Anti-CTLA-4 treatment induces IL-10-producing ICOS+ regulatory T cells displaying IDO-dependent anti-inflammatory properties in a mouse model of colitis.

BACKGROUND AND AIMS: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to act as a negative regulator of T cell function and has been implicated in the regulation of T helper 1 (Th1)/Th2 development and the function of regulatory T cells. Tests were carried out to determine whether anti-CTLA-4 treatment would alter the polarisation of naive T cells in vivo. METHODS: Mice were treated with anti-CTLA-4 monoclonal antibody (mAb) (UC10-4F10) at the time of immunisation or colonic instillation of trinitrobenzene sulfonic acid (TNBS). The cytokines produced by lymph node cells after in vitro antigenic stimulation and the role of indoleamine 2,3 dioxygenase (IDO) and of interleukin-10 (IL-10) were tested, and the survival of mice was monitored. RESULTS: Injection of anti-CTLA-4 mAb in mice during priming induced the development of adaptive CD4(+) regulatory T cells which expressed high levels of ICOS (inducible co-stimulator), secreted IL-4 and IL-10. This treatment inhibited Th1 memory responses in vivo and repressed experimental intestinal inflammation. The anti-CTLA-4-induced amelioration of disease correlated with IDO expression and infiltration of ICOS(high) Foxp3(+) T cells in the intestine, suggesting that anti-CTLA-4 acted indirectly through the development of regulatory T cells producing IL-10 and inducing IDO. CONCLUSIONS: These observations emphasise the synergy between IL-10 and IDO as anti-inflammatory agents and highlight anti-CTLA-4 treatment as a potential novel immunotherapeutic approach for inducing adaptive regulatory T cells.

EGFR, c-erbB-2 and ki-67 in NSCLC and preneoplastic bronchial lesions.

BACKGROUND: The relationships between EGF-R and c-erbB-2 with other factors involved in tumour regulation are not well understood. The aim of this study was to correlate the expression of these markers with tumour proliferation. MATERIALS AND METHODS: The presence of EGF-R, c-erbB-2 and Ki-67 was evaluated by immunohistochemistry in non-small cell lung cancer (NSCLC) and preneoplastic lesions. RESULTS: Forty-two percent of the tumours were positive for EGF-R, 22% for c-erbB-2 and 97% for Ki-67. No statistically significant correlation was found between EGF-R and Ki-67, EGF-R and c-erbB-2 or between c-erbB-2 and Ki-67. With regards to Ki-67, a significant difference in survival was noted in favour of patients who did not express the marker. In preneoplastic lesions, most of the low-grade lesions showed neither EGF-R nor Ki-67 staining. In contrast, most of the high-grade lesions stained positively for these proteins. CONCLUSION: EGF-R and c-erbB-2 do not seem to be correlated with Ki-67 in NSCLC.

A glomic tumour of the stomach treated by laparoscopy.

Glomic tumours are rare tumours usually found on the fingertips, particularly the nail-beds, but they can occur anywhere in the body. The first gastric glomic tumour was identified in 1942 and reported with two other cases in 1951 by Key et al. At present, 100 cases of glomic tumour of the stomach have been reported in the literature. We report a case of benign gastric glomic tumour treated by laparoscopic surgery. This type of tumour is most frequently benign but cases of malignity have been described. The preoperative assessment is important.

Prophylactic cranial irradiation in small cell lung cancer: a systematic review of the literature with meta-analysis.

