bluuebunny/crossref_metadata_2025 huggingface dataset:
Oncocytic papillary carcinoma with lymphoid stroma (Warthin‐like tumour) of the thyroid: a distinct entity with favourable prognosis
Authors: Ludvíková M , Ryška A , Korabečná M , Rydlová M , Michal M
Published: March 2003

Oncocytic papillary carcinoma with lymphoid stroma (Warthin‐like tumour) of the thyroid: a distinct entity with favourable prognosis

Aims: We report the clinicopathological and immunohistochemical characteristics of 12 cases of a recently recognized entity, oncocytic papillary thyroid carcinoma (PC) with lymphoid stroma (Warthin‐like tumour).

Methods and results: The cases were retrieved from the surgical pathology files of our departments. There were 11 female patients and one male patient; they ranged in age from 45 to 85 years (mean 64.2 years). The immunohistochemical profile demonstrated positivity of tumour cells for cytokeratins, thyroglobulin, Leu‐M1 and anti‐mitochondrial antigen. S100 protein‐positive stromal dendritic/Langerhans cells were uniformly present. Polymerase chain reaction, in situ hybridization, and immunohistochemistry for Epstein–Barr virus (EBV) detection revealed no significant positive signal. MIB‐1 labelling index was low, compatible with that of ‘classical’ PC.

Conclusions: Warthin‐like tumour is a rare variant of PC, occurring predominantly in elderly women. Its histological features are distinct and well recognizable, differentiating this tumour from a more aggressive tall‐cell variant of PC. The apparent indolent behaviour seems to be consistent with the presence of dendritic/Langerhans cells and with low proliferative activity. A possible role of EBV in pathogenesis of this lesion was not proven. Further studies are necessary to determine the prognosis and metastatic potential of this neoplasm.
Melanosis of the appendix: common in the paediatric age group
Authors: Graf N S , Arbuckle S
Published: March 2003

Melanosis of the appendix: common in the paediatric age group

Aims: To investigate the incidence of melanosis of the vermiform appendix in a paediatric population, and look for correlations with season, apoptotic rate and inflammation as possible causes.

Methods and results: We examined 300 appendices removed for abdominal pain and incidentally during other procedures over the period January 1996 to March 1999. Melanosis was present in 46% of adequate specimens with an even distribution between sexes and age groups. The two older age groups had a relatively higher incidence of severe involvement compared with the younger age group, although the difference was not statistically significant. We attempted to correlate the presence of melanosis with the season of the year and the peak incidences of paediatric gastrointestinal disease but could find no relationship. No statistically significant correlation was found between apoptotic rate and the presence of melanosis.

Conclusions: The findings suggest melanosis of the appendix is relatively common. It is probably due to apoptosis associated with increased epithelial cell turnover due to many differing causes including infection, with purgative ingestion probably involved in only a minority of paediatric cases.
Liver steatosis in chronic hepatitis C: a morphological sign suggesting infection with HCV genotype 3
Authors: Rubbia‐Brandt L , Leandro G , Spahr L , Giostra E , Quadri R , Malé P J , Negro F
Published: March 2003

Liver steatosis in chronic hepatitis C: a morphological sign suggesting infection with HCV genotype 3

Aims: To identify factors associated with liver steatosis in chronic hepatitis C.

Methods and results: Occurrence and severity of liver steatosis in 254 chronic hepatitis C patients were compared with presence of alcohol abuse, body mass index (BMI) >26, history of intravenous drug addiction and hepatitis C virus (HCV) genotype. Steatosis was found in 109 (43%) patients. The occurrence of steatosis was significantly associated with ongoing alcohol abuse (P=0.03) or HCV genotype 3 (P= 0.003), but not with BMI >26. A moderate to severe steatosis was present in 60% of patients infected with HCV genotype 3, irrespective of the presence of alcohol abuse, BMI >26 or history of intravenous drug addiction. Using a multivariable stepwise logistic regression analysis, infection with genotype 3 had an odds ratio (OR) of 10 (95% confidence interval (CI)=4.56–22) for a liver steatosis, whereas the presence of a cirrhosis at histology had an OR=0.256 (95% CI=0.07–0.92).

Conclusions: A moderate to severe degree of steatosis of the liver is a morphological sign suggestive of infection with HCV genotype 3, independent of other risk factors of a fatty liver, but it may disappear at late stages of the disease.
Cytokeratin 14 immunoreactivity distinguishes oncocytic tumour from its renal mimics: an immunohistochemical study of 63 cases
Authors: Chu P G , Weiss L M
Published: March 2003

Cytokeratin 14 immunoreactivity distinguishes oncocytic tumour from its renal mimics: an immunohistochemical study of 63 cases

Aims: The cytokeratin 14 (CK14) expression in oncocytomas or oncocytic tumours of various tissue origins has not been established. We have studied CK14 expression in 30 cases of oncocytic tumours of various tissue origins and 33 cases of renal cell carcinoma with overlapping features (mimics) by immunohistochemistry.

Methods and results: Immunohistochemistry (ABC–HRP method) was performed for detection of CK14 in 30 cases of oncocytic tumour and 33 cases of renal mimics. To demonstrate CK14 specificity and sensitivity in oncocytic tumours, mES‐13 (an anti‐mitochondrial monoclonal antibody) immunohistochemistry was also performed in 20 of 30 cases on oncocytic tumour and all 33 cases of renal mimics. We found that all 30 cases of oncocytic tumour showed cytoplasmic CK14 positivity. All 20 cases of oncocytic tumour studied with mES‐13 were positive. CK14 immunoreactivity was identified in only four cases of renal cell carcinoma (one conventional renal cell carcinoma with granular cytoplasm and three chromophobe renal cell carcinomas with eosinophilic cytoplasm). In contrast, all 33 cases of renal cell carcinoma were positive for mES‐13 to varying degrees.

