Prognostic impact of microsatellite instability in colorectal cancer patients treated with adjuvant FOLFOX.

BACKGROUND: Colorectal cancer (CRC) patients whose tumours have microsatellite instability (MSI) do not benefit from adjuvant 5-fluorouracil. However, the predictive value of MSI is not known for FOLFOX, now recommended in adjuvant setting. PATIENTS AND METHODS: MSI phenotype was assessed by the pentaplex method. Three-year relapse and disease-free survival (DFS) of patients treated for CRC with FOLFOX 4 in an adjuvant setting were compared according to MSI phenotype. RESULTS: A total of 105 patients (19 MSI, 86 microsatellite stable, MSS) were included. Stage II patients more frequently exhibited MSI (58%) than MSS (21%); (p=0.002). Patients with MSI relapsed significantly less than those with MSS (10.5% vs. 35.0%; p=0.04). DFS was similar for MSI and MSS (p=0.1). In univariate analysis, stage (p=0.0006) and MSI status (p=0.017) were significant predictors of DFS. CONCLUSION: MSI status was associated with significantly fewer relapses and a better prognosis. FOLFOX4 did not alter survival of patients with MSI and can be administered to them.

Small bowel carcinoma revealing HNPCC syndrome.

Small bowel adenocarcinoma is a rare condition with poor prognosis. Like colorectal cancer, small bowel carcinoma may be a part of genetic syndromes with carcinogenetic pathways different from sporadic forms. We report a case of 41-year-old man with small bowel carcinoma revealing hereditary non polyposis colorectal cancer (HNPCC) syndrome. This report supports the systematic study of the MSI status in every patient with a small bowel carcinoma below 60-year-old of age in order to screen for HNPCC syndrome even in the absence of a family history of related cancers.

Identification of a functional EGF-R/p60c-src/STAT3 pathway in colorectal carcinoma: analysis of its long-term prognostic value.

AIMS: The Epidermal Growth Factor-Receptor (EGF-R) is frequently overexpressed in colorectal carcinoma (CRC) and patients can benefit from anti-EGF-R therapy. Yet, the relationship, within tumours, between EGF-R and the activity of downstream effectors such as the non-receptor tyrosine kinase p60c-src and the signal transducer and activator of transcription 3 (STAT3) has not been extensively analyzed. METHODS AND RESULTS: We evaluated EGF-R, tyrosine 416-phosphorylated p60c-src (P-p60c-src), STAT3 and tyrosine 705-phosphorylated STAT3 (P-STAT3) on Tissue Micro Array (TMA) from 126 patients with CRC. Composite immunohistochemistry scores based on the intensity of labelling and the percentage of positive cells were determined on TMA for EGF-R, P-p60c-src, STAT3 and P- STAT3. A high score was found in 56%, 61%, 62% and 27% of the cases for EGF-R, P-p60c-src, STAT3 and P-STAT3 respectively. There was a significant correlation between EGF-R and P-p60c-src (p=0.006) and between P-p60c-src and P-STAT3 (p=0.0009). STAT3 was significantly correlated with vascular emboli (p=0.03) and perineural invasion (p=0.02). CONCLUSIONS: The correlations between EGF-R, P-p60-src and P-STAT3 and some stage-related pathological features point to a critical role for a EGF-R-connected p60c-src-kinase-mediated pathway involving STAT3 and contributing to cell survival and proliferation within CRC tumours.

Microsatellite instability and sensitivitiy to FOLFOX treatment in metastatic colorectal cancer.

