Extent Of Lymphocytic Infiltration Research Articles

Effects of iguratimod on inflammatory factors and apoptosis of submandibular gland epithelial cells in NOD mice

Non-obese diabetic (NOD) mice were taken as primary Sjögren’s syndrome (pSS) model mice to examine the therapeutic impact of iguratimod (IGU) on inflammatory factors levels and apoptosis of submandibular epithelial cells, and provide experimental basis for the treatment of pSS by iguratimod. Twenty-four NOD murine models were divided into the model, high-dose (IGU 30 mg/kg) and low-dose (IGU 10 mg/kg) groups, eight mice per group. The normal control group comprised eight C57B/L mice. From 8 weeks of age, the NOD mice were administered IGU by intragastric gavage administration every day for 8 weeks; their water consumption, saliva secretion, submandibular gland, and spleen indices were measured. The levels of serum inflammatory factor (IL-1β, TNF-α, IL-6, and IL-17) were evaluated, and Bax, caspase-3, and Bcl-2 levels were detected. The histological alterations in the submandibular glands were discovered. IGU can reduce the water intake of NOD mice (p < 0.01), increase the saliva secretion and the submandibular gland index (p < 0.01); reduce the spleen index and the serum inflammatory factors (p < 0.01); improve the pathological tissue damage and cell apoptosis of the submandibular gland (p < 0.05). IGU can reduce the expression levels of inflammatory mediators in the serum and the extent of lymphocyte infiltration and apoptosis in submandibular gland epithelial cells. It can also regulate apoptosis-related protein expression, thereby improving the secretory function of exocrine glands.

In Graves’ disease, thyroid autoantibodies and ultrasound features correlate with distinctive histological features

PurposeLaboratory, imaging, and pathological features of Graves’ disease (GD), although well characterized, have been barely correlated each other. Aim of the study was to link laboratory and ultrasound characteristics of GD with its pathological features.MethodsWe correlated laboratory and ultrasound data at the time of diagnosis in 28 consecutive GD patients who underwent thyroidectomy with their pathological features, i.e., lymphocytic infiltration and follicular hyperplasia (both classified as mild or severe).ResultsThyroid volume correlated positively with the levels of FT4 (P = 0.002, r2 = 0.42), FT3 (P = 0.011, r2 = 0.22), autoantibodies to thyroglobulin (TgAbs) (P = 0.016, r2 = 0.32), autoantibodies to thyroid peroxidase (TPOAbs) (P = 0.011, r2 = 0.34) and the extent of lymphocytic infiltration (P = 0.006 comparing mild to severe lymphocytic infiltration) but not with the levels of autoantibodies to the thyrotropin receptor (TRAbs) and to follicular hyperplasia. Compared to subjects with mild lymphocytic infiltration, those with severe lymphocytic infiltration showed higher levels of TgAbs (316 vs 0.0 IU/mL, P < 0.0001) and TPOAbs (295 IU/mL vs 14 IU/mL, P < 0.0001) and similar levels of TRAbs (7.5 vs 13 IU/mL, P = 0.68). Compared to patients with mild, those with severe follicular hyperplasia had similar levels of TgAbs (76 vs 30 IU/mL, P = 0.31) and TPOAbs (251 IU/mL vs 45 IU/mL, P = 0.26) but higher levels of TRAbs (39 vs 7.2 IU/mL, P < 0.001).ConclusionIn GD, TgAbs and TPOAbs levels correlate with the extent of lymphocytic infiltration, TRAbs levels with the degree of follicular hyperplasia. Thyroid volume, the main factor influencing the severity of hyperthyroidism, is related to lymphocytic infiltration and not to follicular hyperplasia.