Conclusion: The homogeneous, cytoplasmic, and granular CK14 immunoreactivity is sensitive and specific for oncocytic tumours, whereas CK14 immunoreactivity in renal mimics is light and sporadic with peripheral accentuation.
Secondary malignant giant‐cell tumour of bone: molecular abnormalities of p53 and H‐ras gene correlated with malignant transformation
Authors: Oda Y , Sakamoto A , Saito T , Matsuda S , Tanaka K , Iwamoto Y , Tsuneyoshi M
Published: March 2003

Secondary malignant giant‐cell tumour of bone: molecular abnormalities of p53 and H‐ras gene correlated with malignant transformation

Aims: We report two cases of secondary malignant giant‐cell tumour occurring without irradiation therapy. To elucidate the mechanism of malignant transformation in this tumour, we searched for the molecular abnormalities of p53, MDM2 and the H‐ras genes.

Methods and results: These cases were retrieved after a review of 103 cases of primary giant‐cell tumour of bone, registered in our institute. One case occurred in the distal femur of a 42‐year‐old female after surgical curettage, while the other arose in the acetabulum of a 25‐year‐old male after en bloc resection. Microscopically, the malignant tumour in the distal femur was composed of a proliferation of ovoid or fusiform cells arranged in fascicles with high mitotic activities. The malignant transformed tumour in the acetabulum was made up of pleomorphic tumour cells with atypical mitoses. In the tumour of the distal femur, both p53 and H‐ras mutations were detected. Abnormal nuclear accumulation of p53 protein and c‐myc expression were also revealed by immunohistochemistry. In both cases, the recurrent malignant tumour over‐expressed MMP‐9 and revealed a higher MIB‐1‐labelling index compared with the primary conventional giant‐cell tumour.

Conclusions: Our results suggest that multiple oncogene or tumour suppressor gene mutations may play an important role during malignant transformation in conventional giant‐cell tumours.
Patterns of episialin/MUC1 expression in endometrial carcinomas and prognostic relevance
Authors: Sivridis E , Giatromanolaki A , Koukourakis M I , Georgiou L , Anastasiadis P
Published: March 2003

Patterns of episialin/MUC1 expression in endometrial carcinomas and prognostic relevance

Aims: To investigate episialin/MUC1 expression in the normal, hyperplastic and neoplastic endometrium, and relate patterns of tumour MUC1 reactivity with histopathological characteristics, oestrogen and progesterone receptor (ER and PR) status, bcl‐2 and p53 oncoproteins and with clinical behaviour.

Methods and results: We studied 42 normally cycling endometria, 45 endometrial hyperplasias of various forms, and 111 endometrial carcinomas of endometrioid and non‐endometrioid cell types with specific monoclonal antibodies employing standard immunohistochemical techniques. The follow‐up period ranged from 34 to 182 months with a median of 86 months. Epithelial mucin episialin/MUC1 was consistently expressed in the normal endometrium, following a cyclical pattern: ‘apical membrane staining’ in early and mid‐proliferative endometrium; ‘purely cytoplasmic staining’ in late proliferative endometrium; and ‘cytoplasmic staining with intraluminal secretions’ in secretory endometrium. Immunostaining patterns in simple and complex hyperplasia were similar to late proliferative endometrium, while atypical hyperplasias and endometrial carcinomas either simulated patterns of proliferative endometrium or lacked MUC1 reactivity. Membranous MUC1 positivity was statistically more frequent in endometrioid carcinomas compared with carcinomas of non‐endometrioid type (P = 0.006). Cytoplasmic MUC1 positivity was significantly associated with poor prognosis, while MUC1‐negative carcinomas were associated with PR expression and an improved survival (P=0.04). There was no association of MUC1 patterns with bcl‐2 and p53 immunoreactivity or with other histopathological variables.

Conclusions: Episialin/MUC1 is an integral component of the normal premenopausal endometrium and is probably hormonally regulated. It is frequently expressed in endometrial hyperplasias and carcinomas. The loss of MUC1 expression from endometrial carcinomas is associated with a favourable prognosis.
Secretory carcinoma of the breast: a tumour analogous to salivary gland acinic cell carcinoma?
Authors: Hirokawa M , Sugihara K , Sai T , Monobe Y , Kudo H , Sano N , Sano T
Published: March 2003

Secretory carcinoma of the breast: a tumour analogous to salivary gland acinic cell carcinoma?

Aims: Acinic cell‐like breast carcinoma is a newly recognized entity, and few acinic cell‐like breast carcinoma cases have been reported. All reported acinic cell‐like breast carcinomas were counterparts of the solid type of acinic cell carcinoma of the salivary gland. We report here three cases of secretory breast carcinoma with acinic cell differentiation, and discuss the similarity between secretory breast carcinoma and acinic cell carcinoma of the salivary gland.

Methods and results: The cases were histologically identical to acinic cell carcinoma of the salivary gland: papillary‐cystic type in case 1, a mixture of papillary‐cystic, microcystic and follicular type in case 2, and microfollicular type in case 3. Immunohistochemically, the tumour cells were positive for salivary‐type amylase, lysozyme, S100 protein and α1‐antitrypsin, and negative or less reactive for gross cystic disease fluid protein‐15 and oestrogen receptor. All three cases did not reveal metastasis or recurrence.

Conclusions: These cases were typical of secretory breast carcinoma, and were clinically, histologically and immunohistochemically analogous to acinic cell carcinoma of the salivary gland. We emphasize that secretory breast carcinoma and acinic cell carcinoma of the salivary gland may be identical lesions.
How should we grade CIN?
Authors: Heatley M K
Published: March 2003

How should we grade CIN?