BACKGROUND: Microsatelite instability (MSI) is the consequence of the inactivation of a mismatch repair gene and is observed in approximately 15% of colon cancer cases. Patients with MSI colon cancer do not benefit from 5-fluorouracil (5-FU)-based chemotherapy. A current treatment of reference for colon cancer is a combination of 5-FU and oxaliplatin (FOLFOX). The aim of this study was to determine the efficiency of the FOLFOX treatment in patients with metastatic MSI colon cancer. PATIENTS AND METHODS: Tumour specimens were collected from patients with metastatic colon cancer treated with FOLFOX 4 modified or FOLFOX 6; these two regimens are based on 85 mg/m2 and 100 mg/m2 oxaliplatin, respectively. The MSI status was assessed by measuring the length of five monomorphic mononucleotide markers. The FOLFOX regimen was evaluated as a first-line treatment according to WHO criteria. RESULTS: Forty patients (22 men, 18 women), median age 63.5 years (27-83 years) were treated with FOLFOX 4 or 6. Nine patients had tumours exhibiting high MSI (MSI group) and 31 patients had tumours exhibiting microsatellite stability (MSS group). In the MSS group, 11 partial responses (36%) were observed, while there were only two in the MSI group (22%) (no significant difference). The two patients who were responders in the MSI group were treated with FOLFOX 6. The overall survival was not significantly different for MSI and MSS patients. CONCLUSION: No significant differences in the overall response rate or overall survival between the two groups of patients were observed. However, these results suggest that patients with MSI colon cancer are more sensitive to a higher dose of FOLFOX.

Impact of EGFR expression on colorectal cancer patient prognosis and survival.

BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in many types of cancers, especially colorectal cancer (CRC), and seems to reflect more aggressive histological and clinical behaviors. The aim of this study was to evaluate EGFR immunohistochemical reactivity in CRC biopsies, and to analyze its relationship with various histological and clinical characteristics and survival. PATIENTS AND METHODS: A composite EGFR score, obtained by multiplying the grade (% positive cells) by the intensity of labeling (0-9) was used to define patients with low or high EGFR expression whose clinicopathological features were then compared. Univariate tests and multivariate Cox proportional hazards model were applied for data analysis. RESULTS: Tissue sections from 150 CRC patients with a median follow-up of 40 months were examined. Median patient age at diagnosis was 70 years (range 38-89 years). EGFR reactivity was positive for 143 patients (97%) and high for 118 (80%). According to multivariate analysis, EGFR overexpression was significantly associated with tumor stage, with a higher percentage of EGFR overexpression in T3 than T4 (P=0.003) and not with overall survival. CONCLUSIONS: EGFR was overexpressed in this CRC patient population and was significantly associated with TNM (tumor-node-metastasis) stage T3. In the context of a new therapeutic strategy using EGFR-targeted therapies, although EGFR remains a controversial prognostic factor, this expression-stage association may play a crucial role in a decision to initiate an adjuvant treatment.

Cyclooxygenase-2 is expressed frequently and early in Barrett's oesophagus and associated adenocarcinoma.

AIMS: To establish the prevalence of cyclooxygenase-2 (COX-2) expression in a large series of resected Barrett's adenocarcinoma and associated preneoplastic lesions and to correlate this expression with clinicopathological data and prognosis. METHODS: COX-2 expression was assessed by immunohistochemistry in resected surgical specimens of 66 Barrett's adenocarcinomas and 32 cases of Barrett's mucosa (with dysplasia in 17 cases). RESULTS: Epithelial expression of COX-2 protein was increased in Barrett's mucosa compared with normal oesophagus. Epithelial expression of COX-2 was found in 91% of Barrett's specialized mucosa negative for dysplasia, 94% of Barrett's mucosa with dysplasia, and 97% of Barrett's adenocarcinoma. COX-2 expression was significantly higher in the well-differentiated adenocarcinomas when compared with the poorly differentiated tumours. There was no significant correlation between COX-2 expression and the other pathological features of the tumours. Survival analysis showed no significant prognostic value for COX-2. CONCLUSION: Our results confirm up-regulation of COX-2 in Barrett's oesophagus-metaplastic and dysplastic-and in Barrett's adenocarcinoma. Increased COX-2 expression did not differ during the progression from Barrett's oesophagus negative for dysplasia to Barrett's adenocarcinoma and is related to adenocarcinoma whose histology is well differentiated. This suggests that enhanced expression of COX-2 may occur early during Barrett's-associated neoplastic transformation.