Focal Myositis with CD8+T-Cell predominance: an Inflammatory Myositis Mimicking a Soft Tissue Neoplasm

Abstract Introduction/Objective FM is a rare self-limiting T-cell rich lesion arising within muscles of young adults as a solitary lesion and can be confused with a variety of neoplastic/inflammatory conditions or lymphoma. Here we describe a rare T-cell rich variant of FM with CD8 predominance. Methods/Case Report A 51-year-old female presented with two-month history of left trapezius swelling. MRI showed an enhancing tumor within the muscle, suspicious of sarcoma, less likely myeloma. Results (if a Case Study enter NA) Biopsy showed diffuse infiltration of small lymphocytes in a fibrotic background and atrophic skeletal muscle. These lymphocytes stained positive for CD2, CD3, CD7, CD8, CD5 (partial), TIA1 (partial), CD43, CD57 and negative for CD4, CD30, CD56, CD57, granzyme B, perforin, BCL-6, BCL-2, Pax5, TCL1, and CD56. Ki-67 was (&amp;lt;10%) with few background CD20+ B cells. By flow cytometry, the CD8+ T-cells co-express CD2, CD3, CD7, with dim CD5 expression. TCR gene rearrangement study by PCR showed no clonal TCR Gamma gene rearrangement. Conclusion FM is extremely rare with only 22 cases well-described in the literature, all predominantly composed of CD4+ T-cells, clinically concerning for low-grade sarcomas, as inflammatory myofibroblastic tumor, inflammatory leiomyosarcoma, or liposarcoma. Careful analysis is essential for correct diagnosis. Mimics include other causes of myositis, such as polymyositis and inclusion body myositis. Depending on the extent of lymphocytic infiltrate, gene rearrangement studies might be necessary to rule out clonality. Recognition of this rare entity with excellent prognosis is crucial to provide appropriate management and avoid unnecessary, aggressive procedures.

176P Type of TP53 alteration may correlate with the extent of lymphocytic infiltration in high-grade serous ovarian carcinomas

176P Type of TP53 alteration may correlate with the extent of lymphocytic infiltration in high-grade serous ovarian carcinomas

CXCL13 Neutralization Attenuates Neuropsychiatric Manifestations in Lupus-Prone Mice

Neuropsychiatric lupus (NPSLE), the nervous system presentation of systemic lupus erythematosus (SLE), remains challenging to treat due to its unclear pathogenesis and lack of available targeted therapies. A potential contributor to disease progression is brain tertiary lymphoid structures (TLS); these ectopic lymphoid follicles that can develop tissue-targeted antibodies have recently been described in the MRL/lpr lupus mouse strain, a classic model for studying NPSLE. The brains of MRL/lpr mice show a significant increase of CXCL13, an important chemokine in lymphoid follicle formation and retention that may also play a role in the disease progression of NPSLE. The aim of the present study was to inhibit CXCL13 and examine the effect of this intervention on lymphoid formation and the development of neurobehavioral manifestations in lupus mice. Female MRL/lpr mice were injected with an anti-CXCL13 antibody, an IgG1 isotype-matched antibody, or PBS either three times a week for 12 weeks intraperitoneally (IP) starting at 6-8 weeks of age, or continuously intracerebroventricularly (ICV) with an osmotic pump over a two-week period starting at 15 weeks of age. Cognitive dysfunction and depression-like behavior were assessed at the end of treatment. When treatment was delivered IP, anti-CXCL13 treated mice showed significant improvement in cognitive function when compared to control treated mice. Depression-like behavior was attenuated as well. Furthermore, mice that received anti-CXCL13 by the ICV route showed similar beneficial effects. However, the extent of lymphocyte infiltration into the brain and the general composition of the aggregates were not substantively changed by anti-CXCL13 irrespective of the mode of administration. Nevertheless, analysis of brain gene expression in anti-CXCL13 treated mice showed significant differences in key immunological and neuro-inflammatory pathways that most likely explained the improvement in the behavioral phenotype. Our results indicate that CXCL13 affects the behavioral manifestations in the MRL/lpr strain and is important to the pathogenesis of murine NPSLE, suggesting it as a potential therapeutic target.

Cancer-immune topology influences lung cancer evolution

The extent of lymphocyte infiltration controls cancer subclone divergence, and a single immune cold region can increase the risk of relapse.

High Ki-67 expression is a marker of poor survival in apocrine breast carcinoma.