The grading of cervical intraepithelial neoplasia (CIN) is problematic. CIN represents a morphological continuum, but biopsies displaying this lesion are classified into two (e.g. Bethesda) or three grade categories, sometimes with poor reproducibility. There are also difficulties in reliably distinguishing low‐grade CIN from its reactive simulants. Because of problems with inter‐ and intra‐observer disagreement in the grading of CIN and the diagnosis of low‐grade lesions, three expert contributions were commissioned to address the question `how should we grade CIN?'.
Clinicopathological significance of the `keloid‐like' collagen and myxoid stroma in advanced rectal cancer
Authors: Ueno H , Jones A , Jass J R , Talbot I C
Published: March 2003

Clinicopathological significance of the `keloid‐like' collagen and myxoid stroma in advanced rectal cancer

Aim: To establish the histological categorization of fibrotic stroma which reflects the biological behaviour of advanced rectal cancer.

Methods and results: Six hundred and twenty‐seven surgically resected cases of advanced rectal carcinoma were examined. We histologically categorized fibrotic stroma in the invasive frontal region into three groups: type A, multiple fine and mature fibres were stratified into layers; type B, broad bands of eosinophilic hyalinized collagen (`keloid‐like' collagen) were intermingled; type C, myxoid stroma. Type A stroma was observed in 63% of patients, type B stroma in 25%, type C stroma in 12%. The incidence of type A stroma decreased in accordance with Dukes stage (98% in Dukes A; 73% in B; 41% in C1; 29% in C2) and conversely, there was an increase of C type (0% in Dukes A; 4% in B; 20% in C1; 54% in C2). Stroma type had a significant correlation with long‐term survival (80% of 5‐year survival in type A stroma; 54% in type B; 26% in type C). Based on multivariate analysis, it was found that the stromal pattern had independent prognostic value, together with nodal involvement, growth pattern, and lymphocyte infiltration.

Conclusions: Tumour fibrotic stroma may play an important role as a regulator of neoplastic behaviour. Pathological categorization of the fibrotic stroma is helpful for predicting the prognostic outcome of patients with rectal carcinoma.
Recent advances in immunohistochemistry in gynaecological pathology
Authors: McCluggage W G
Published: March 2003

Recent advances in immunohistochemistry in gynaecological pathology

Recent years have witnessed significant developments in the use of immunohistochemistry in diagnostic gynaecological pathology. This review details the most significant of these. In ovarian pathology, differential cytokeratin staining (CK7 and 20) assists in distinguishing between a primary ovarian adenocarcinoma and a metastatic adenocarcinoma, especially of colorectal origin. The development of markers characteristic of ovarian sex cord‐stromal tumours (especially α‐inhibin) facilitates diagnosis of these neoplasms which is often difficult by morphology alone due to the wide differential diagnosis. In the uterus, the distinction between a primary endometrial and endocervical adenocarcinoma may be facilitated by use of a small panel of antibodies, including CEA, ER and vimentin. Newly developed antibodies such as CD10 and h‐caldesmon may be of use in the diagnosis of uterine mesenchymal lesions, especially in the distinction between endometrial stromal and smooth muscle lesions. Proliferation markers, such as MIB1, are of value in the cervix in the diagnosis of preinvasive squamous and glandular lesions. Recent studies have shown that cervical adenoma malignum exhibits a gastric phenotype. Advances have also been made in trophoblastic disease with the development of antibodies reactive against trophoblast such as α‐inhibin, mel‐Cam and p57. A newly developed monoclonal antibody HMGIC which is expressed in vulvovaginal aggressive angiomyxoma may prove to be of value in the often difficult distinction of this lesion from its histological mimics.
CD34+ stromal cells and hyalinized vascular changes in the anal fibroepithelial polyps
Authors: Sakai Y , Matsukuma S
Published: March 2003

Aims:  To elucidate the pathogenesis of the anal fibroepithelial polyp, we examined surgically resected lesions histopathologically.

Methods and results:  Twenty‐seven surgically resected anal fibroepithelial polyps were investigated histologically with an additional immunohistochemical examination using anti‐CD34. For a control study, the surgical specimens of the anal canal showing non‐polypoid lesions, obtained from haemorrhoidectomy (18 specimens) and rectectomy (five specimens) due to rectal cancer without anal canal involvement, were also analysed. We demonstrated characteristic spindle or stellate cells immunohistochemically positive for CD34 in the anal fibroepithelial polyps (24/27, 89%). The number of CD34+ cells was statistically related to the size of anal fibroepithelial polyps, although CD34+ stromal cells were recognized in the non‐polypoid anal submucosa and haemorrhoids. We also found hyalinized vascular changes in the base of six anal fibroepithelial polyps examined. These features were not detected in the non‐polypoid anal canal.

Conclusions:  An increase in CD34+ stromal cells may play a role in the enlargement of anal fibroepithelial polyps. CD34+ stromal cells are suggested to be distinctive mesenchymal cells with a capability for tissue repair and overgrowth. The vascular impairment could be secondary change associated with localized tissue damage by abnormal traction.
Prognostication of invasive ductal breast cancer by quantification of E‐cadherin immunostaining: themethodology and clinical relevance
Authors: Elzagheid A , Kuopio T , Ilmen M , Collan Y
Published: March 2003

Prognostication of invasive ductal breast cancer by quantification of E‐cadherin immunostaining: the methodology and clinical relevance

Aims:  We tried to improve the evaluation of E‐cadherin immunostaining in paraffin sections, to distinguish the less aggressive variants of ductal infiltrating breast cancer from other variants.