Clinical characteristics and light and transmission electron microscopic sperm defects of infertile men with persistent unexplained asthenozoospermia.

OBJECTIVE: To determine, with the use of transmission electron microscopy (TEM), the proportion of patients with permanent unexplained asthenozoospermia (<30% motility) who have an abnormality of sperm axonemal and periaxonemal structures. DESIGN: Retrospective study. SETTING: A university-affiliated public hospital. PATIENT(S): Sixty-one infertile men whose semen was submitted to TEM analysis because of persistent unexplained asthenozoospermia. MAIN OUTCOME MEASURE(S): The results of quantitative TEM analysis of the tails of the spermatozoa. INTERVENTION(S): None. RESULT(S): Based on a comparison with the axonemal anomalies observed in nine fertile control patients, the infertile population was divided into three groups: group I, with no detectable axonemal defects (26.2%); group II, with axonemal anomalies in either the midpiece or the principal piece (29.5%); and group III, with axonemal anomalies in both the midpiece and the principal piece (44.3%). However, defects in the mitochondrial sheath, fibrous sheath, and sperm head (acrosomic and postacrosomic cap) were observed in at least 50%, 30%, and 50%, respectively, of the patients in each group. The proportion of dense fiber anomalies of the midpiece increased significantly from group I to group III. No differences were observed between the three groups in sperm characteristics, anamnesis information, or clinical data. CONCLUSION(S): In patients with persistent unexplained asthenozoospermia, the frequent association of periaxonemal anomalies with axonemal deficiencies strongly suggests that axonemal deficiencies are not the unique cause of decreased motility.

Ultrastructural identification of Sertoli cells in the semen of subfertile men. About four cases.

In this work Sertoli cells were identified in the semen of subfertile men using transmission electron microscopy. This observation is rare and has only been reported before once. These results would favour of seminiferous epithelium alterations and could be correlated with the presence of immature seminal line elements or non sperm cells in prospective studies.

[Excretory azoospermia: contribution of exploratory and curative surgery. Apropos of a follow-up of 33 patients]. / Les azoospermies excrétoires: apport de la chirurgie exploratrice et curative. A propos du suivi de 33 patients.

Thirty-three patients with azoospermia of apparently excretory origin underwent surgery for epididymis-deferens anastomosis and/or epididymal sperm puncture. Pathology examinations of the epididymal fluid and biopsies of the testicles or epididymis were performed at surgery. Based on the clinical presentation, sperm results and per-operative findings, patients were divided into six groups by etiology: idiopathic azoospermia (n = 5), post-infectious azoospermia (n = 15), agenesia of the excretory (n = 6) or secretory (n = 3) ducts, vasectomy (n = 2), and obstruction of the ejaculatory ducts (n = 2). Peroperative identification of spermatozoa at epididymal puncture or biopsy was statistically more frequent in patients with agenesis of the excretory ducts than in patients with post-infectious or idiopathic azoospermia. Biopsies of the testicle led to the diagnosis of secretory azoospermia in 3 cases and revealed a functional parenchyma in all the other groups of patients. Epididymis-deferens anastomosis was performed in 45% of the cases and was successful in 13%. Rate of fertility with the intracytoplasmic sperm injection was 33%; there was no difficulty in using fresh or frozen sperm. Clinical pregnancy was continued to term with frozen sperm. This study confirms that testicular function is preserved in excretory azoospermia. With or without epididymis-deferens anastomosis, epididymal spermatozoa can generally be preserved for later use. Couples should however be counselled on the delays to contraception which may vary from months to years.

Absence of c-Ki-ras gene mutation in malignant and premalignant Barrett's oesophagus.

