Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia.

PURPOSE: In patients with neutropenia, thoracic computed tomography (CT) halo and air-crescent signs are recognized as major indicators of invasive pulmonary aspergillosis (IPA). Nevertheless, the exact timing of CT images is not well known. PATIENTS AND METHODS: Seventy-one thoracic CT scans were analyzed in 25 patients with neutropenia with surgically proven IPA. RESULTS: On the first day of IPA diagnosis with early CT scan (d0), a typical CT halo sign was observed in 24 of 25 patients. At that time, the median number of thoracic lesions was two (range, one to six), and pulmonary involvement was bilateral in 12 cases. The halo sign was present in 68%, 22%, and 19% of cases on d3, d7, and d14, respectively. Similarly, the air-crescent sign was seen in 8%, 28%, and 63% of cases on the same days. Otherwise, a nonspecific air-space consolidation aspect was seen in 31%, 50%, and 18% of cases on the same days. The analysis of calculated aspergillary volumes on CT showed that, despite antifungal treatment, the median volume of lesions increased four-fold from d0 to d7, whereas it remained stable from d7 to d14. Overall, 21 patients (84%) were cured by the medical-surgical approach. CONCLUSION: In patients with neutropenia, CT halo sign is a highly effective modality for IPA diagnosis. The duration of the halo sign is short, and it demonstrates the value of early CT. The increase of the aspergillosis size on CT in the first days after IPA diagnosis is not correlated with a pejorative immediate outcome when using a combined medical-surgical approach.

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.

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.

Minocycline pneumonitis and eosinophilia. A report on eight patients.

We identified eight patients (six women and two men) who had pulmonary infiltrates during treatment with minocycline hydrochloride between 1989 and 1992 in French referral centers for drug-induced pulmonary diseases. Clinical files, chest roentgenograms, computed tomographic scans, pulmonary function, and bronchoalveolar lavage data were reviewed. Minocycline treatment was given for acne (n = 4), genital infection (n = 3), and Lyme disease (n = 1). The duration of treatment averaged 13 +/- 5 days (mean +/- SE); the total dose, 2060 +/- 540 mg. Patients presented with dyspnea (n = 8), fever (n = 7), dry cough (n = 5), hemoptysis (n = 1), chest pain (n = 2), fatigue (n = 3), and rash (n = 3). Chest roentgenograms showed bilateral infiltrates in all cases. Pulmonary function was measured in five patients; four had airflow obstruction and two had mild restriction. Blood gas tests demonstrated hypoxemia in seven patients (58 +/- 3 mmHg). Seven patients had blood eosinophilia (1.76 +/- 0.2 x 10(9)/L). Bronchoalveolar lavage (performed in seven patients) showed an increased proportion of eosinophils (0.30 +/- 0.07). The Cd4+/CD8+ ratio was determined in four cases and was low in three. Transbronchial lung biopsy, performed in two patients, showed interstitial pneumonitis in both patients, with marked infiltration by eosinophils in one patient. The outcome was favorable in all patients. Because of severe symptoms, steroid therapy was required in three patients. Rechallenge was not attempted. We conclude that minocycline can induce the syndrome of pulmonary infiltrates and eosinophilia, that presenting symptoms may be severe and may culminate in transient respiratory failure, and that the disease has a favorable prognosis.

The lung in inflammatory bowel disease.

