver lymphomas usually present with the clinical picture of a liver tumor, and are characterized by a predominantly portal invasion by lymphoid cells of the B-cell phenotype. We report a case of primary sinusoidal lymphoma of the liver, in a 36 year-old male patient, revealed by homogeneous hepatosplenomegaly and infiltration of liver sinusoids by morphologically normal lymphocytes, without destruction of the parenchyma. Immunohistochemistry in paraffin-embedded tissue sections was positive for the pan T-cell marker MTI, weakly positive for UCHLI, and negative for CD3, and B-cell markers were negative; these findings were consistent with the diagnosis of T-cell lymphoma. The clinical, histological and immunological presentation of this lymphoma was similar to that of hepatosplenic gamma delta T-cell lymphoma. Autoimmune hemolytic anaemia preceded the lymphoma. Despite chemotherapy, the patient died 24 months after the initial presentation in the leukemic phase. A better understanding of this exceptional but characteristic entity is required for an accurate and early diagnosis.

[Double gastric and thyroid localization of MALT lymphoma with lymphocytic thyroiditis]. / Double localisation d'un lymphome du MALT avec atteinte gastrique et thyroïdienne sur une thyroïdite lymphocytaire.

Case report of a 82 year old man, with double localisation of low grad MALT lymphoma. The first one is in the thyroid gland, with a lymphocytic thyroiditis background; the second one gastric, is revealed by fibroscopy performed after thyroidectomy. The fact that gastric lymphoma could be a primary or secondary entity is discussed.

Metastasizing eccrine porocarcinoma: report of a case and review of the literature.

Eccrine porocarcinoma is a rare malignant tumor arising from the intraepidermal ductal portion of the eccrine sweat gland (acrosyringium). It usually affects older persons and is located most commonly on the lower extremities. We describe a 55-year-old man with an aggressive metastasizing eccrine porocarcinoma diagnosed 10 years after the primary lesion. The metastatic lesions were located in the public area and scrotum and were associated with progressive lymphedema. Several biopsy specimens revealed numerous tumor cells in the dermis and especially in the lumina of lymph and blood vessels. Immunohistochemical studies showed staining with cytokeratin KL1, epithelial membrane antigen, Ca 15-3, and Ca 19-9. Vimentin, S-100 protein, neuron specific enolase, and carcino-embryonic antigen were negative. Treatment with carbon dioxide laser failed. The use of interferon alfa-2a for 9 months stopped progression of the tumor.

[Renal nephrogenic nephroma: an little known exceptional tumor. Apropos of a case disclosed by xanthogranulomatous pyelonephritis]. / Le néphrome néphronogène rénal: une tumeur exceptionnelle peu connue. A propos d'un cas révélé par une pyélonéphrite xantho-granulomateuse.

The authors report a new case of an exceptional benign renal tumour: nephronogenic nephroma, composed of differentiation of the blastema into primitive nephronic formations. It raises the problem of differential diagnosis with adult Wilms' tumour and renal blastematosis. In this patient, it was associated with segmental xanthogranulomatous pyelonephritis, presenting in the form of psoïtis and an abscess of the thigh. Total nephrectomy was performed.

[Cystic dystrophy in an aberrant pancreas. Contribution of computerized tomography and MRI]. / Dystrophie kystique sur pancréas aberrant. Apport de la TDM et de l'IRM.

Case report of a cystic dystrophia appearing in an ectopic pancreas. The clinical diagnosis was preoperatively suspected by the findings of CT scan revealing a tumor located in the wall of the duodenum and by the data of MRI indicating its cystic and fibrotic structure. A focus of reacting pancreatitis was found in the vicinity of the cystic dystrophia while the remaining pancreas was normal. The surgical treatment was a duodenopancreatectomy, justified by the potential risks of complications.

Portal hypertension in lymphoproliferative and myeloproliferative disorders: hemodynamic and histological correlations.

The pathogenesis of portal hypertension in patients with lymphoproliferative and myeloproliferative disorders is not fully understood. We investigated 20 patients with myeloproliferative disease and 47 patients with lymphoproliferative disease. Transvenous liver biopsies and hepatic vein pressure gradient measurements were performed in all patients, and portal vein blood flow was measured by pulsed Doppler sonography in 31 of these patients and in 22 normal volunteers. The hepatic vein pressure gradient was significantly higher in patients with hepatic infiltrates, fibrosis or both than in patients without hepatic lesions (8.3 +/- 5.0 mmHg vs. 4.1 +/- 2.3 mmHg; p < 0.01). Portal vein blood flow was significantly higher in patients with hematological disease than in normal volunteers (31.2 +/- 15.5 ml/min.kg vs. 14.2 +/- 4.6 ml/min.kg;p < 0.01). In 81.8% of patients with hepatic infiltrates, fibrosis or both and increased portal vein blood flow, the hepatic vein pressure gradient was greater than 6 mm Hg. Although we saw a significant correlation between splenic vein blood flow and portal vein blood flow (n = 20; p < 0.01), we found no significant correlation between splenic vein blood flow and hepatic vein pressure gradient or spleen size. Hepatic infiltration and fibrosis appear to be major determinants of increased hepatic vein pressure gradient, probably because they increase intrahepatic vascular resistance. The role of increased splenic blood flow is probably not determinant. However, because portal pressure was not measured directly in this study, the incidence of portal hypertension may have been underestimated.

[Difficult diagnosis of a biliary cyst. A case report]. / Kyste biliaire de diagnostic difficile. A propos d'un cas.

A 26 year-old man presented a hepatic cyst complicated by intracystic bleeding. Clinical and biological features (chronic pancreatitis), ultrasound and computed tomography findings apparent hepatic and splenic location), macroscopic aspects (inflammatory changes, brown-colored fluid) as well as microscopic characteristics (thickened cyst-wall, absence of epithelium) of both cysts suggested the diagnosis of pancreatic pseudocysts. The diagnosis of hepatic cyst was carried out on histological examination showing Meyenburg and neuro-fibrillar complexes. Occurrence of complications (bleeding, size enlargement) may modify typical histological aspect of hepatic cyst.