PURPOSE: A systematic review of the literature was carried out to determine the role of prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC). METHODS: To be eligible, full published trials needed to deal with SCLC and to have randomly assigned patients to receive PCI or not. Trials quality was assessed by two scores (Chalmers and ELCWP). RESULTS: Twelve randomised trials (1547 patients) were found to be eligible. Five evaluated the role of PCI in SCLC patients who had complete response (CR) after chemotherapy. Brain CT scan was done in the work-up in five studies and brain scintigraphy in six. Chalmers and ELCWP scores are well correlated (p < 0.001), with respective median scores of 32.6 and 38.8 %. This meta-analysis based on the available published data reveals a decrease of brain metastases incidence (hazard ratio (HR): 0.48; 95 % confidence interval (CI): 0.39 - 0.60) for all the studies and an improvement of survival (HR: 0.82; 95 % CI: 0.71 - 0.96) in patients in CR in favour of the PCI arm. Unfortunately, long-term neurotoxicity was not adequately described. CONCLUSIONS: PCI decreases brain metastases incidence and improves survival in CR SCLC patients but these effects were obtained in patients who had no systematic neuropsychological and brain imagery assessments. The long-term toxicity has not been prospectively evaluated. If PCI can be recommended in patients with SCLC and CR documented by a work-up including brain CT scan, data are lacking to generalise its use to any CR situations.

Expression of p53 in preneoplastic and early neoplastic bronchial lesions.

p53 alteration has been reported to be an early event in bronchial carcinogenesis. Our study purpose was to determine the rate of p53 expression in the various preneoplastic and early neoplastic bronchial lesions obtained by biopsy during fluorescence bronchoscopy and to analyse its association with patients characteristics. Various stages of preneoplastic lesions as well as radio-occult lung cancer were studied in biopsies obtained by fluorescence bronchoscopy. We assessed the expression of p53 by immunohistochemistry using monoclonal antibody clone DO7. The p53 expression was considered as positive if > or = 1% of cells were positive and the level of positivity was expressed in percentage of positive cells. Fourteen patients were included in each category of preneoplastic lesions. At the threshold of 1% of positive cells p53 expression was observed in 28.5% of the patients with a histologically normal epithelium. This number of positive patients increased with the severity of preneoplastic lesions and reached 100% in the mild dysplasia. The mean rates of p53 positive cells for normal epithelium, hyperplasia, metaplasia, mild and severe dysplasia, carcinoma in situ and invasive radio-occult carcinoma were respectively 0.9, 3.4, 9.1, 20.5, 50.2, 34.7 and 42.5%. There was no statistically significant correlation between p53 expression and patient characteristics such as sex, age, smoking habits and indication for fluorescence bronchoscopy. The alteration of p53 expression in patients with high risk of lung cancer was an early event: this abnormality increased with the severity of the lesions, without significant correlation with patient characteristics.

CXCR4 expression in vitreoretinal membranes.

BACKGROUND/AIM: Proliferative vitreoretinopathy (PVR) and macular pucker (MP) vitreoretinal membranes are caused by abnormal cell migration. By their role in chemotactism, chemokine receptors represent good candidates to sustain this process. The authors thus investigated the expression of one of them, CXCR4, in these pathologies. METHODS: Three PVR and four MP membranes were surgically removed and processed for immunochemical studies with antibodies for CXCR4, cytokeratins or smooth muscle actin. RESULTS: CXCR4 expression was found in all membranes. There was no relation between severity of PVR or MP and presence of CXCR4. In addition, there was no difference in CXCR4 expression between MP and PVR. CONCLUSION: CXCR4 is expressed in PVR and MP. Further experiments are needed to test if CXCR4 and other chemokine receptors are implicated in vitreoretinal membrane formation.

Expression of thrombospondin in non-small cell lung cancer.

