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Annales de Pathologie 04/2013; 33(2):79. · 0.25 Impact Factor
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Annales de Pathologie 04/2013; 33(2):142-4. · 0.25 Impact Factor
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ABSTRACT: BACKGROUND: Prognosis of KRAS wild-type and mutant metastatic colorectal cancer (MCRC) patients (pts) treated with bevacizumab (BEV)-containing chemotherapy is not significantly different. Since specific KRAS mutations confer different aggressive behaviors, the prognostic role of prevalent KRAS mutations was retrospectively evaluated in MCRC pts treated with first line FIr-B/FOx, associating BEV to triplet chemotherapy. METHODS: Tumor samples were screened for KRAS codon 12, 13 and BRAF V600E mutations by SNaPshot and/or direct sequencing. MCRC pts <75-years-old were consecutively treated with FIr-B/FOx: weekly 12 hour-timed-flat-infusion/5-fluorouracil (900 mg/m2 on days 1,2, 8, 9, 15, 16,22, 23), irinotecan plus BEV (160 mg/m2 and 5 mg/kg, respectively, on days 1,15); and oxaliplatin (80 mg/m2, on days 8,22). Pts were classified as liver-limited (L-L) and other/multiple metastatic (O/MM). Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test. RESULTS: Fifty-nine pts were evaluated at a median follow-up of 21.5 months. KRAS mutant pts: c.35 G > A, 15 (25.4%); c.35 G > T, 7 (11.8%); c.38 G > A, 3 (5%); other, 3 (5%). KRAS wild-type, 31 pts (52.7%). The objective response rate (ORR), PFS and OS were, respectively: c.35 G > A mutant, 71%, 9 months, 14 months; other than c.35 G > A mutants, 61%, 12 months, 39 months. OS was significantly worse in c.35 G > A pts compared to KRAS wild-type (P = 0.002), KRAS/BRAF wild-type (P = 0.03), other MCRC patients (P = 0.002), other than c.35 G > A (P = 0.05), other codon 12 (P = 0.03) mutant pts. OS was not significantly different compared to c.35 G > T KRAS mutant (P = 0.142). CONCLUSIONS: KRAS c.35 G > A mutant status may be significantly associated with a worse prognosis of MCRC pts treated with first line FIr-B/FOx intensive regimen compared to KRAS/BRAF wild type and other than c.35 G > A mutant pts.
BMC Medicine 03/2013; 11(1):59. · 6.03 Impact Factor
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ABSTRACT: Colorectal cancers (CRCs) with microsatellite instability (MSI) are associated with a good prognosis and a high density of tumor-infiltrating lymphocytes (TILs). We have undertaken to determine the link between TIL densities and MSI CRC histologic features.
Using tissue microarrays, T-cell sub-population infiltration, including T cells (CD3), cytotoxic T cells (CD8) and regulatory T cells (FoxP3) were studied in 86 MSI CRCs. We separately analyzed TILs of the stromal and epithelial compartments in the tumor center, the tumoral invasion margin and associated normal tissue.
For FoxP3+ TIL density in the tumor center stromal compartment, we found a strong negative correlation with T4 stage (p = 0.01), node invasion (p<0.001) and VELIPI (vascular emboli, lymphatic invasion and perinervous invasion) criteria (p = 0.002).
The strong correlation between regulatory T cell density and the absence of VELIPI criteria suggests that this sub-group of T cells is preferentially associated with less invasive tumors.
PLoS ONE 01/2013; 8(4):e61001. · 4.09 Impact Factor
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Gemma Bruera,
Katia Cannita,
Daniela Di Giacomo,
Aude Lamy,
Giancarlo Troncone,
Antonella Dal Mas,
Gino Coletti,
Thierry Frebourg, Jean Christophe Sabourin,
Mario Tosi,
Corrado Ficorella,
Enrico Ricevuto
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ABSTRACT: BACKGROUND: Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of metastatic colorectal cancer (MCRC), particularly integrated with secondary liver surgery in liver-limited (L-L) patients. The prognostic value of the KRAS genotype in L-L and other or multiple metastatic (O/MM) MCRC patients treated with the FIr-B/FOx regimen was retrospectively evaluated. METHODS: Tumoral and metastatic samples were screened for KRAS codon 12 and 13 and BRAF mutations by SNaPshot and/or direct sequencing. Fit MCRC patients <75 years were consecutively treated with FIr-B/FOx regimen: weekly 12-h timed flat-infusion/5-fluorouracil (TFI 5-FU) 900 mg/m2, days 1, 2, 8, 9, 15, 16, 22 and 23; irinotecan (CPT-11) 160 mg/m2 plus BEV 5 mg/kg, days 1, 15; oxaliplatin (OXP) 80 mg/m2, days 8, 22; every 4 weeks. MCRC patients were classified as L-L and O/MM. Activity and efficacy were evaluated and compared using log-rank test. RESULTS: In all, 59 patients were evaluated: 31 KRAS wild-type (53%), 28 KRAS mutant (47%). At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were not significantly different. PFS and OS were significantly different in L-L compared to O/MM evaluable patients. In KRAS wild-type patients, clinical outcome of 12 L-L compared to 18 O/MM was significantly different: PFS 21 versus 12 months and OS 47 versus 28 months, respectively. In KRAS mutant patients, the clinical outcome of 13 L-L compared to 14 O/MM was not significantly different: PFS 11 months equivalently and OS 39 versus 19 months, respectively. CONCLUSIONS: The KRAS genotype wild-type and mutant does not significantly affect different clinical outcomes for MCRC patients treated with the first-line FIr-B/FOx intensive regimen. KRAS wild-type patients with L-L disease may achieve a significantly prolonged clinical outcome due to integration with secondary liver surgery, with respect to KRAS mutant patients.