Methods and results:  The method graded the membrane staining and estimated the fraction of area of cancer tissue stained at the respective staining grade, resulting in an immunohistochemical staining index. At the cut‐point 0.35 the index divided all 157 patients (P=0.0188), and 57 node‐positive patients (P= 0.0006) into two groups of different survival. In multivariate analysis (all patients) E‐cadherin immunoscore was inferior to mitotic index (SMI) (P=0.0002), but still significant (P=0.0031). Among node‐positive patients E‐cadherin was even more powerful and superior (P=0.0001) to the still significant SMI (P=0.0023), and E‐cadherin immunostaining and the mitotic activity (SMI) combined did not need the support of other prognosticators in the Cox model.

Conclusions:  The study suggests that E‐cadherin immunostaining can be used efficiently in finding patients with favourable outcome among node‐positive patients.
Alteration of PTEN expression in endometrial carcinoma is associated with down‐regulation of cyclin‐dependent kinase inhibitor, p27
Authors: An H‐J , Lee Y‐H , Cho N‐H , Shim J‐Y , Kim J‐Y , Lee C , Kim S‐J
Published: March 2003

Aims:  PTEN is a recently identified tumour suppressor inactivated in a wide variety of human cancers, including endometrial cancers. Mutation of the PTEN tumour suppressor gene has been reported in approximately 50–83% of endometrial adenocarcinoma. Despite this fact, study of the expression of PTEN protein in human tumours is limited. PTEN protein functions as a tumour suppressor by regulating the cell cycle and survival through signal transduction pathway. PTEN protein was considered to have a dual‐specificity phosphatase activity, but it is now known that its principal physiological activity is mainly derived from its lipid phosphatase activity. The cyclin‐dependent kinase inhibitor, p27, has been suggested as a downstream target of cell cycle arrest of PTEN in various in vitro studies. In this study, we evaluated the alteration of PTEN protein expression in endometrial carcinoma and assessed its relationship to the expression of p27, the presumed downstream target of PTEN.

Methods and results:  Immunohistochemical staining was performed on 66 cases of endometrial carcinoma including 61 endometrioid type and five serous type, using antibodies to PTEN and p27. Loss or decrease of PTEN expression was observed in 66% (40/61 cases) of uterine endometrioid carcinoma, whereas most uterine serous carcinoma (4/5 cases) showed intense PTEN expression. Four (30%) of 13 endometrial hyperplasia synchronous with endometrioid carcinoma demonstrated complete loss of PTEN expression. All endometrioid carcinoma synchronous with PTEN‐negative endometrial hyperplasia showed loss of PTEN expression. Alteration of PTEN expression was not correlated with histological grade or stage. Decreased immunoreactivity of p27 was found in 48 cases (79%) of 61 endometrioid carcinoma, and 76% (36 cases) of them also showed loss or decrease of PTEN expression. Four of five uterine serous carcinoma revealed strong p27 immunoreactivity, all of which showed intense PTEN expression. A positive correlation between PTEN and p27 expression was statistically significant (Mantel–Haenszel χ2 test, P=0.001). Immunoreactivity of p27 was not related to histological grade and clinical stage.

Conclusion:  These results show that PTEN and p27 are differentially expressed in endometrioid type carcinoma compared with those of the serous type, and suggest that the cyclin‐dependent kinase inhibitor, p27, is a downstream target of PTEN‐dependent cell cycle arrest in endometrial carcinoma.
Immunohistochemical expression of CD10 and t(14;18) chromosomal translocation may be indicators of follicle centre cell origin in nodal diffuse large B‐cell lymphoma
Authors: McCluggage W G , Catherwood M , Alexander H D , McBride H A , Smith M E F , Morris T C M
Published: March 2003

Aims:  Although diffuse large B‐cell lymphoma is categorized as a distinct entity in the REAL classification of lymphomas, it represents a heterogeneous group of neoplasms. A subgroup is probably of follicle centre cell origin and may evolve from a pre‐existing follicular lymphoma. The t(14;18) chromosomal translocation can be demonstrated in the majority of follicular lymphomas and the aim of this study was to investigate the prevalence of t(14;18) translocation in a series of de novo nodal diffuse large B‐cell lymphomas. We correlated this with the immunohistochemical expression of CD10, bcl2 and bcl6, markers which are usually expressed by the neoplastic cells in follicular lymphomas. We also correlated these parameters with the presence or absence of p53 protein expression by the neoplastic cells.

Methods and results:  Nodal diffuse large B‐cell lymphomas (n=34) were stained immunohistochemically with monoclonal antibodies to CD10, bcl2, bcl6 and p53 (D07). Polymerase chain reaction (PCR) for the t(14;18) translocation was also performed. Fourteen, 24 and 29 (41%, 71%, 85%) cases exhibited positivity for CD10, bcl2 and bcl6, respectively. In 12 cases there was positivity with D07 (35%). By PCR, the t(14;18) translocation was identified in five cases (15%), four of which were positive for CD10 and bcl2 and all of which were positive for bcl6. One of five cases positive for the chromosomal translocation exhibited positivity with D07.