Apocrine carcinoma is avery rare type ofbreast cancer, which represents 0.5-4% ofall breast cancers. Theaim ofthestudy was to analyze biological and clinical features ofapocrine carcinoma and their influence on patients survival. The studied group consists of57 patients, who underwent treatment between 1987 and 2010. Expression ofER, PgR, HER2, AR, GCDFP-15, EGFR, CK 5/6, CK 8/18 and Ki-67 was assessed immunohistochemically on formalin-fixed paraffin-embedded tissue sections. Presence ofemboli and extent oflymphocyte infiltration were assessed on haematoxylin-eosin-stained slides. In the investigated group, 16 cases were ER/PgR positive and 49 were AR-positive. ER/PgR-negative tumours were often characterised by CK5/6 and EGFR positivity. The presence ofAR was related to HER-2 and GCDFP-15 expression and tumours with expression ofCK5/6 were more likely be EGFR positive and had higher Ki-67 LI. Higher probability of10-years OS and DFS was observed in patients with tumours characterized by Ki-67 LI<20% (p=0.036 and p=0.009, respectively). Favourable trend in OS was noted for patients with smaller tumours (p=0.053), without lymph node metastases (p=0.074) and without EGFR expression (p=0.060). In apocrine breast carcinoma expression ofKi-67 is one ofthemost important factors influencing patients' survival.

Abstract 4149: Extensive characterization of the adenosine pathway in human solid tumors gives a hint on cancer indication selection for the A2A receptor antagonist EOS100850

Abstract Extracellular adenosine is an immunosuppressive metabolite generated by sequential action of the two ectonucleotidases CD39 and CD73. Tissue hypoxia, which is frequently observed in neopleastic tissues, increases CD39 and CD73 expression, and is a major driver of extracellular adenosine accumulation. High levels of adenosine, predominantly signaling through the A2A receptor (A2AR), dampen innate and adaptive immune cell responses, leading to suppression of antitumor immunity. We therefore developed EOS100850, a potent and highly selective A2A receptor antagonist to treat a wide range of tumor types. With the aim to support selection of cancer indications for EOS100850, we used immunohistochemistry and computer-assisted image analysis to extensively characterize the expression and spatial distribution of markers of the adenosine pathway and the extent of lymphocyte infiltration in ten tumor types. First, 318 primary tumor specimens included in disease-specific tissue microarrays from nine cancer indications were screened for expression of CD39, CD73 and infiltration of A2AR+, CD8+ and Foxp3+ cells. CD39 and CD73 were expressed by immune cells, endothelial cells and other stromal cells as well as by tumor cells, and their expression was increased in hypoxic tumor regions. Expression levels of the two adenosine-generating enzymes were variable among the analyzed cancer types, with lung and gastric tumors displaying the highest levels of expression of CD39 (78% and 95% of samples with high CD39 expression, respectively) and gastric, uterine and lung cancers displaying the highest levels of CD73 (&amp;gt;70% of samples with high CD73 expression). A2AR staining was observed on different immune cell populations, and significantly correlated with CD8+ and Foxp3+ cell densities (p values &amp;lt;0.0001). A2AR+ immune cells were frequently detected in lung, gastric and head and neck tumors (&amp;gt;80% positive samples) but not in kidney and prostate tumors (&amp;lt;20% positive samples). To encompass the inherent heterogeneity of tumor tissues, the expression and spatial distribution of CD39, CD73, A2AR and lymphocyte populations were further analyzed in several lung, colorectal and breast primary tumor resections. These tumor types display high, medium and low levels of the adenosine cloud markers, respectively. CD39 expression as well as densities of A2AR+, CD8+ and Foxp3+ cells were all higher in the tumor surrounding stroma than in the center of the tumor in the three cancer types. Moreover, CD39 and A2AR were significantly correlated with CD8+ and Foxp3+ cell densities in the tumor center but not in the stroma. Altogether these data strongly support the relevance of targeting A2AR and the adenosine pathway in immuno-oncology, and pave the way to the identification of the cancer types that will benefit more from EOS100850. Citation Format: Noemie Wald, Chiara Martinoli, Marjorie Mercier, Annelise Hermant, Florence Nyawouame, Joao Marchante, Charlotte Moulin, Vanesa Bol, Stefano Crosignani, Veronique Bodo. Extensive characterization of the adenosine pathway in human solid tumors gives a hint on cancer indication selection for the A2A receptor antagonist EOS100850 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4149.