Aims-To establish the prevalence of c-Ki-ras gene mutations in codons 12 and 13 in 28 surgically resected Barrett's adenocarcinomas and 18 associated preneoplastic lesions in Barrett's oesophagus.Methods-Mutations were detected using the polymerase chain reaction followed by restriction fragment length polymorphism analysis. Human colon carcinoma cell lines with well characterised mutations in codons 12 and 13 were used as positive controls and to test the sensitivity of the method.Results-c-Ki-ras gene mutations were not detected in any of the 28 specimens of Barrett's adenocarcinoma or in the 18 specimens of Barrett's oesophagus (nine non-dysplastic cases, three cases with low and six with high grade dysplasia).Conclusions-These results suggest that the c-Ki-ras gene is not involved in the development of cancer in Barrett's oesophagus.

[Benign glandular inclusions in inguinal and abdominopelvic lymph nodes in gynecologic pathology]. / Les inclusions glandulaires bénignes dans les ganglions lymphatiques inguinaux et abdominopelviens en pathologie gynécologique.

From 4 cases recently seen at the Institut Gustave-Roussy, this report describes the pathological and evolutive features of benign glandular inclusions in inguinal, pelvic or abdominal lymph nodes. These lesions are defined by the presence of tubular formations in lymph nodes, lined by a single layer of epithelium which is cuboidal or columnar and resembled that of tubal epithelium with ciliated, secretory and intercalary cells. In most cases, benign glandular inclusions in lymph nodes still quiescent. In rare instances, they may proliferate and become papillary. The association of proliferating glandular inclusions in lymph nodes with borderline tumor of the ovary raises the problem of their primary or metastatic origin. However, their pathological features argues for a primary origin in lymph nodes. Thus, we think that a metastatic potential of borderline tumors of the ovary is not supported by any convincing argument.

[Action of 13-cis-retinoic acid and aromatic retinoid on several cutaneous parameters in hyperseborrheic rats]. / Action de l'acide 13-cis-rétinoïque et du rétinoïde aromatique sur divers paramètres cutanés, chez le rat rendu hyperséborrhéique.

Castrated rats submitted to androgenic stimulation present hyperseborrhea with an increase in foamy cells associated with an increase in cutaneous lipids and a change in the number of epidermal cell layers. 13-cis-retinoic acid and aromatic retinoid (Ro 10-9359) were given orally during 17 days (10 mg/kg) to castrated rats which had received a testosterone implant. Cyproterone acetate was chosen as the antiandrogenic drug; it was given at doses of 10 mg/kg i.m. once every other day. As opposed to cyproterone acetate, the two substances studied had no effect on the seminal vesicle and ventral prostate. 13-cis-retinoic acid and retinoic aromatic acid increased the total number of epidermal layers: In the case of 13-cis-retinoic acid, the increase involves especially the nonnucleated cell layers, whereas with retinoid aromatic acid it involves the nucleated cell layer. The number of sebaceous glands is not changed by either products, on the other hand, the number of foamy cells is considerably decreased and the weight of cutaneous lipids is decreased as well.

[The place of urinary cytology in the diagnosis of urothelial tumors]. / Place de la cytologie urinaire dans le diagnostic des tumeurs urothéliales.

A cytologic study was done in three groups of patients, either for screening purposes or for the follow up of vesical tumors already treated by transurethral resection or cystectomy. The reliability of urinary cytology is closely related to the degree of tumor anaplasia (81,8% positive cytology in grade III tumors). When a cytologic and cystoscopic follow-up is done, the results of these two methods are in agreement in 60% of the cases. In the follow up of patients already treated for vesical tumors, the association of cystoscopy and cytology increases the discovery of recurrences by 40%. The persistence of isolated positive cytologies is indicative of highly malignant lesions (grade III). In cystectomized patients, a close correlation exists between the histologic grade and the positivity of the cytologic survey. A cytologic follow up after cystectomy helps to discover a greater number of urethral recurrences.