Conclusions:  In this study the t(14;18) translocation was identified in 15% of diffuse large B‐cell lymphomas, all but one of which exhibited positivity for CD10, bcl2 and bcl6. These may represent cases of follicle centre cell origin which may or may not have evolved from a pre‐existing follicular lymphoma. It is possible that positivity for CD10 especially may identify cases which are of follicle centre cell origin and that the absence of t(14;18) translocation in some of these cases may reflect the fact that the translocation cannot normally be demonstrated in all follicular lymphomas. Whether the presence or absence of the translocation and the immunophenotype are prognostically important should be investigated further.
34βE12 expression along the whole spectrum of neuroendocrine proliferations of the lung, from neuroendocrine cell hyperplasia to small cell carcinoma
Authors: Sturm N , Rossi G , Lantuéjoul S , Laverrière M‐H , Papotti M , Brichon P‐Y , Brambilla C , Brambilla E
Published: March 2003

Aims:  Monoclonal antibody 34βE12 (Ck34βE12) recognizes a set of cytokeratins (1, 5, 10, 14) expressed in normal stratified squamous epithelium. We have recently reported its expression in squamous cell carcinoma and basaloid carcinoma, in contrast to large cell neuroendocrine carcinoma, an entity with overlapping morphological features with basaloid carcinoma. We have now examined the role of Ck34βE12 in discriminating between neuroendocrine and non‐neuroendocrine proliferations.

Methods and results:  We performed an immunohistochemical study of 228 cases, comprising the whole spectrum of lung neuroendocrine proliferations and tumours. All cases of neuroendocrine cell hyperplasia (n = 15), tumorlet (n = 23), typical carcinoid (n = 27) and atypical carcinoid (n = 23) were completely negative for Ck34βE12. Although the neuroendocrine cells of small cell lung carcinoma and large cell neuroendocrine carcinoma were consistently negative, a strong and diffuse positive staining was found in the non‐neuroendocrine components of combined small cell carcinoma (three of eight cases) and combined large cell neuroendocrine carcinoma (11 of 12 cases). In addition, scattered Ck34βE12+ cells were noted in 11 of 64 (17%) large cell neuroendocrine carcinoma and in seven of 56 (12.5%) small cell carcinoma, which were not obviously histologically combined. This heterogeneity of high‐grade neuroendocrine tumours was not observed in carcinoids which lack Ck34βE12 clusters of reactive cells. There was mutual exclusion between expression of neuroendocrine markers and that of Ck34βE12.

Conclusion:  We conclude that 34βE12 expression excludes the neuroendocrine nature of tumour cells and uncovers the real frequency of combined forms in high‐grade neuroendocrine tumours.
Breast carcinoma in women over the age of 85: distinct histological pattern and androgen, oestrogen, and progesterone receptor status
Authors: Honma N , Sakamoto G , Akiyama F , Esaki Y , Sawabe M , Arai T , Hosoi T , Harada N , Younes M , Takubo K
Published: March 2003

Aims:  The pathogenesis of breast carcinoma in very elderly women is of interest, because oestrogen levels are likely to be extremely low during the development of the disease. In an effort to understand the pathogenesis of breast carcinoma in these women, this study was undertaken to compare the histological patterns and hormone receptor status of breast carcinomas arising in very elderly and younger women.

Methods and results:  Thirty‐seven breast carcinomas from women over the age of 85 years at the time of their operation were examined histologically and compared with those from a large group of premenopausal women. The proportions of mucinous carcinoma and apocrine carcinoma were significantly greater in older women. The expression of steroid hormone receptors was studied immunohistochemically. Androgen receptor‐positive carcinomas were significantly more frequent among older women, whereas progesterone receptor‐positive carcinomas were significantly less frequent. There was no statistically significant difference in oestrogen receptor‐α or ‐β expression between the tumours from both groups.

Conclusion:  Breast carcinomas in women over the age of 85 years have a different morphological spectrum from carcinomas in younger age groups and may have different pathogenesis mechanisms that may be more dependent on androgen and androgen receptor interaction. Differences from the results of the other studies are discussed.
Protein kinase C mediates the signal for interferon‐γ mRNA expression in cytotoxic T cells after their adhesion to laminin
Authors: LI  , KOBAYASHI  , YUAN  , WANG  , MATSUSHITA  , HAMADA  , KIMURA  , YAGITA  , OKUMURA  , HOSOKAWA
Published: March 2003

A cytotoxic T‐cell line, CTLL‐2 cells, showed spreading after adhering to extracellular matrix proteins such as fibronectin (FN), laminin (LN) and hyarulonic acid (HA). The adhesion of CTLL‐2 cells to LN was mediated by very late activation antigen‐6 (VLA‐6). Expression of interferon‐γ (IFN‐γ) mRNA was enhanced in CTLL‐2 cells, also when they adhered to extracellular matrix proteins; and the enhanced IFN‐γ mRNA expression by adhering to LN was blocked by anti‐α6 antibody. Calphostin C, a protein kinase C (PKC) inhibitor, markedly inhibited the enhancement of IFN‐γ mRNA expression in a dose‐dependent manner, which suggested that PKC acted as a second messenger in the IFN‐γ mRNA expression mediated by the interaction of VLA‐6 with LN in CTLL‐2 cells. Furthermore, confocal laser‐microscopic analysis and Western blot analysis revealed that PKC‐α was activated after CTLL‐2 cells adhered to LN. PKC activity translocated from the cytosol fraction to the particulate fraction, after CTLL‐2 cells adhered to LN. Altogether, we suggest that PKC plays an important role in the signal transduction for IFN‐γ mRNA expression after cytotoxic T cells adhere to LN.
Multifaceted inhibition of anti‐tumour imm_une mechanisms by soluble tumour necrosis factor receptor type I
Authors: SELINSKY  , BOROUGHS  , HALSEY Jr  , HOWELL
Published: March 2003