OBJECTIVE: Initially considered as an inhibitor of angiogenesis, the role of thrombospondin is currently controversial. The primary purpose of our study was to determine the expression of thrombospondin (TSP) in invasive lung tumours. The secondary objectives were to investigate its relationship with other factors related to angiogenesis and to assess their clinicopathological significance. MATERIALS AND METHODS: From January 1993 to September 1998, we collected non-small cell lung cancer (NSCLC) and normal nearby-matched tissues from surgical specimens of 64 patients. Using these specimens, we assessed the expression of TSP by immunohistochemistry with monoclonal antibody to human TSP (clone 11.4). This expression was also correlated with other factors directly or indirectly related to angiogenesis:p53, Ki-67 as proliferation factor and microvessel count determined with anti-CD-31 antibody. RESULTS: The resected tumours (stages I-IIIB) consisted of 30 adenocarcinomas, 24 squamous cell carcinomas, 5 bronchioalveolar carcinomas, 4 adenosquamous carcinomas and 1undifferentiated NSCLC. The mean values of TSP expression in neoplastic and normal related tissues were 63.08% and 86.57 %, respectively. This difference was statistically significant (p = 0.02). There was a higher level of variability of TSP expression between tumours than between normal tissues. The expression of TSP in NSCLC was statistically correlated to the expression of TSP in normal matched tissues (coefficient correLation rate = 0.31, p<0.01). The median expression of p53, Ki-67 and microvessel count in tumours was 45.00%, 38.80% and 8.33%, respectively. The correlations between TSP and the other biological variables and between these latter variables themselves were not statistically significant. No statistically significant difference was observed in survival according to TSP expression. CONCLUSION: TSP appeared to be decreased in NSCLC in comparison with normal matched tissue. The TSP expression was not correlated with the other studied variables and was not associated with a significant difference in survival.

How 'hot' is the pathologically positive sentinel lymph node in breast cancer patients?

When many lymph nodes are found by using lymphoscintigraphic techniques performed to detect the sentinel lymph nodes (SLNs) in breast cancer, it is usual to find that the 'hottest' SLN is not always the node that is pathologically positive (pN+). Various criteria have been proposed to define which radioactive lymph nodes should be removed. In order to determine the frequency with which the hottest SLN 'fails' to be pN+, and to determine which criteria best define the radioactive lymph node to be removed, we reviewed and analysed our cases in which more than one SLN was detected and where there was also at least one pN+ node. From a series of 181 patients, 40 were selected. In 11 of these 40 cases (27.5%), the hottest SLN was not pN+. Radioactivity levels in the pN+SLN of these 11 patients ranged from 2% to 94% of the activity of the hottest SLN. Twenty-one patients (52.5%) showed only micrometastatic (pN1a) disease in one or more SLNs. In four of these patients (19%) the pN1a SLN was not the hottest node. Two of the patients had radioactivity levels in the pN+SLN which were more than 50% of that of the hottest SLN. In another two of these patients (9.5%), radioactivity levels were lower than 50% of that of the hottest node (respectively, 38% and 2%). However, in these two last cases, the first and hottest SLN removed surgically was found, by the pathologist, to consist of six nodes. Macrometastases (dimensions greater than 2 mm) were found in 19 patients. In 12 of these patients, the hottest SLN was macrometastatic although macrometastases and/or micrometastases were found in other 'cooler' SLNs in four of them. In another seven of these patients (36.8%), macrometastases were found in SLNs with radioactive levels lower than 51% of that of the hottest node. One patient (with three SLNs) out of the 40 (2.5%) had one SLN pN+ with less than 10% of that of the hottest. In fact, it contained only one micrometastasis and its activity was equal to 2%. Upon pathological examination, however, the hottest lymph 'node' was found to consist of six nodes. It is concluded that, with four intra-mammary and peritumoural injections of 99mTc labelled nanosized colloids of Human Serum Albumin (Nanocoll R: Sorin: 74 MBq and 0.05 mg per injection) performed 18-24 h before using a gamma probe to detect the SLNs, the hottest SLN was not the pathologically positive node in 27.5% of patients in our series. By using the activity in the hottest SLN as the reference point, and 10% of this activity as the lower threshold for removing active SLNs, the sensitivity of the technique is 97.5%.

[Detection of extra chromosomes 12 by fluorescent in situ hybridization (FISH) in ovarian stromal tumors. Study of 12 cases and review of the literature]. / Détection de chromosomes 12 surnuméraires par hybridation in situ fluorescente (FISH) dans des tumeurs stromales ovariennes.

