Françoise Piard

Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery.

PURPOSE The prognosis of invasive pulmonary aspergillosis (IPA) occurring in neutropenic patients remains poor. We studied whether new strategies for early diagnosis could improve outcome in these patients. PATIENTS AND METHODS Twenty-three histologically proven and 14 highly probable IPAs in 37 hematologic patients (neutropenic in 36) were analyzed retrospectively. RESULTS The most frequent clinical signs associated with IPA were cough (92%), chest pain (76%), and hemoptysis (54%). Bronchoalveolar lavage (BAL) was positive in 22 of 32 cases. Aspergillus antigen test was positive in 83% of cases when tested on BAL fluid. Since October 1991, early thoracic computed tomographic (CT) scans were systematically performed in febrile neutropenic patients with pulmonary x-ray infiltrates. This approach allowed us to recognize suggestive CT halo signs in 92% of patients, compared with 13% before this date, and the mean time to IPA diagnosis was reduced dramatically from 7 to 1.9 days. Among 36 assessable patients, 10 failed to respond (amphotericin B [AmB] plus fluorocytosyne, n = 2; itraconazole + AmB, n = 8) and died of aspergillosis. Twenty-six patients were cured or improved by antifungal treatment (itraconazole with or without AmB, n = 22; voriconazole, n = 4). In 15 of 16 cases, surgical resection was combined successfully with medical treatment. Achievement of hematologic response, early diagnosis, unilateral pulmonary involvement, and highest level of fibrinogen value < 9 g/L were associated with better outcome. CONCLUSION In febrile neutropenic patients, systematic CT scan allows earlier diagnosis of IPA. Early antifungal treatment, combined with surgical resection if necessary, improves IPA prognosis dramatically in these patients.

Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers.

The RAS‐MAPK, PI (3)K signaling pathways form a network that play a central role in tumorigenesis. The BRAF, KRAS and PI3KCA genes code 3 partners of this network and have been found to be activated by mutation in colorectal cancer; these mutations lead to unrestricted cell growth. We evaluated the clinicopathological features and the prognosis of patients with activated‐network colon cancers in a population‐based study. A total of 586 colon adenocarcinomas were evaluated using sequencing for mutations of KRAS and PI3KCA, and allelic discrimination for mutation of BRAF. Clinicopathological characteristics were correlated to the risk of bearing a mutation of the network using logistic regression. Three‐year survival rates were compared with the Log rank test. A multivariate survival analysis using the Cox model was performed. After adjustment for age and microsatellite instability, activation of the network by mutation of at least 1 of the 3 genes was significantly associated with female sex (p = 0.02) and proximal location (p < 0.001). Lower levels of 3‐year survival were associated with activation of the network by mutation of at least 1 of the 3 genes (59.4 and 69.4%, respectively; p = 0.009). These results remained significant in a multivariate analysis adjusted for sex, age, location, stage and microsatellite instability (HR = 1.48; CI CI95% = [1.07–2.04]). Our study is the first report to underline the potential role of RAS‐MAPK, PI (3)K network mutations on survival in colon cancers. Because of the role of this signaling network on anticancer agents, the evaluation of its mutations could have clinical implications.

Adenoma‐carcinoma sequence or “de novo” Carcinogenesis?. A study of adenomatous remnants in a population‐based series of large bowel cancers

Although it is well known that colorectal cancers can arise on a preexisting adenoma or de novo, the relative importance of these two pathways is still highly controversial. The authors studied the proportion of cancers with adenomatous remnants in a nonselected population‐based series of 1630 resected colorectal cancers, so that they could estimate by subsite the importance of the adenoma‐carcinoma sequence. Four factors appeared to be related independently to the presence of adenomatous tissue within cancers in a multiple logistic model: tumor extension, growth pattern, location, and size. It appeared that infiltrating and ulcero‐infiltrating tumors, which represented 39.8% of all resected colorectal cancers, very rarely displayed adenomatous tissue (0.5%), whereas it was more common in fungating and ulcero‐fungating cancers (25.8%; P < 0.001). In these exophytic cancers, the presence of adenomatous tissue was related very closely to the tumor size and extension, and it was seen in as many as 83% of small cancers (< 2 cm) limited to the mucosa or submucosa. Right colon cancer showed consistently fewer adenomatous remnants than left colon or rectal cancer. These figures suggest that there are roughly two types of colorectal cancers, one of the infiltrating or ulcero‐infiltrating type, which usually would arise de novo and account for approximately 40% of all colorectal cancer cases, and the exophytic type, which would mainly follow an adenoma‐carcinoma sequence, although some might be de novo cancers, in particular in the right colon. Cancer 1992; 69:883–888.