Soluble tumour necrosis factor receptor type I (sTNFRI) is a potent inhibitor of TNF with the potential to suppress a variety of effector mechanisms important in tumour imm_unity. That sTNFRI influences tumour survival in vivo is suggested by results from human clinical trials of Ultrapheresis®, an experimental extracorporeal treatment for cancer. While the considerable clinical benefit provided by Ultrapheresis® is correlated with the removal of plasma sTNFRI, there is no direct evidence that sTNFRI inhibits imm_une mechanisms which mediate tumour cell elimination. To evaluate formally the ability of sTNFRI to inhibit these mechanisms, we have engineered sTNFRI production into the TNF‐sensitive murine fibrosarcoma cell line, L929. Soluble TNFRI‐secreting L929 cells display increased resistance to direct lysis by TNF, and to lysis by syngeneic lymphokine‐activated killer cells and cytotoxic T cells. These findings confirm the suggestion that sTNFRI inhibits imm_unological mechanisms important in tumour cell eradication, and further support a role for sTNFRI in tumour survival in vivo. In addition, these observations suggest the development of methods for more specific removal and/or inactivation of sTNFRI as promising new avenues for cancer imm_unotherapy.
Human and murine T‐cell responses to allelic forms of a malaria circumsporozoite protein epitope support a polyvalent vaccine strategy
Authors: ZEVERING Y. , KHAMBOONRUANG C. , GOOD* M. F.
Published: March 2003

Mouse models and a recent vaccine trial have indicated the importance of T‐cell immunity to the circumsporozoite protein (CSP) of malaria sporozoites. One of the major impediments for the development of a CSP‐based vaccine is that human T‐cell epitopes, identified on the CSP, span regions of significant point mutational polymorphism. Studies with human and mouse T‐cell clones have indicated that this polymorphism affects T‐cell cross‐reactivity to Th2R and Th3R, the two most polymorphic and immunodominant epitopes. We extend this observation with polyclonal human T‐cell lines, from 11 donors, raised to known variants of Th2R. These lines showed limited but variable cross‐reactivity with the heterologous peptides. T cells from B10.A4(R) (I‐Ak) mice immunized with each of 18 natural variants of Th2R indicated a similar, limited, cross‐reactivity. I‐Ak competition assays showed that a number of peptides were unable to bind because of a single polymorphic residue. In both the human and mouse assays, analysis of the sequences of immunogenic cross‐reactive and non‐cross‐reactive peptides suggested that the individual polymorphic residues affect the three‐dimensional conformation of the peptide within the major histocompatibility complex (MHC) groove in an, as yet, unpredictable way. These observations argue that design of an epitope able to generate broad cross‐reactivity is, to date, not possible. However, despite the limited cross‐reactivity of the individual human T‐cell lines, most of the donors had T‐cell repertoires capable of recognizing all or nearly all of the variants tested, which supports a strategy using a multivalent vaccine.
Specific antigen targeting to surface IgE and IgG on mouse bone marrow‐derived mast cells enhances efficiency of antigen presentation
Authors: TKACZYK C. , VIGUIER M. , BOUTIN Y. , FRANDJI P. , DAVID B. , HÉBERT J. , MÉCHERI S.
Published: March 2003

The discovery that bone marrow‐derived mast cells can express major histocompatibility complex class II molecules and act as antigen‐presenting cells prompted us to evaluate this function when antigen is internalized through fluid‐phase endocytosis or via specific uptake by using IgG and IgE antibodies. This study was performed using a specific T‐cell hybridoma developed against Lol p 1, the major allergen of grass pollen Lolium perenne. Expression of FcγR and FcεRI by mast cells led us to investigate the influence of IgG‐ and IgE‐targeted antigen on the antigen‐presenting function of mast cells. Internalization of Lol p 1 through different specific IgG monoclonal antibodies (mAb) resulted in the activation of Lol p 1‐specific T‐cell hybridoma at concentrations about 100‐fold less than that required for T‐cell stimulation by uncomplexed antigen. IgE‐complexed Lol p 1, which facilitates trapping of antigen by mast cells, induced an accelerated and more efficient antigen‐presenting capacity of mast cells than that obtained with uncomplexed antigen. However, aggregation of anti‐dinitrophenyl (DNP) IgE mAb by the irrelevant antigen DNP–human serum albumin did not substantially increase the capacity of mast cells to present Lol p 1 to T cells. This suggests that the mere aggregation of FcεRI is not sufficient for enhanced antigen presentation mediated by IgE. Tissue distribution and strategic location of mast cells at the mucosal barriers and their capacity to process the antigen through efficient fluid‐phase pinocytosis as well as IgG‐ and IgE‐dependent targeting of antigens provide mast cells with a prominent role in immune surveillance.
Lack of SC/pIgR‐mediated epithelial transport of a human polymeric IgA devoid of J chain: in vitro and in vivo studies
Authors: VAERMAN  , LANGENDRIES  , GIFFROY  , BRANDTZAEG  , KOBAYASHI
Published: March 2003

Three human polymeric IgA (pIgA) myeloma proteins of tetrameric size were compared for their J‐chain content, their in vitro secretory component (SC)‐binding ability, and their capacity to be transcytosed by polymeric immunoglobulin receptor (pIgR)‐expressing epithelial cells in vitro and rat hepatocytes in vivo. One of the three pIgA preparations, pIgA‐L, was shown to lack J chain and was unable to combine with purified free human and rat SC, whereas pIgA‐G and pIgA‐C contained J chain and combined readily with SC. Furthermore, pIgA‐L was not transferred into rat bile after intravenous injection, and was hardly transported apically by polarized Madin–Darbey canine kidney cell monolayers expressing the human pIgR, whereas pIgA‐G and pIgA‐C were efficiently transported in both test systems. Together with our recent demonstration that antibodies to human J chain block the SC/pIgR‐mediated epithelial transport of pIgA, these data unanimously confirm the proposed key role of J chain in the epithelial transport of polymeric immunoglobulins into exocrine secretions.
Evidence for a link between iron metabolism and Nramp1 gene function in innate resistance against Mycobacterium avium
Authors: GOMES  , APPELBERG
Published: March 2003