Respiratory involvement in patients with inflammatory bowel disease (IBD) has been reported mainly since 1976. This form of involvement should clearly be separated from interstitial lung disease due to sulfasalazine or mesalamine, although the distinction may be difficult in some cases. We report the data of an ongoing Registry containing 33 cases (23 cases receiving no drug therapy) with ulcerative colitis or, less often, Crohn's disease, who developed varied bronchopulmonary problems. In several cases, the exact diagnosis and the relation of the bronchopulmonary disease to IBD had not been established for many years, thus delaying effective treatment with steroids. In most cases (28/33), respiratory involvement followed the onset of IBD (8 of these 28 cases were postcolectomy), and in the remainder, respiratory manifestations predated the IBD. Patterns of involvement included: 1) Airway inflammation, in the form of subglottic stenosis, chronic bronchitis, severe chronic bronchial suppuration, bronchiectasis, and chronic bronchiolitis. In cases with large airway involvement, endoscopy showed exuberant inflammatory tissue in the airways and narrowing of tracheal and/or bronchial lumen. Histologically, airways were heavily infiltrated by a dense aggregate of inflammatory cells, and there were mucosal ulcerations. 2) Varied patterns of interstitial lung disease, mainly bronchiolitis obliterans with organizing pneumonia, and pulmonary infiltrates and eosinophilia. (3) Miscellaneous other forms of involvement including striking neutrophilic necrotic parenchymal nodules (corresponding histologically to sterile aggregates of neutrophils), and serositis. Steroids were very effective in the majority of cases. Inhaled steroids were of durable benefit in patients with chronic bronchitis, but less often so in those with chronic bronchial suppuration, bronchiectasis, or chronic bronchiolitis. Steroids administered orally led to marked improvement in patients with interstitial lung disease and necrotic nodules, but lacked effectiveness in several patients with severe airway inflammation or chronic bronchiolitis. Intravenous steroids were required in the initial management of life-threatening complications such as asphyxiating subglottic stenosis or extensive interstitial lung disease. Bronchial lavages with methylprednisolone were effective in some patients with severe airway inflammation. Patients with IBD can develop varied inflammatory complications in the lung, and a sizable fraction of these complications is steroid-sensitive.

What is the best way to assess microsatellite instability status in colorectal cancer? Study on a population base of 462 colorectal cancers.

The assessment of the microsatellite instability (MSI) status in colorectal cancers is presently warranted for three reasons: 1) as a screening tool for hereditary nonpolyposis colorectal cancer, 2) as a prognostic marker, and 3) as a potential predictive factor of chemotherapy response. The aim of this study was to evaluate, on a large scale with tissue samples coming from a number of different sources, the difficulties met with routine use of immunohistochemistry (IHC) and to determine if it really does offer an accurate alternative to PCR genotyping. Colorectal carcinomas from 462 consecutive patients resected in public or private hospitals were assessed for MSI status by two methods: MSI testing (with BAT-26 microsatellite) and IHC detection of hMLH1, hMSH2, and hMSH6 proteins. Of the 398 cancers tested, immunohistochemistry was noncontributory in 42 (10.5%), focal in 9 (2.3%), and discordant with the PCR results in 36 (9%). For these 87 cases, complementary analyses were performed to explain discrepancy. After additional IHC assay with modified processing protocols, 8 cases remained noncontributory, 2 focal, and 28 discordant: 18 microsatellite stability IHC/MSI PCR and 10 MSI IHC/microsatellite stability PCR. For these discordant cases, we performed a multiplex PCR assay on DNA extracted from the frozen sample and BAT-26 was amplified from DNA extracted from the paraffin blocks used for IHC. Four discordant cases were reclassified after PCR multiplex assay (3 as MSI and 1 as microsatellite stability). Five other cases displayed intratumoral heterogeneity and 19 remained discordant. The discrepancy could be partly explained by variable technical protocols of fixation in the different laboratories, leading to variations in staining quality and difficulties in IHC interpretation. This population-based study is the first one to show that IHC is not sensitive and specific enough to be used routinely. Immunohistochemistry analysis of MMR proteins must be performed in standardized conditions and interpreted by confirmed pathologists. It cannot replace PCR as long as protocols are not optimized and harmonized.

Expression of the chemokine RANTES in pulmonary Wegener's granulomatosis.

Wegener's granulomatosis (WG) is an inflammatory, destructive, angiotropic lesion. The inflammatory process involves accumulation of macrophages, lymphocytes, and polymorphonuclear neutrophils. We studied 6 lung biopsy specimens from patients with WG to characterize the cellular infiltrate and to analyze the mechanism of immune cell recruitment. We show that lymphocytes accumulating in WG lesions are mostly memory CD4(+)CD45RO(+) T lymphocytes and, although less numerous, CD8(+)CD45RO(+) T lymphocytes. Few if any B lymphocytes or natural killer cells are present within lesions. The chemokine RANTES (regulated upon activation in normal T cells, expressed and secreted) has been reported to recruit memory T lymphocytes and macrophages selectively. We used reverse-transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry to study its production in WG. RANTES was expressed at a higher level in WG lungs than in normal controls, especially around microabscesses. As visualized immunohistochemically in serial sections with anti-RANTES monoclonal antibody, RANTES production was produced mainly by macrophages. Expression of the gene coding for interferon-gamma (IFN-gamma), a potent RANTES inducer, was also studied. Its expression was also much stronger in WG than in controls. Our observations are consistent with a cascade of events leading to the recruitment of immune cells in WG, sequentially involving production of IFN-gamma by T lymphocytes and RANTES production by macrophages, leading to the homing of memory T-helper lymphocytes and macrophages. HUM PATHOL 32:320-326.