How many nodes must be examined to accurately stage gastric carcinomas? Results from a population based study.

There are few population based data about lymphadenectomy practices in resections for stomach carcinoma. The aim of the current study was to describe these practices and to determine how many nodes must be examined in order to accurately stage gastric carcinoma.

Prognosis of gastric carcinoma after curative surgery: A population-based study using multivariate crude and relative survival analysis

A population-based series of 246 gastric cancer patients operated for cure and who survived the postoperative phase was reviewed to determine prognostic factors after potentially curative treatment. The overall five-year observed survival rate was 34.8%, and the relative survival rate was 43.9%. Previous history of gastric ulceration, tumor location, tumor size, gross appearance, extension within the gastric wall, and number of proximal lymph nodes involved were significantly related to both crude and relative survival rates. Age was a significant prognostic factor when considering crude survival rates, but it had no influence on relative survival rates. Multivariate analysis of crude and relative survival gave similar results except for age. The covariates retained in the final model were, by decreasing importance, extension within the gastric wall, lymph node involvement, gross appearance and tumor location. Combining the two major prognostic criteria, tumor extension through the gastric wall and lymph node involvement, four prognostic categories could be determined with five-year corrected survival rates ranging from 92% in patients with a carcinoma limited to the gastric wall to 17% in patients with more than two positive nodes whatever the extension in the gastric wall. Gross appearance had no influence on prognosis for carcinomas limited to the gastric wall, but had a significant impact on prognosis of more extended carcinomas. From these data, a simple staging system requiring only routinely available pathological data was proposed. This classification could be helpful for planning multicenter clinical trials on this disease where progress in therapy is needed.

MRI for evaluating Congenital bile duct abnormalities

Congenital bile duct diseases consist of ductal plate development abnormalities and are genetically determined. These biliary abnormalities are encountered mainly in congenital fibrocystic diseases, represented by congenital hepatic fibrosis and different forms of Caroli disease. On the other hand, polycystic hepatic diseases also present cystic abnormalities, which could be confused with biliary dilatations, especially in the perihilar area. Further, intricate forms between Caroli and polycystic hepatic diseases are possible. In congenital bile duct paucity, which is extremely rare, the biliary tree, located on the opposite, is not visible. MRI modalities for the analysis of the biliary tree are mainly represented by T2-weighted sequence, also known as MR cholangiography (MRCP), and T1 gadolinium-enhanced sequences. Familiarity with the most common appearances of congenital bile duct dilations, its variants, and related complex diseases facilitates accurate diagnosis and allows and helps avoid misinterpretation.

Cellular localisation of Survivin: impact on the prognosis in colorectal cancer

Purpose: The present study was designed to determine whether the nuclear or cytoplasmic expression of survivin, was related to clinicopathological parameters and survival in sporadic colon carcinomas. Methods: Western blotting of cell fractions and immunocytochemical methodology were used in five human colon cancer cell lines. Immunohistochemical study was performed in formalin-fixed paraffin-embedded section from 46 patients with sporadic colorectal adenocarcinomas with a polyclonal antibody directed against survivin. Apoptotic index was evaluated by using the M30 antibody. Survival rates were estimated by the Kaplan–Meier method and compared using the log-rank test. Multivariate survival analysis was performed by the Cox proportional hazards model. Results: Western blotting and immunocytochemistry analyses confirmed that survivin could be detected both in the nucleus and the cytoplasm. Immunohistochemical analysis demonstrated that 39% of tumours expressed survivin in the nucleus and 41% in the cytoplasm. No relationship was observed between survivin expression and clinicopathological features. Unexpectedly, the apoptotic index appeared to be linked with high survivin nuclear expression. Overall, 3-year observed survival rate was 73% in patients with cytoplasmic survivin expression versus 48% for negative expression (P=0.14). Survival was 72% versus 50% for positive nuclear survivin expression versus negative (P=0.16). After adjustment for age and stage, cytoplasmic survivin expression was a significant prognostic factor. A high level of expression was associated to a better survival: RR=0.35 [0.13–0.98], P=0.045. Conclusion: These results indicate that the analysis of the subcellular expression of survivin is a determining factor to define the prognostic value. Its evaluation, using a polyclonal antibody, might help clinicians in the stratification of patients with colorectal cancer.