In the mouse, the progression of the Mycobacterium avium infection is highly dependent on the Nramp1 gene. Strains of mice that express the Nramp1D169 allele are highly susceptible to M. avium infections, while Nramp1G169 strains of mice can control them. Recently, the Nramp1 gene has been cloned and characterized as coding a transmembrane protein, probably involved in divalent cation transport. One possible function of this protein could be the transport of iron out of the parasite‐harbouring phagosome. Previous work in our lab has shown both in vitro (in macrophage cultures) and in vivo, that the growth rate of M. avium is highly dependent on the amount of iron available in the system. To try to correlate this with the Nramp1 gene function, BALB/c (susceptible) and C.D2 (resistant) congenic mice were treated for 20 days with different doses of iron‐dextran, so as to induce different degrees of iron overload, and infected with M. avium 2447. Iron administration increased M. avium growth in infected organs in a dose‐dependent manner at the same time as it decreased the difference in mycobacterial growth between the two mouse strains. These results indicate that an excess of iron hampers Nramp1‐encoded function, strongly suggesting a direct involvement of the Nramp1‐encoded protein in the transport of this cation.
Functional role of CD95 ligand in concanavalin A‐induced intestinal intraepithelial lymphocyte cytotoxicity
Authors: GHORESCHI  , MUDERS  , ENDERS
Published: March 2003

Freshly isolated murine intestinal intraepithelial lymphocytes (IEL) express CD95 ligand (CD95L), as shown by reverse transcription–polymerase chain reaction (RT–PCR) and fluorescence‐activated cell sorter (FACS) analysis. Between 15 and 25% of IEL could be stained with an antibody to CD95L. Therefore it was investigated whether the CD95L/CD95 pathway was effective in IEL cytotoxicity. Stimulation of IEL in vitro with concanavalin A (Con A) induced a strong cytotoxic response, which was much higher when using CD95‐expressing target cells. This effect was most evident when comparing the specific lysis of CD95‐transfected target cells of the leukaemia cell line L1210 with that of the untransfected parental cell line. In addition, an antibody to CD95 was able to dramatically reduce the specific lysis of CD95‐expressing target cells. After stimulation with Con A, which is able to bind to CD95L, the effects were more obvious compared with the triggering of the T‐cell receptor (TCR)‐αβ or γδ. On the other hand, EGTA reduced the Con A‐induced cytotoxicity. Together these findings support a role of the CD95L/CD95 pathway in IEL cytotoxicity, even though the reaction was Ca2+ sensitive. As a function, CD95L‐expressing IEL should be able to contribute to the elimination of CD95‐expressing target cells in the intestine.
Role of interleukin‐2 in superantigen‐induced T‐cell anergy
Authors: CORNWELL  , ROGERS
Published: March 2003

T‐cell anergy is a state of immunological tolerance characterized by unresponsiveness to antigenic stimulation. Previous studies have shown that anergy is induced in T cells following stimulation in the absence of adequate costimulatory signals. These cells fail to respond to stimulation via the T‐cell receptor (TCR), and fail to produce normal levels of interleukin‐2 (IL‐2). We present results here which show that low concentrations of the superantigen staphylococcal enterotoxin A (SEA) in the absence of antigen‐presenting cells induced both proliferation and anergy in the A.E7 T‐cell clone. Furthermore, under these conditions, the A.E7 clone remained responsive to exogenous IL‐2. Fluorescence‐activated cellular cytometry analysis revealed unaltered expression of the TCR/CD3 complex in the anergized clone; however, both CD4 and CD25 expression increased after 24 hr of stimulation by SEA under these conditions. Interestingly, a low level of IL‐2 production was measured during the induction of anergy. Most strikingly, stimulation of the A.E7 clone by SEA in combination with exogenous IL‐2 resulted in a more pronounced state of anergy. These results suggest that the induction of anergy is a process that is essentially independent of the production of IL‐2.
Movement disorders in encephalitis induced by Rhodococcus aurantiacus infection relieved by the administration of L‐dopa and anti‐T‐cell antibodies
Authors: MIN  , ASANO  , KOHANAWA  , MINAGAWA
Published: March 2003

Mice injected with Rhodococcus aurantiacus by the intravenous (i.v.) route show neurological disorders, hemiparesis, vertical headshake and turn‐round gait after day 7 postinfection (p.i.). Neurological symptoms caused by i.v. inoculation of R. aurantiacus were relieved by treatment with levodopa (l‐dopa). R. aurantiacus was isolated from the brain and was found to be completely eliminated at day 7 p.i. Focal encephalitis was mainly observed in the brain stem, and T cells could be isolated from the brain after day 7 p.i. Administration of both an anti‐CD4 monoclonal antibody (mAb) and an anti‐CD8 mAb suppressed neurological symptoms. These results suggest that R. aurantiacus induces movement disorders in mice, and that the symptoms are mediated by T cells infiltrating the brain, rather than directly by the bacterium.
Inhibitory effect of interleukin‐16 on interleukin‐2 production by CD4+ T cells
Authors: OGASAWARA  , TAKEDA‐HIROKAWA  , SEKIGAWA  , HASHIMOTO  , KANEKO  , HIROSE
Published: March 2003