Are there several types of colorectal carcinomas? Correlations with genetic data.

Molecular studies have shown that different genetic pathways are involved in the history of colorectal carcinomas. This suggests that a correlation exists between the molecular, clinical and pathological features of tumours. Two large groups can be individualized: the first group is characterized by allelic losses and hyperdiploidy. These LOH (for loss of heterozygosity)-positive tumours represent 80% of colorectal carcinomas. Among them more than two-thirds are located in the distal colon. They have the worst prognosis. The second group has a normal diploid pattern and a phenotypic microsatellite instability without allelic losses. These tumours represent 10-15% of all colorectal carcinomas and about 30% of the right-sided tumours. They are associated with a better prognosis. In the future, it would perhaps be better to classify colorectal carcinomas according to their molecular features rather than to their topographical localizations.

Effect of different doses of dietary calcium on murine colonic cell proliferation.

One-hundred and twenty 6-week-old 257BL/65 mice were fed for 2 or 7 weeks with diets supplemented with different combinations of bile acids and calcium. The effect of calcium, bile acids and the duration of these treatments on proliferative indices of the colonic mucosa was studied with a multiway analysis of variance. In mice not treated with bile acids, a low level (0.1%) of calcium in the diet was related to a significantly higher number of cells in each compartment of the crypt, compared with diets supplemented with 0.5 and 1% calcium (P < 0.01). There was no difference between the groups fed with normal and high calcium diets. Bile acids significantly increased proliferative indices in all animal groups whatever the duration of the treatment; however, this effect was significantly lower in the mice fed with 0.5% and 1% calcium than in those fed with 0.1% calcium (P < 0.01). There was a significant interaction between the effect of bile acids and the effect of calcium regarding the number of labeled cells and the labeling indices. Duration of the treatment had little effect on these indices. The effect of bile acids on colonic proliferative activity could be significantly reduced by calcium supplementation, and this effect was stable with time. Although there was no toxic effect of the highest calcium diet, there was no advantage in increasing the calcium dose beyond 0.5%.

Intramural neovascularization and haemorrhages are major long-term effects of intravascular gamma-radiation after stenting.

Structural changes that might influence the structural integrity of the vessel in response to intravascular brachytherapy (IVB) and stenting were examined, focus being on the importance of neovascularization in rabbit stented arteries. Stents were implanted in the infrarenal aortas of rabbits, immediately followed by gamma IVB or a sham radiation procedure, and the arteries harvested at 6 months. Labelling for von Willebrand factor showed an increase in adventitial and medial neovascularization in irradiated versus control arteries group (5.04+/-0.89 versus 1.51+/-0.23 mm(-2), respectively; p=0.004). Moreover, intramedial haemorrhages (free hemosiderin deposition) and inflammation (macrophages) were only observed in irradiated arteries. No significant change in expression of matrix metalloproteinase 1, 2 or 3 was observed between the irradiated and control group while collagen content decreased in the irradiated versus the control group (10.05%+/-1.48% versus 31.92%+/-3.12%, respectively; p<0.001). The study supports the hypothesis that IVB associated with stenting induces late deleterious effects on the medial layer, characterized by formation of intramural neovessels, haemorrhages and a decrease in collagen content.

[Prostatic carcinoma: cytopuncture. Technic, cytological aspects, diagnostic value]. / Carcinomes prostatiques: cytoponction. Technique, aspects cytologiques, intérêt diagnostique.