Multispectral quantitative analysis of tumor-infiltrating lymphocyte (TIL) in triple negative breast cancer.

e24123Background: Standardized evaluation of TIL is currently based on the extent of lymphocytic infiltration into the tumor stroma for breast cancer. However, the distributions of subpopulations a...

Morphological Evaluation of Tumor-Infiltrating Lymphocytes (TILs) to Investigate Invasive Breast Cancer Immunogenicity, Reveal Lymphocytic Networks and Help Relapse Prediction: A Retrospective Study.

Tumor-infiltrating lymphocytes (TILs) in breast cancer are a key representative of the tumor immune microenvironment and have been shown to provide prognostic and predictive biomarkers. The extent of lymphocytic infiltration in tumor tissues can be assessed by evaluating hematoxylin and eosin (H&E)-stained tumor sections. We investigated tissue microarrays of 31 invasive breast cancer patients, looking at quantity and topological distribution of CD3+, CD8+, CD20+, Ki67+, FoxP3+ TILs and CD3+/FoxP3+, CD8+/FoxP3+ cell ratios. We separately evaluated TILs at the invasive edge and at the center of the tumor, to find any clinical implications of tumor heterogeneity. No statistically significant difference was found in quantity and distribution of both TIL subsets and TIL ratios, by comparing patients who suffered from a local or distant recurrence of the tumor (relapse group: 13 patients) with patients not showing cancer relapse (non-relapse group: 18 patients). In the whole sample, we observed three main statistically significant positive correlations: (1) between CD3+ and CD8+ T-cells; (2) between FoxP3+ and Ki67+ lymphocyte infiltration; (3) between CD3+/FoxP3+ cell ratio (C3FR) and CD8+/FoxP3+ cell ratio (C8FR). Tumor heterogeneity and stronger positive TIL associations were found in the non-relapse group, where both CD3–CD8 and FoxP3-Ki67 inter-correlations were found to be significant at the center of the tumor, while the correlation between C3FR and C8FR was significant at the invasive edge. No correlations between TIL subsets were detected in the relapse group. Our findings suggest the existence of stronger inter-subtype lymphocytic networks in invasive breast cancer not showing recurrence. Further evaluations of clinical and topological correlations between and within TIL subsets are needed, in addition to the assessment of TIL quantification and distribution, in order to follow up on whether morphological evaluation of TILs might reveal the underlying lymphocytic functional connectivity and help relapse prediction.

A gene signature of chemo-immunization to predict outcome in patients with triple negative breast cancer treated with neoadjuvant chemotherapy.

575 Background: In patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after anthracycline-based neoadjuvant chemotherapy (NACT) is associated with a better prognosis. We aimed to develop a genomic signature from pre-treatment samples to predict the extent of TILs after NACT, and then to test its prognostic value on survival. Methods: Using 99 pre-treatment samples (training set), we generated a four-gene signature that predicts post-NACT TILs using the LASSO technique. Prognostic value of the signature on survival was assessed on the training set (n=99) and then evaluated on an independent validation set including 185 patients with TNBC treated with NACT. Results: A four-gene signature, assessed on pre-treatment samples and combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 predicted the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, a one-unit increase in the signature value was associated with distant-relapse free survival (DRFS) (HR: 0.28, 95%CI: 0.13-0.63, p=0.002). For the validation set, the four-gene signature was significantly associated with DRFS in the entire set (HR: 0.26, 95%CI: 0.11-0.59, p=0.001) and in the subset of patients with residual disease (HR: 0.23, 95%CI: 0.10-0.55, p&lt; 0·001). Conclusions: We developed a four-gene signature of chemotherapy-induced immune-activation, which predicts outcome in patients with TNBC treated with NACT. [Table: see text]