Signalling through CD4 by human immunodeficiency virus (HIV)‐1 envelope glycoprotein (gpl20) and/or anti‐CD4 antibodies can promote T‐cell activation and anergy. Interleukin (IL)‐16 is a competence growth factor for CD4+ T cells that can induce a G0 to G1 cell cycle transition but cannot induce cell division. The receptor of this cytokine is thought to be the CD4 molecule, although the binding epitope of IL‐16 differs from that of HIV. We have demonstrated that both HIV‐1/gp120 and IL‐16 induced CD4+ T‐cell dysfunction, as indicated by suppression of mitogen‐induced IL‐2 production. Two anti‐CD4 antibodies with different binding sites on CD4 also showed an inhibitory effect on IL‐2 production. These results indicate that promotion of CD4+ T‐cell anergy via the CD4 molecule does not depend on the binding sites of the CD4 ligands.
Reactivity of the immunoglobulin E in bovine gelatin‐sensitive children to gelatins from various animals
Authors: SAKAGUCHI  , HORI  , EBIHARA  , IRIE  , YANAGIDA  , INOUYE
Published: March 2003

It has been reported that most children who showed anaphylaxis to measles, mumps and rubella vaccines containing bovine gelatin as a stabilizer have anti‐bovine gelatin IgE. The present study was designed to investigate the reactivity of IgE in bovine gelatin‐sensitive children to gelatins from various animals, and the antigenic cross‐reactivity between the gelatins. Serum samples taken from 10 children who showed anaphylaxis to vaccines containing bovine gelatin were used in this study. The level of anti‐bovine gelatin IgE in these serum samples ranged from 11·0 to 251 Ua/ml. The IgE in most of the children reacted to kangaroo and mouse gelatins, to which they had had little or no exposure as a food or a vaccine stabilizer. The IgE binding to kangaroo and mouse gelatins was completely inhibited by bovine gelatin, whereas reciprocal inhibition was not complete, indicating that antigenic cross‐reactivity is present between the mammalian gelatins. Only one child had strong IgE reactivity to fish gelatins, and this reactivity was not inhibited by bovine gelatin, indicating that no antigenic cross‐reactivity exists between bovine and fish gelatins. Most of the children who displayed sensitivity to bovine gelatin showed IgE reactivity to other mammalian gelatins. This reactivity may be due primarily to the antigenic cross‐reactivity between mammalian gelatins.
Modulation of experimental blood stage malaria through blockade of the B7/CD28 T‐cell costimulatory pathway
Authors: TAYLOR‐ROBINSON  , SMITH
Published: March 2003

Recent studies have implicated cytokines associated with CD4+ T lymphocytes of both T helper (Th)1 and Th2 subsets in resistance to experimental blood stage malaria. As the B7/CD28 costimulatory pathway has been shown to influence the differentiation of Th cell subsets, we investigated the contribution of the B7 molecules CD80 and CD86 to Th1/Th2 cytokine and immunoglobulin isotype profiles and to the development of a protective immune response to malaria in NIH mice infected with Plasmodium chabaudi. Effective blockade of CD86/CD28 interaction was demonstrated by elimination of interleukin (IL)‐4 and up‐regulation of interferon (IFN)‐γ responses by P. chabaudi‐specific T cells and by reduction of P. chabaudi‐specific immunoglobulin G1 (IgG1). The shift towards a Th1 cytokine pattern corresponded with efficient control of acute parasitaemia but an inability to resolve chronic infection. Moreover, combined CD80/CD86 blockade by using anti‐CD80 and anti‐CD86 monoclonal antibodies raised IFN‐γ production over that seen with CD86 blockade alone, with augmentation of this Th1‐associated cytokine reducing levels of peak primary parasitaemia. These results demonstrate that IL‐4 production by T cells in P. chabaudi‐infected NIH mice is dependent upon CD86/CD28 interaction and that IL‐4 and IFN‐γ contribute significantly, at different times of infection, to host resistance to blood stage malaria. In addition, combined CD80/CD86 blockade resulted in preferential expansion of IFN‐γ‐producing T cells during P. chabaudi infection, suggesting that costimulatory pathways other than B7/CD28 may contribute to T‐cell activation during continuous antigen stimulation. This study indicates a role for B7/CD28 costimulation in modulating the CD4+ T‐cell response during malaria, and further suggests involvement of this pathway in other infectious and autoimmune diseases in which the Th cell immune response is also skewed.
Importance of thioredoxin in the proteolysis of an immunoglobulin G as antigen by lysosomal Cys‐proteases
Authors: KERBLAT  , DROUET  , CHESNE  , MARCHE
Published: March 2003

For disulphide‐bonded antigens, reduction has been postulated to be a prerequisite for proteolytic antigen processing, with subsequent production of major histocompatibility complex (MHC) class II binding fragments. The murine monoclonal immunoglobulin G (IgG) CE25/B7 was used as a multimeric antigen in a human model. Native IgG is highly resistant to proteolysis and has been previously found to be partially reduced at early steps of cell processing to become a suitable substrate for endopeptidases. The role of the oxidoreductase thioredoxin (Trx) was assessed in the reduction of the IgG by cleavage of H–L and H–H disulphide bonds. Recombinant human Trx (rTrx) has been assayed in a proteolytic in vitro system on IgG using endosomal and lysosomal subcellular fractions from B lymphoblastoid cells. rTrx is required in a dose‐dependent manner for development of efficient proteolysis, catalysed by thiol‐dependent Cys‐proteases, such as cathepsin B. We demonstrated that cathepsin B activity was stimulated by the addition of rTrx. Thus, we propose that Trx‐dependent IgG proteolysis occurred, on the one hand by means of the unfolding of the IgG after disulphide reduction, becoming a substrate of lysosomal proteases, and on the other hand by Cys‐proteases such as cathepsin B that are fully active upon the regeneration of their activity by hydrogen donors.