Transrectal fine needle aspiration of the prostate is an excellent method of diagnostic approach. The simplicity of its application and its reliability in the positive cases make it particularly valuable. Therefore, this method should be used more currently as diagnostic tool in prostatic carcinoma.

[Treatment and prognosis of stomach cancers in the population of the Cote d'Or's District (1976-1985)]. / Traitement et pronostic des cancers de l'estomac dans la population du département de la Côte-d'Or (1976-1985).

The present study on treatment and prognosis of gastric cancers is based on the data of the digestive tract cancer registry set up for the French department of Côte-d'Or. During the 1976-1985 period, 784 cases of gastric cancer were diagnosed. Resection for cure was performed in 41.3% of gastric cancers and that proportion remained the same during the course of the study period. Operative mortality was 18.5% after resection for cure and 26.7% after palliative surgery. The overall survival rate was 31.7% at 1 year, 17.0% at 3 years, and 13.0% at 5 years. Ten different criteria (personal data, histologic and therapeutic parameters) were studied in relation to survival. With the univariate analysis, the survival rates were related to age, duration of the symptoms, history of previous gastric ulcer, tumour location, stage of diagnosis and treatment. Only 4 aspects were of good prognosis according to the multivariate analysis (Cox model): extension limited to the gastric wall, resection for cure, duration of the symptoms and location to the antrum or the angulus. These results underline the fact that the prognosis of gastric cancer in a well-defined population remains poor. Because of its severity, gastric cancer still represents a major cancer problem.

[Colorectal hyperplasic polyps in the population of Côte-d'Or, between 1976 and 1985]. / Les polypes hyperplasiques colo-rectaux dans la population du département de la Côte-d'Or, entre 1976 et 1985.

The data of the polyp registry of the Côte d'Or was used to study the characteristics of hyperplasic polyps detected in a well defined-population. In the 1976-1985 10-yr period, 1,222 hyperplasic polyps were resected in 874 Côte d'Or residents. They represented 17% of all polyps. The incidence rate standardized according to the world reference population was 21.9/100,000 in males and 8.1/100,000 in female. The male predominance was observed in all age groups. The incidence of hyperplasic polyps increased by a mean of 19.8% per year in males and 26.6% in females (P less than 0.001). Hyperplasic polyps were discovered twice as often in patients living in an urban area than in patients living in a rural area (P less than 0.001). Hyperplasic polyps were smaller than 5 mm in 91.4% of cases and were located in the rectum in 59.4% of the cases. They were associated with an adenoma in 21.0% of the cases. In the case of a rectal hyperplasic polyp, 10.5% of the patients had an adenoma in the left colon and 2.8% in the right colon. A rectal hyperplasic polyp cannot be considered as a marker of the presence of a large bowel adenoma. The relationship between hyperplasic polyp and colorectal cancer needs to be established.

[Hepatic mesenchymal hamartoma in children. Immunohistochemical, ultrastructural and flow cytometric case study]. / L'hamartome mésenchymateux du foie de l'enfant. Etude immunohistochimique, ultrastructurale et en cytométrie en flux d'un cas.

Mesenchymal hamartoma is a rare liver lesion. This lesion was found in a 7-month-old girl with high serum alphafaetoprotein serum levels and was composed of loose connective tissue containing a certain number of epithelial cells of biliary or hepatic origin. Immunohistochemical studies showed that cytokeratins 7 and 19 were localized in bile duct epithelium. The ultrastructural study showed that the hamartoma was composed of well differentiated ductal structures surrounded by a myxoid mesenchyma with cysts formed either from degenerative mesenchymal areas or from dilated ducts. Flow cytometric analysis of nuclei from frozen tissue revealed that the lesion was DNA aneuploid, with a DNA index of 1.28.

[Cavernous hemangioma of the liver associated with angiosarcoma: malignant transformation?]. / Hémangiome caverneux du foie associé à un angiosarcome: transformation maligne?

Angiosarcoma of the liver is a rare tumor. Its treatment is usually regarded as unsuccessful and its prognosis extremely poor. The authors report the case of a solitary and encapsulated hepatic tumor characterized by the association of a cavernous hemangioma surrounded by an angiosarcoma. The hypothesis of an eventual malignant transformation of cavernous hemangiomas of the liver is raised.