BMC Medicine 11/2012; 10(1):135. · 6.03 Impact Factor
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Isabelle Soubeyran,
Isabelle Mahouche,
Aude Grigoletto,
Thierry Leste-Lasserre,
Guillaume Drutel,
Christophe Rey,
Stephane Pedeboscq,
France Blanchard,
Veronique Brouste, Jean-Christophe Sabourin,
Yves Bécouarn,
Josy Reiffers,
François Ichas,
Francesca De Giorgi
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ABSTRACT: The human p53 gene is a tumor suppressor mutated in half of colon cancers. Although p53 function appears important for proliferation arrest and apoptosis induced by cancer therapeutics, the prognostic significance of p53 mutations remains elusive. This suggests that p53 function is modulated at a posttranslational level and that dysfunctions affecting its modulators can have a prognostic impact. Among p53 modulators, homeodomain interacting protein kinase (HIPK) 2 emerges as a candidate "switch" governing p53 transition from a cytostatic to a proapoptotic function. Thus, we investigated the possible prognostic role of HIPK2 on a retrospective series of 80 colon cancer cases by setting up a multiplexed cytometric approach capable of exploring correlative protein expression at the single tumor cell level on TMA. Crossing the data with quantitative PCR and p53 gene sequencing and p53 functional assays, we observed the following: despite a strong impact on p21 transcription, the presence of disabling p53 mutations has no prognostic value, and the increased expression of the HIPK2 protein in tumor cells compared with paired normal tissue cells has a strong impact on survival. Unexpectedly, HIPK2 effect does not appear to be mediated by p53 function because it is also observed in p53-disabling mutated backgrounds. Thus, our results point to a prominent and p53-independent role of HIPK2 in colon cancer survival.
American Journal Of Pathology 05/2011; 178(5):1986-98. · 4.89 Impact Factor
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ABSTRACT: KRAS genotyping is mandatory before anti-epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer, which is the second leading cause of cancer-related death in the United States and in Europe. Thus, large-scale KRAS mutation screening is needed for efficient patient management and in the future metastatic colorectal cancer genotyping might also include the detection of the BRAF V600E mutation, which is a very strong negative prognostic factor in colorectal cancer. We report our experience of routine KRAS/BRAF mutation screening practice performed on 1130 formalin-fixed paraffin-embedded tumor samples from 992 colorectal cancer patients. DNA was extracted from macrodissected tumor areas highlighted by a pathologist, KRAS codons 12/13 and BRAF V600E mutations were assessed in a single SNaPshot® multiplex assay and each mutation was confirmed by an independent analysis. KRAS and BRAF mutations were, respectively, present in 41.8 and 6.5% of the tumor samples. If KRAS and BRAF mutations were mutually exclusive, four samples presented two concomitant KRAS mutations. Genotyping of paired primary tumors and metastases from 44 patients indicated that 5 patients (11.4%) presented discordant KRAS mutational status. KRAS genotype heterogeneity was also observed within primary tumor sites in seven cases. Non-reproducible KRAS artefactual mutations were detected in 53 samples (4.7%). We found that the prominent mechanism leading to these artefactual mutations was the fragmentation of DNA occurring during tissue processing. Routine KRAS genotyping performed on formalin-fixed paraffin-embedded tissues requires, therefore, the development of quality control scheme for molecular pathology, especially because of DNA damages induced by formalin fixation. The tumor heterogeneity observed in some patients indicates that it should be more appropriate to perform KRAS genotyping on metastases if sample is available.