Soluble Factors Secreted by T Cells Promote β-Cell Proliferation

Type 1 diabetes is characterized by infiltration of pancreatic islets with immune cells, leading to insulin deficiency. Although infiltrating immune cells are traditionally considered to negatively impact β-cells by promoting their death, their contribution to proliferation is not fully understood. Here we report that islets exhibiting insulitis also manifested proliferation of β-cells that positively correlated with the extent of lymphocyte infiltration. Adoptive transfer of diabetogenic CD4+ and CD8+ T cells, but not B cells, selectively promoted β-cell proliferation in vivo independent from the effects of blood glucose or circulating insulin or by modulating apoptosis. Complementary to our in vivo approach, coculture of diabetogenic CD4+ and CD8+ T cells with NOD.RAG1−/− islets in an in vitro transwell system led to a dose-dependent secretion of candidate cytokines/chemokines (interleukin-2 [IL-2], IL-6, IL-10, MIP-1α, and RANTES) that together enhanced β-cell proliferation. These data suggest that soluble factors secreted from T cells are potential therapeutic candidates to enhance β-cell proliferation in efforts to prevent and/or delay the onset of type 1 diabetes.

Clinical pathological and mammographic correlation of invasive lobular carcinoma in the context of breast density

Introduction It has been proposed that areas of increased breast density, as defined mammographically, might represent a non-obligate precursor of breast cancer. However, the association between breast density, invasive lobular carcinoma (ILC) and that of its precursor lesions, lobular carcinoma in situ /atypical lobular hyperplasia (LCIS/ALH), has not been investigated yet. We also aimed to investigate whether specific pathological features contribute with the mammographic presentation of ILC (e.g., speculated vs occult). Methods The radiology and pathology of 147 patients were reviewed for radiological-pathological correlation. Immunohisto-chemistry was performed on tissue microarrays. Results This analysis revealed that women with dense breasts and ILC were more likely to be young, to have mammographically occult tumours and to have an increased frequency and extent of LCIS/ALH. The following features were also significantly associated with the mammographic presentation of ILC: the extent of lymphocytic infiltrate, the appearance of the tumour stroma and the expression of cyclin E. This study addressed for the first time the mammographic appearance of ILC in the context of the surrounding non-neoplastic breast parenchyma.

Intraosseous lymphocytic infiltrates after hip resurfacing arthroplasty

To identify a possible role of lymphocytic infiltrates in failure mechanism of the metal-on-metal hip resurfacing arthroplasty, the extent of lymphocytic infiltration was compared with reasons for prosthesis failure in a series of retrieval specimens. One hundred eighty-one femoral head and neck remnants were subjected to thorough analysis of histological findings and clinical data. Lymphocytic infiltrates were considered weak to moderate in 52 (28.7%) and excessive in ten (5.5%) cases. Six cases with excessive lymphocytic infiltrates belonged to the group of 33 (18.2%) revisions without obvious cause (periprosthetic fracture, component loosening, and infection) for prosthesis failure. Excessive lymphocytic infiltrates were strongly linked to the presence of proliferative desquamative synovitis (p < 0.0001). Both the excessive lymphocytic infiltrates and proliferative desquamative synovitis were associated with female gender (p < 0.05). We hypothesize that a specific cause of groin pain might be related to excessive intraosseous lymphocytic infiltrates and explained possibly by the hypersensitivity reaction of the delayed type after the hip resurfacing arthroplasty. Proliferative desquamative synovitis might constitute another morphologic feature associated with the delayed type hypersensitivity reaction.

Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration.