Why do results conflict regarding the prognostic value of the methylation status in colon cancers? the role of the preservation method

BackgroundIn colorectal carcinoma, extensive gene promoter hypermethylation is called the CpG island methylator phenotype (CIMP). Explaining why studies on CIMP and survival yield conflicting results is essential. Most experiments to measure DNA methylation rely on the sodium bisulfite conversion of unmethylated cytosines into uracils. No study has evaluated the performance of bisulfite conversion and methylation levels from matched cryo-preserved and Formalin-Fixed Paraffin Embedded (FFPE) samples using pyrosequencing.MethodsCouples of matched cryo-preserved and FFPE samples from 40 colon adenocarcinomas were analyzed. Rates of bisulfite conversion and levels of methylation of LINE-1, MLH1 and MGMT markers were measured.ResultsFor the reproducibility of bisulfite conversion, the mean of bisulfite-to-bisulfite standard deviation (SD) was 1.3%. The mean of run-to-run SD of PCR/pyrosequencing was 0.9%. Of the 40 DNA couples, only 67.5%, 55.0%, and 57.5% of FFPE DNA were interpretable for LINE-1, MLH1, and MGMT markers, respectively, after the first analysis. On frozen samples the proportion of well converted samples was 95.0%, 97.4% and 87.2% respectively. For DNA showing a total bisulfite conversion, 8 couples (27.6%) for LINE-1, 4 couples (15.4%) for MLH1 and 8 couples (25.8%) for MGMT displayed significant differences in methylation levels.ConclusionsFrozen samples gave reproducible results for bisulfite conversion and reliable methylation levels. FFPE samples gave unsatisfactory and non reproducible bisulfite conversions leading to random results for methylation levels. The use of FFPE collections to assess DNA methylation by bisulfite methods must not be recommended. This can partly explain the conflicting results on the prognosis of CIMP colon cancers.

Subcellular expression of c-IAP1 and c-IAP2 in colorectal cancers: relationships with clinicopathological features and prognosis.

The Inhibitor of Apoptosis Protein (IAP) family includes several critical cell death inhibitors, the expression of which could be involved in colorectal carcinogenesis. Among them, c-IAP1 and c-IAP2 expression has never been investigated in colorectal cancer. The present study was designed to determine whether expression of both IAPs was related to pathological parameters and survival in sporadic colon carcinomas. Analysis of five human colon cancer cell lines by both western blotting of cell fractions and immunocytochemistry showed that the two IAPs could be expressed both in the nucleus and in the cytoplasm. Immunohistochemical analysis of a series of 46 sporadic colorectal adenocarcinomas demonstrated that c-IAP1 expression was more frequent in the nucleus (85%), and that c-IAP2 was more often expressed in the cytoplasm (82%). A significant association was identified between a strong lymphoid infiltrate in the stroma and the nuclear expression of c-IAP2 (p = 0.02). No other relationship was observed between IAP expression and pathological features. After adjusting by age and stage, the relative risk of death was lower for cytoplasmic c-IAP1, cytoplasmic c-IAP2, and nuclear c-IAP2 expression. It was higher for nuclear c-IAP1 expression. These associations were not statistically significant, but this work underlines the importance of taking into account the subcellular location of the IAP family members in the evaluation of their prognostic significance.

Promoter CpG island methylation of RET predicts poor prognosis in stage II colorectal cancer patients

Improved prognostic stratification of patients with TNM stage II colorectal cancer (CRC) is desired, since 20–30% of high‐risk stage II patients may die within five years of diagnosis. This study was conducted to investigate REarranged during Transfection (RET) gene promoter CpG island methylation as a possible prognostic marker for TNM stage II CRC patients.