Modern Pathology 04/2011; 24(8):1090-100. · 4.79 Impact Factor
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ABSTRACT: KRAS genotyping is mandatory before anti-epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer, which is the second leading cause of cancer-related death in the United States and in Europe. Thus, large-scale KRAS mutation screening is needed for efficient patient management and in the future metastatic colorectal cancer genotyping might also include the detection of the BRAF V600E mutation, which is a very strong negative prognostic factor in colorectal cancer. We report our experience of routine KRAS/BRAF mutation screening practice performed on 1130 formalin-fixed paraffin-embedded tumor samples from 992 colorectal cancer patients. DNA was extracted from macrodissected tumor areas highlighted by a pathologist, KRAS codons 12/13 and BRAF V600E mutations were assessed in a single SNaPshot® multiplex assay and each mutation was confirmed by an independent analysis. KRAS and BRAF mutations were, respectively, present in 41.8 and 6.5% of the tumor samples. If KRAS and BRAF mutations were mutually exclusive, four samples presented two concomitant KRAS mutations. Genotyping of paired primary tumors and metastases from 44 patients indicated that 5 patients (11.4%) presented discordant KRAS mutational status. KRAS genotype heterogeneity was also observed within primary tumor sites in seven cases. Non-reproducible KRAS artefactual mutations were detected in 53 samples (4.7%). We found that the prominent mechanism leading to these artefactual mutations was the fragmentation of DNA occurring during tissue processing. Routine KRAS genotyping performed on formalin-fixed paraffin-embedded tissues requires, therefore, the development of quality control scheme for molecular pathology, especially because of DNA damages induced by formalin fixation. The tumor heterogeneity observed in some patients indicates that it should be more appropriate to perform KRAS genotyping on metastases if sample is available.Keywords: BRAF; cetuximab; colorectal cancer; formalin-fixed paraffin-embedded; KRAS; mutation; SNaPshot
Modern Pathology 04/2011; 24(8):1090-1100. · 4.79 Impact Factor
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Clinical Chemistry 03/2011; 57(7):1077-9. · 7.91 Impact Factor
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Annales de Pathologie 02/2011; 31(1):1. · 0.25 Impact Factor
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ABSTRACT: In ten ovarian endometriomas of diameter exceeding 30 mm, managed by complete vaporization of the inner surface using plasma energy followed by cystectomy, we performed histologic evaluation of the depth of necrosis and the effectiveness of endometrial tissue ablation. We observed that plasma energy allows the ablation of endometrial tissue with minimal damage to the ovarian parenchyma, which suggests that this technique might be of particular interest for women with risk factors of postoperative ovarian reserve impairment, such as recurrent and bilateral endometriomas.
Fertility and sterility 12/2010; 95(5):1853-6.e1-4. · 3.97 Impact Factor
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Jean-Christophe Sabourin
Annales de Pathologie 10/2010; 30(5):335. · 0.25 Impact Factor
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ABSTRACT: The aim of this study was to estimate whether or not the size of an endometrioma is related to the thickness of the ovarian parenchyma inadvertently excised along with the cyst wall.
We performed a retrospective study including 35 women who had undergone endometrioma cystectomy, using an ovarian tissue sparing procedure. In total 38 specimens were studied by three pathologists as three women presented bilateral localizations, and all cyst diameters measured at least 30 mm. For each endometrioma, serial sections were performed, and on each section four different sites were randomly chosen to measure the thickness of glandular epithelium and stroma, of subjacent fibrosis, depending on the cyst, and of the ovarian parenchyma removed with the cyst. The diameter of the ovary was measured preoperatively either by MRI or ultrasound, and the area of the internal wall was then calculated. The relationships between the mean thickness of ovarian parenchyma removed and the variables were estimated and a multiple regression model identified independent predictors for ovarian parenchyma thickness.
Adjacent ovarian tissue was found in 37 cases (97%). The mean thickness of ovarian tissue removed was 1173 +/- 711 microm and that of the cyst wall was 851 +/- 499 microm. The thickness of the ovarian parenchyma removed presented a direct proportional relationship with cyst diameter (P = 0.015), and consequently with cyst wall area (P = 0.032). This relationship with cyst diameter was independent after adjustment on other variables (P = 0.032).
Endometrioma cystectomy even though performed with an accurate surgical technique leads to significant ovarian tissue removal, the thickness of which increases proportionally with cyst diameter.