Chromosomic aberrations play a major role in the initiation and the progression of benign as well as malignant tumors. In particular, trisomy 12 is frequently observed in female genitourinary tract tumors and constitutes a recurrent and often unique anomaly in stromal ovarian tumors such as fibrothecomas. Today, the genetic analysis of fresh or fixed solid tumors is enabled by the fluorescent in situ hybridization method (FISH). Using FISH and/or conventional cytogenetics, we analysed 12 ovarian stromal tumors (6 fibromas, 3 fibro thecomas and 3 thecomas). All of these tumors were benign and trisomy 12 was observed in all cases. Moreover, 3 cases presented trisomy and tetrasomy for chromosome 12 simultaneously. The high frequency of trisomy 12 in this tumor type suggests that this abnormality might be implicated in ovarian tumorigenesis.

[VEGF and survival of patients with lung cancer: a systematic literature review and meta-analysis]. / VEGF et survie des patients atteints d'un cancer pulmonaire. Revue systématique avec méta-analyse.

The process of angiogenesis is an important factor in tumour development. One of the principal factors implicated in this process is vascular endothelial growth factor (VEGF) which induces, among other things, an increase in vascular permeability. We have undertaken a systematic review of the English and French literature in order to clarify its effect on the survival of patients with small cell (SCLC) and non-small cell (NSCLC) lung cancer. To be eligible studies had to deal with the the evaluation of VEGF or its receptors in lung cancer and describe the relationship of their expression to survival. The survival figures were subject to meta-analysis after a methodological evaluation by means of a specific numerical scale evaluating the design of the study, the methodology (including laboratory techniques), and the analysis of results. Among the 20 studies selected 15 identified VEGF expression, using univariate analysis, as a statistically significant indicator of poor prognosis. 17 reported sufficient data to allow aggregation of the survival figures, of which 15 were devoted to NSCLC (1,549 patients). The median overall methodological score was 48.3% (range 21.8-72.4%), without significant difference (p=0.63) between studies eligible or non-eligible for meta-analysis. The meta-analysis, using the authors' threshold of positivity for VEGF, showed that VEGF is an unfavourable prognostic factor in NSCLC (HR=1.48; 95% confidence interval 1.27-1.72). The data were insufficient to determine the prognostic value of VEGF in SCLC and that of its two receptors Flt-1 and KDR, with 1, 2 and 1 published studies respectively. In conclusion the expression of VEGF in MSCLC is a factor indicating a poor prognosis.

[EGF-R expression correlation between biopsy and surgical specimens of lung carcinoma]. / Corrélation entre l'expression d'EGF-R dans les biopsies et les pièces chirurgicales des cancers bronchiques.

INTRODUCTION: Most of the time, biological parameters are evaluated on tissues obtained on surgical samples of the primary tumour. New approaches in non small cell lung cancer (NSCLC) treatment consist to administer neoadjuvant chemotherapy or anti-EGF-R (epidermal growth factor receptor) drug. METHODS: We assessed the expression of EGF-R by immunohistochemistry on biopsy samples and on the paired resected tumours in 27 patients. RESULTS: The mean percentage of EGF-R positive neoplastic cells was 11% in surgical specimens compared to 28% in biopsy specimens (p=0.02) although a good correlation (R=0.67; p=0.0001) between biopsies and surgical specimens was observed. Furthermore, the positivity (cut-off > 1% cells) rate was not statistically different between biopsies (55%) and tumours (48%) (p=0.63). In term of positivity rate, we found 85% concordant results between biopsies and resected tumours, 4% false negative and 11% false positive on biopsies in comparison with the resected tumours. The positive and negative predictive value of the biopsies were respectively 80% and 92%. CONCLUSIONS: The evaluation of EGF-R by immunohistochemistry on biopsies may provide reliable information about non small cell lung cancer EGF-R status.