The present study examined the extent and distribution of lymphocyte infiltration in demyelinated lesions in the cerebral cortex of multiple sclerosis (MS) patients. Tissue sections from the brain of 10 MS patients and five patients without neurological disease were double labeled for myelin basic protein and the lymphocyte markers CD3, CD4, CD8, CD45RO, and CD20. The highest density of CD3-positive T cells was found in MS white matter lesions (40.4/10 high power fields (hpf)). Fewer T cells were detected in cortical lesions that extended through both white and gray matter (12.1/10 hpf; P < 0.001). The lowest number of T cells was detected in intracortical demyelinated lesions (1.1/10 hpf). This was equal to the lymphocyte density in nondemyelinated cerebral cortex within the same tissue block (1.1/10 hpf) or cerebral cortex in control brains (1.8/10 hpf). A similar distribution was found using the CD4, CD8, and CD45RO markers. CD20-positive B cells were scarce in all specimens examined. These data indicate that areas of intracortical demyelination in chronic MS are not associated with an increased number of lymphocytes, or an altered distribution of lymphocyte subsets, when compared with control areas in MS and control patients. This finding indicates that the extent of lymphocyte infiltration in MS lesions is dependent on lesion location.

Lymphocytic infiltration surrounding liver metastases from colorectal cancer.

Tumor infiltrating lymphocytes (TILs) have been recognized as a tumor-host reaction in various primary neoplasms. Although several studies reported TILs surrounding metastatic liver tumors, to the authors' knowledge few evaluations of the clinical significance of such features in patients with colorectal liver metastases have been carried out. Forty-one patients who underwent initial hepatic resection for liver metastases from colorectal cancer were studied. Lymphocytic infiltration surrounding metastatic liver tumor was graded as weak or dense according to the mean number of TILs from 10 high-power microscopic fields (< or =50 or >50/HPF). Dense lymphocytic infiltration between the metastatic tumor and hepatic parenchyma was seen in 18 of 41 patients (44%). Histologically, tumor invasion of the portal vein was rare in patients with dense TILs (12%) compared with patients with weak TILs (36%). Patients with dense TILs survived longer than patients with weak TILs after hepatic resection (P = 0.013). Multivariate analysis using the Cox proportional hazard model identified this pathological variable as a significant independent prognostic factor after hepatic resection. The extent of lymphocytic infiltration between the metastatic nodule and hepatic parenchyma may reflect host defensive activity in the liver and is closely related to prognosis in patients who underwent hepatic resection for liver metastases from colorectal cancer.

Sub-lethal radiation enhances anti-tumor immunotherapy in a transgenic mouse model of pancreatic cancer.

BackgroundIt is not uncommon to observe circulating tumor antigen-specific T lymphocytes in cancer patients despite a lack of significant infiltration and destruction of their tumors. Thus, an important goal for tumor immunotherapy is to identify ways to modulate in vivo anti-tumor immunity to achieve clinical efficacy. We investigate this proposition in a spontaneous mouse tumor model, Rip1-Tag2.MethodsExperimental therapies were carried out in two distinctive trial designs, intended to either intervene in the explosive growth of small tumors, or regress bulky end-stage tumors. Rip1-Tag2 mice received a single transfer of splenocytes from Tag-specific, CD4+ T cell receptor transgenic mice, a single sub-lethal radiation, or a combination therapy in which the lymphocyte transfer was preceded by the sub-lethal radiation. Tumor burden, the extent of lymphocyte infiltration into solid tumors and host survival were used to assess the efficacy of these therapeutic approaches.ResultsIn either intervention or regression, the transfer of Tag-specific T cells alone did not result in significant lymphocyte infiltration into solid tumors, not did it affect tumor growth or host survival. In contrast, the combination therapy resulted in significant reduction in tumor burden, increase in lymphocyte infiltration into solid tumors, and extension of survival.ConclusionsThe results indicate that certain types of solid tumors may be intrinsically resistant to infiltration and destruction by tumor-specific T lymphocytes. Our data suggest that such resistance can be disrupted by sub-lethal radiation. The combinatorial approach presented here merits consideration in the design of clinical trials aimed to achieve T cell-mediated anti-tumor immunity.