Human Reproduction 04/2010; 25(6):1428-32. · 4.47 Impact Factor
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Annales de Pathologie 02/2010; 30(1):2-6. · 0.25 Impact Factor
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Jean-Christophe Sabourin,
Jean-Christophe Fournet,
Homa Adle-Blassette,
Frédéric Bibeau,
Béatrix Cochand-Priollet,
Serge Guyetant,
Xavier Leroy,
François Paraf,
Natacha Patey,
Nathalie Rioux-Leclercq,
Magalie Svrcek,
Philippe Vielh
Annales de Pathologie 02/2010; 30(1):1. · 0.25 Impact Factor
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ABSTRACT: We describe a case of oligodendroglioma arising in an ovarian mature cystic teratoma associated with a loss of heterozygosity on the long arm of chromosomes 19 and 10. To our knowledge it is the second case reported in the literature at this site and the first one described in association with a characterized genetic alteration. The patient was 29 years old and presented with a history of 4 months of pelvic pain. Ultrasound examination showed a cystic mass arising in the left adnexa suggesting a teratoma. At laparotomy a cystic ovoid mass was found arising from the left adnexa, completely replacing the ovary. An ovariectomy was performed. Macroscopically a multilocular cyst containing hair, sebum, and a relatively well-defined solid zone of grayish-pink color strongly suggestive of a cerebral tissue, was observed. Microscopic analyses confirmed the teratomatous nature of the cyst. The solid area was composed of mature glial tissue in which was observed a proliferation of monotonous cells with round and homogenous nuclei, surrounded by a clear halo of cytoplasm ("honeycomb appearance") which immunohistochemically showed positivity for glial fibrilar acidic protein and for neurofilament protein. Ki-67 labeling index was about 3%. These findings were consistent with a low-grade oligodendroglioma arising in a mature ovarian cystic teratoma. Reverse transcription-polymerase chain reaction analysis showed a characterized loss of heterozygosity occurring in tumor DNA on chromosomes 10q and 19q13.
International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 08/2009; 28(4):367-71. · 2.07 Impact Factor
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David Tougeron,
Emilie Fauquembergue,
Alexandre Rouquette,
Florence Le Pessot,
Richard Sesbo|[uuml]||[eacute,
Mich|[egrave]|le Laurent,
Pascaline Berthet,
Jacques Mauillon,
Fr|[eacute]|d|[eacute]|ric Di Fiore, Jean-Christophe Sabourin,
Pierre Michel,
Mario Tosi,
Thierry Fr|[eacute]|bourg,
Jean-Baptiste Latouche
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ABSTRACT: Colorectal cancers with microsatellite instability are characterized by an important density of tumor-infiltrating lymphocytes and a good prognosis. Microsatellite instability results from the inactivation of the DNA mismatch repair system and induces secondary somatic frameshift mutations within target genes harboring repeat sequences in their coding frame. By disrupting the open reading frame, frameshift mutations can result in the appearance of potentially immunogenic neopeptides. To determine the frameshift mutations inducing a T-cell response during the development of a tumor with microsatellite instability, we studied in 61 colorectal cancer patients with microsatellite instability, using a fluorescent multiplex PCR comparative analysis, the relative frequency of frameshift mutations within 19 target genes and analyzed the correlation of these frameshift mutations with the density of CD3+ tumor-infiltrating lymphocytes. The four most frequently mutated genes were ACVR2 (92%), TAF1B (84%), ASTE1/HT001 (80%) and TGFBR2 (77%). The vast majority (95%) of the tumors exhibited at least three frameshift mutations, and the number of frameshift mutations was associated with tumor progression (TNM stage, wall invasion and tumor diameter). Tumor-infiltrating lymphocyte density was associated with the overall number of frameshift mutations and with the presence of frameshift mutations within two target genes, namely ASTE1/HT001 and PTEN. These results strongly argue for the clinical relevance of immunotherapy of colorectal cancers with microsatellite instability.Keywords: microsatellite instability, replication error phenotype, tumor-infiltrating lymphocytes, hereditary nonpolyposis colorectal cancer, neoantigens
Modern Pathology 06/2009; 22(9):1186-1195. · 4.79 Impact Factor
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ABSTRACT: Adenomatoid tumors are benign neoplasms of mesothelial origin, which involve the feminine and masculine genital tracts. They are more generally casually discovered. Our study presents an adenomatoid tumour, of cystic shape, which enables discussion of the histogenesis of this tumour and enlightenment of differential diagnoses which can at times result in an incorrect malignant diagnosis.
Annales de Pathologie 05/2009; 29(2):134-7. · 0.25 Impact Factor
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ABSTRACT: Using data from 27 women with deep rectal endometriosis, managed by segmental resection, we observed that in 89% of cases active glandular endometrial foci were responsible for a deeper infiltration of rectal layers than that of fibrosis and smooth fibers by 5 mm on average. These data might be useful for surgeons performing rectal nodule excision, suggesting the benefits of administrating postoperative medical treatment to reduce the risk of rectal recurrences caused by remaining active endometriotic foci.
Fertility and sterility 05/2009; 92(4):1250-2. · 3.97 Impact Factor
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Jean-Yves Scoazec, Jean-Christophe Sabourin,
Homa Adle-Biassette,
Marie-Pierre Bralet,
Marie-Pierre Chenard-Neu,
Béatrix Cochand-Priollet,
Catherine Guettier,
Vincent Molinié,
François Paraf,
Nathalie Patey,
Philippe Vielh
Annales de Pathologie 03/2009; 29(1):1-2. · 0.25 Impact Factor