[Subcutaneous nodules and lung cavitated nodules]. / Nodules sous-cutanés et nodules pulmonaires excavés.

An african 22-year old man consulted because of disseminated subcutaneous nodules which appeared two months ago with an increasing number. He also complained from productive cough, wheezing and dyspnea on exertion. A chest CT-scan revealed multiple cavitated nodular lesions in both lungs.

[Mediastinal mass, pulmonary infiltration, and meningitis]. / Masse médiastinale, infiltrat pulmonaire et méningite.

A 42 year-woman suffering from a non-small cell lung cancer, presenting initially as a mediastinal tumor, is hospitalized for fever, headaches and nausea. An aseptic meningitis is diagnosed. The patient died despite the administration of broad spectrum antibiotics and antituberculous agents. The differential diagnoses are presented.

Immune thrombocytopenic purpura at the diagnosis of Hodgkin disease.

We describe the case of a 76-year-old male presenting a thrombocytopenia at the diagnosis of Hodgkin disease. Basing on bone marrow biopsy and evolution, we diagnosed an immune thrombocytopenia and treated with intravenous gammaglobulins. The platelet count normalized in a few days under this therapy. Immune thrombocytopenia purpura (ITP) is a rare complication of Hodgkin disease (HD). It seems to be due to the production of antibodies directed against platelet membrane proteins. The patient's and the lymphoma's characteristics are not predictive for it to happen. The evolution of HD is also not influenced by its occurrence. Various treatments (including corticoids and immunomodulating agents) have been tried with different efficiencies.

COX-2 expression during early lung squamous cell carcinoma oncogenesis.

Cyclooxygenase (COX)-2 is implicated in the oncogenesis of many cancers, and COX-2 inhibitors are effective in preventing the development of tumours, such as in colon cancer. Its expression is increased in nonsmall cell lung cancer and is associated with poor prognosis. The present study assessed COX-2 expression in normal bronchial epithelium, as well as in all the putative precursors of squamous cell carcinomas. COX-2 expression was studied by immunohistochemistry in 106 biopsies collected during autofluorescence bronchoscopy in consecutive patients at high-risk for lung cancer. All biopsies corresponding to normal epithelium or low-grade lesions (lesions up to moderate dysplasia) did not show increased COX-2 expression. Lesions were positive for COX-2 in eight out of 14 severe dysplasia patients, eight out of 14 in situ carcinomas and five out of eight invasive carcinomas. A strong statistically significant difference in COX-2 expression was found between normal epithelium or low-grade lesions and high-grade lesions (severe dysplasia or worse). The positive and negative predictive values of COX-2 expression for high-grade lesion were 100% and 82.35%, respectively. In conclusion, bronchial precursors of squamous cell carcinoma showed increased cyclooxygenase-2 expression and were segregated into low- versus high-grade with a high positive predictive value. Thus, cyclooxygenase-2 appears as a potential early marker of squamous cell carcinoma.

Langerhans' cell histiocytosis arising at the site of basal cell carcinoma excision.

Langerhans' cell histiocytosis (LCH) may be associated with a wide range of neoplastic disorders. However, the combination of a LCH and a basal cell carcinoma (BCC) of the skin still represents a highly unusual condition. In this publication, we report the case of a 48-year-old woman who developed a localized LCH involving the area of a previously excised BCC. Although the exact pathogenesis of this peculiar association remains yet to be elucidated, the hypothesis of an exaggerated Langerhans' cell reaction in response to the underlying BCC appears to be attractive.

Fragile histidine triad protein expression in nonsmall cell lung cancer and correlation with Ki-67 and with p53.