Lacrimal gland fluid secretion and lymphocytic infiltration in the NZB/W mouse model of Sjögren’s syndrome

Purpose. The fluid secretory impairment of lacrimal and salivary glands in Sjögren’s syndrome (SS) is thought to be related to the extent of lymphocytic infiltration (LI) and subsequent loss of glandular tissue. In this study, we examine the correlation between the extent of tear flow reduction and the extent of LI of lacrimal glands in the NZB/W mouse, a model of SS. Methods. We stimulated tear production by topical application of carbachol onto the gland while fluid was collected from the lacrimal duct. The lacrimal glands were removed after fluid collection for histology. Results. Fluid secretion in response to carbachol was less in the majority of young NZB/W females compared to C57 control animals and none of the glands showed LI. Fluid secretion was also impaired in the majority of old NZB/W females, and the extent of LI was highly variable. Some of the old SW females also showed blunted fluid secretory responses and some degree of focal LI. Young SW females showed no LI and most animals exhibited normal flow responses. Analysis of paired flow and LI measurements showed no correlation between LI and flow impairment in any of the groups or in the pooled data. Carbachol-stimulated protein secretion from lacrimal gland slices in vitro were similar in young and old SW and NZB/W mice. Conclusions. These results suggest that LI alone is not sufficient to explain the secretory dysfunction in the NZB/W mouse model of Sjögren’s syndrome.

Cytokine gene expression in autoimmune thyroiditis in BioBreeding/Worcester rats.

The intrathyroidal cytokine gene expression in human autoimmune thyroid disease is difficult to interpret because surgical specimens mostly reflect the autoimmune disease at a late stage. Because it is not possible to investigate early stages of thyroiditis in humans, the Bio Breeding/Worcester (BB/W) rat was used as a model. To characterize the lymphocytic thyroiditis (LT) of BB/W rats further and to evaluate early increases of cytokine gene expression in LT, we investigated the interleukin (IL)-2, -4, -6, -10, -12p40, interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) gene expression in the thyroids, spleens, and livers of BB/W rats with and without histological evidence for thyroiditis. The gene expression of these cytokines was determined by Genescan (PE Applied Biosystems, Foster City, CA) fragment analysis using reverse polymerase chain reaction (RT-PCR). Serum thyroglobulin (Tg) antibody concentrations were measured and the extent of lymphocytic infiltration of one thyroid lobe was histologically graded. Cytokine gene expression in rats with and without LT was compared in three groups of rats: 55-day-old rats after 24 days of iodine administration, 75-day-old rats after 45 days of iodine administration, and 101-day-old rats. In the thyroids of the BB/W rats no expression of IL-4 or IL-10 was detectable. The number of rats with detectable TNF-alpha, IFN-gamma, IL-2, IL-12p40 gene expression was significantly higher in rats with LT. Rats with LT had significantly higher IL-12p40 mRNA levels. There were no significant differences in the IL-6 gene expression between rats with and without LT. A correlation between the level of lymphocytic infiltration and the TNF-alpha (r = 0.56, p < 0.0065) and TG antibody concentration (r = 0.62, p < 0.0065) was found. Therefore, the early cytokine gene expression in the BB/W rat is characterized by Th1-related cytokines like IL-2 and IFN-gamma. Whether the detected IL-12p40 (10 rats) and IFN-gamma (5 rats) gene expression in animals without LT is an early indicator for the development of LT remains to be determined.

Possible prognostic value of histopathologic parameters in patients with carcinoma of the oral tongue.

The current TNM staging system is helpful but still not enough to accurately determine prognosis of the patients with squamous cell carcinomas of the oral tongue. Histopathologic variables, however, may be more helpful for predicting nodal metastasis and locoregional recurrences. In this respect, histopathologic examinations were done retrospectively of tumor specimens from 60 patients with squamous cell carcinomas of the oral tongue. Besides T-stage and nodal involvement, histopathologic parameters of tumor thickness, perineural invasion, lymphovascular space invasion, the extent of lymphocyte infiltration and the invasion pattern statistically correlated with locoregional recurrences. For nodal metastasis, tumor thickness of 10 mm or more and the type of invasion pattern were statistically significant. These results revealed that the variables described should be used for managing oral tongue cancers.