[Cancers of the rectum and colon in the Côte-d'Or department: treatment, prognosis]. / Les cancers du rectum et du côlon dans le département de la Côte-d'Or: traitement, pronostic.

The population based registry of digestive cancers in the french county of Côte-d'Or enables a study of the treatment and prognosis of colorectal cancers. During 1976-1981, 587 rectal cancers and 717 colon cancers were diagnosed. Curative resection was performed in 61 p. 100 of rectal and colon cancers. Operative mortality after curative resection was 9.7 p. 100 for rectal cancers and 13.1 p. 100 for colon cancers. The overall 5 year observed survival rate was 26.5 p. 100 for rectal cancers and 29.8 p. 100 for colon cancers. After curative surgery, 5 year corrected survival rates was 57.2 p. 100 for rectal cancers and 66.9 p. 100 for colon cancers. Five year survival rate was related to the topography of the cancer (it was lower for caecal cancers), to the macroscopic type of growth (it was higher for exophytic carcinomas than for infiltrative carcinomas) and to the size (it was higher for tumors less than 3 cm than for larger tumors). The major determinant of the survival was the pathological stage of the tumor. Patients with Dukes' A lesions at the time of curative surgery had almost the same life expectancy as persons without rectum or colon cancer. These data suggest that a substantial improvement in prognosis might result from earlier diagnosis of the disease. This commands modifications in the policy of detection of colorectal cancers.

[Peliosis hepatis in dermatomyositis treated with azathioprine and corticoids]. / Péliose hépatique au cours d'une dermatomyosite traitée par azathioprine et corticoïdes.

We report a case of peliosis hepatis in a 47-year old male patient with dermatomyositis treated with azathioprine and corticosteroids. Three months after the combined treatment was initiated, the patient developed right thoracic herpes zoster, agranulocytosis and liver enlargement with signs of portal hypertension. Needle biopsy of the liver revealed peliosis. Azathioprine was withdrawn. The clinical and laboratory abnormalities disappeared progressively. The main causes of peliosis hepatis are considered. Up to now, azathioprine had been held responsible for peliosis hepatis only in renal transplant recipients.

[Recommendations for editing pathology reports of colorectal cancer]. / Recommandations pour la rédaction des comptes rendus anatomopathologiques des cancers colorectaux.

The purpose of these recommendations is to provide an informative report for the clinician. The recommendations have been divided into two major areas 1) a standardized form, 2) items that provide an informative gross description and diagnostic features that are recommended to be included in every report. In special circumstances, the recommendations may not be applicable.

[Glandulo-cystic polyps of the stomach. Apropos of 12 cases and review of the literature]. / Les polypes glandulo-kystiques de l'estomac. A propos de 12 cas et revue de la littérature.

We report 12 cases of cystic glandular fundic polyps detected in 7 women and 5 men. As in the 238 similar previously reported cases these lesions were always located in the fundic gastric mucosae and did not involve the muscularis mucosae. They were discovered by endoscopy in patients with minor abdominal discomfort. They were less than 5 mm in diameter and were more often multiple and sessile; only a few of them were pedunculate. They consisted of mucosal cysts lined with cuboidal, parietal or chief cells and surrounded with a normal lamina propria. If in 213 cases, these polyps were not associated with polyposis coli in 37 cases they occurred with a Gardner's syndrome or a familial adenomatosis coli. These benign lesions are without malignant potential. Careful gastroscopic follow up with biopsy is recommended for all patients with multiple gastric polyps. The etio-pathogenesis of these polyps is still unknown. Their relationship to familial polyposis coli or to Gardner's syndrome is obscure.

[Cholangiocarcinoma arising from biliary micro-hamartomas in a man suffering from hemochromatosis]. / Cholangiocarcinome développé sur micro-hamartomes biliaires chez un malade atteint d'hémochromatose.

A case of cholangiocarcinoma arising from multiple bile duct hamartomas (von Meyenburg complexes) is reported in a 68-year-old man. This man has been treated for genetic hemochromatosis for 2 years. The diagnosis of cholangiocarcinoma was suspected by a systematic ultrasound test and made through the pathological examination of the resected specimen. Only six cases have already been reported. Our case is peculiar because it occurred on a genetic hemochromatosis.