Fragile histidine triad (FHIT) is a tumour suppressor gene, which is altered in a variety of epithelial tumours, including lung cancer. Biochemical and functional pathways of its tumourigenicity are not yet understood. Its role in tumour proliferation is particularly controversial. The purpose of this study was to correlate the expression of FHIT protein in nonsmall cell lung cancer (NSCLC) with tumour proliferation as estimated by Ki-67 antigen and with p53, a suppressor gene. FHIT, Ki-67 and p53 expression were evaluated by immunohistochemistry in 119 resected NSCLC. Altogether, 58 tumours were negative (expression <10%) for FHIT. The median expression in tumours was 15% positive cells, in comparison with 100% in normal matched lung tissue. The expression was as strong as in normal tissue in only 19 cases. FHIT expression was significantly lower in squamous cell carcinoma (SCC) (5%) than in adenocarcinoma (ADC) (64%). The median expression of Ki-67 was 20% and 69% of tumours were positives (expression >10%). Ki-67 expression was significantly higher in SCC (33.3%) than in ADC (10%). The loss of FHIT protein was not correlated with the expression of p53 (median: 7.5%, 58% of positive tumours for a cut-off of 10% of positive cells) or Ki-67. But percentage of labelled cells for p53 and Ki-67 were significantly correlated. The results suggest that for fragile histidine triad, the pathway of tumourigenesis is independent of p53 and of tumoural proliferation, as reported previously in vitro.

Epidermal growth factor receptor expression in pre-invasive and early invasive bronchial lesions.

The 1999 World Health Organization/International Association for the Study of Lung Cancer histological classification of preneoplastic bronchial lesions has been shown to be reproducible but little is known about its biological significance. The current study evaluated the correspondence between the morphological changes of the bronchial epithelium and epidermal growth factor receptor (EGF-R) expression. Thirteen normal bronchial epithelia, 19 hyperplasia, 16 metaplasia, 10 mild dysplasia, one moderate dysplasia, 10 severe dysplasia (SD), 14 carcinoma in situ (CIS) and 11 microinvasive tumours were assessed. A global EGF-R score obtained by the sum of the positivity score plus the EGF-R staining intensity score was calculated for each lesion. A global EGF-R score of >5 was reached only in one metaplasia, in six SD, in six CIS and in six microinvasive tumours. There was no difference in EGF-R expression between normal, hyperplastic and metaplastic epithelia versus mild dysplasia or between severe dysplasia versus CIS and microinvasive tumours but there was a statistically significant difference between mild versus severe dysplasia. This study demonstrates that epidermal growth factor receptor expression rate changes with the stage of the bronchial lesion, increasing from normal epithelium to carcinoma in situ and microinvasive tumours with a statistically significant difference between mild versus severe dysplasia.

The role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analysis.

The prognostic value of epidermal growth factor receptor (EGF-R) for survival of patients with lung cancer remains controversial. The authors performed a systematic review of the literature in order to clarify its impact. Published studies were identified using an electronic search in order to aggregate the available survival results, after a methodological assessment using a scale specifically designed by the European Lung Cancer Working Party (ELCWP). To be eligible, a study had to have dealt with EGF-R assessment in lung cancer patients on the primary site and to have analysed survival according to EGF-R expression. Among the 16 eligible studies, 14 assessed any nonsmall-cell lung cancer (NSCLC) subtype, one adenocarcinoma only and one squamous-cell carcinoma only. The overall median quality score was 56.3%, with no significant difference either between studies assessable or not assessable for meta-analysis or between studies with significant and nonsignificant results. One individual trial reported a survival benefit for patients with EGF-R expression, three a survival disadvantage and 12 no statistically significant difference. Eleven studies (2,185 patients) provided sufficient data to allow a meta-analysis of the survival results. EGF-R expression positivity was determined according to the cut-off as determined by the authors. The meta-analysis showed that EGF-R expression was not a statistically significant prognostic factor for survival in NSCLC. In the subgroup of studies using immunohistochemistry, statistical tests reached a significant level against EGF-R. Epidermal growth factor receptor might be a poor prognostic factor for survival in nonsmall-cell lung cancer. The amplitude of the impact is small, however, and may be subject to publication bias.