Peritumoral Inflammatory Cells Research Articles

Assessment of tumoral and peritumoral inflammatory reaction in cutaneous malignant melanomas.

Skin cancer is one of the most common types of cancer, with an increasing worldwide incidence in recent decades. The main risk factor for increasing the skin cancer incidence is ultraviolet (UV) radiation. Of the two major forms of skin cancer (melanomas and non-melanotic cancers), the cutaneous melanoma (CM) is the most aggressive form, causing about 80% of the deaths resulted from this type of tumor. Malignant melanoma develops through malignant transformation of melanocytes in the skin because of prolonged exposure to solar or artificial UV. The malignant transformation of the melanocytes in the skin is accompanied by the presence of a local inflammatory reaction that, in the initial stages of carcinogenesis, would oppose to tumor development. Chronic exposure to UV or other etiopathogenic factors induces chronic inflammation, which, by producing inflammatory molecules (cytokines, chemokines, prostaglandins), constitutes a tumoral microenvironment that favors carcinogenesis, tumor invasion, metastasis, and the presence of neoplastic "mutant cells" that avoid the protective action of the immune system. Using immunohistochemistry techniques, we assessed the intra- and peritumoral inflammatory infiltrate cells in CM. The chronic inflammatory infiltrate presented more intense in the peritumoral stroma compared to the intratumoral one, heterogenous, more intensely composed of lymphocytes, plasma cells, macrophages, and mast cells (MCs), the most numerous cells in the inflammatory infiltrate being T-lymphocytes, plasma cells and macrophages; B-lymphocytes and MCs were in a small number, especially intratumorally. Inflammatory cells had a direct contact with tumor cells, blood vessels, connective matrix, suggesting that the inflammatory microenvironment plays an important role in carcinogenesis, tumor invasion, local angiogenesis, and tumor metastasis.

Immunohistochemical expression of PD-L1 and its correlation with microsatellite status in endometrial and ovarian clear cell carcinomas: a cross-sectional study

BackgroundClear cell carcinoma is an uncommon histologic subtype of ovarian and endometrial carcinoma with poor response to Platinium-based chemotherapy agents at high stages. Blockage of Programmed cell Death Ligand-1 (PD-L1), can be used in targeted immunotherapy. This study investigated Mismatch Repair Deficiency (MMR-D) status, PD-L1 expression, and the correlation between PD-L1 expression and microsatellite instability (MSI) status in ovarian and endometrial clear cell carcinomas.MethodsOvarian clear cell carcinoma (OCCC) (n = 28) and endometrial clear cell carcinoma (ECCC) (n = 28) samples were evaluated for PD-L1 (in tumoral and peri-tumoral inflammatory cells), MSH6 and PMS2 expression by immunohistochemistry (IHC) study. PD-L1 expression > 1% in tumor cells and > 5% in peritumoral inflammatory cells were considered positive.ResultsThe prevalence of PD-L1 expression was higher in ECCC (20/28, 71.43%) compared to OCCC tumor cells (16/28, 57.15%) (p > 0.05), while expression in peritumoral inflammatory cells was significantly higher in ECCC (25/28, 89.29%) compared to OCCC (11/28, 39.28%) (p < 0.05). MMR-D was observed in 5 cases, four OCCCs and one ECCC, among which, four (80%) showed PD-L1 expression in peritumoral inflammatory and tumor cells. The only OCCC case with extensive PD-L1 expression in tumor cells (> 50%) exhibited MSH6/MSH2 loss. No significant correlation was noted between PD-L1 expression and the pathologic stage or survival.ConclusionPD-L1 expression was significantly associated with clear cell morphology, especially in the endometrium, independent of MMR protein status.

The histopathological features and their prognostic impact in the postoperative follow-up of colorectal cancer patients.

The validation of histological prognostic markers in colorectal cancer not only for survival parameters but also for early postoperative outcomes is of paramount importance. The aim of our study was to search for the tumor histopathological (HP) characteristics that may influence the postoperative morbidity, especially the occurrence of anastomotic leakage. Our results indicated that peritumoral inflammatory cell infiltrate appeared to correlate with both anastomotic fistula and overall postoperative complications. Likewise, high-grade and undifferentiated colorectal tumors seemed to be correlated with a higher incidence of postoperative leakage and complications. No relation could be established between the other HP features and the postoperative untoward outcomes.

Evaluation of peritumoral inflammatory infiltration and its relationship with different prognostic factors in cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers. Prognostic factors, such as tumor thickness, play a crucial role in the management of these patients. Peritumoral inflammatory infiltration has been shown to influence the prognosis of malignancies. This study aimed to determine different prognostic factors and investigate peritumoral inflammatory infiltration in patients with cSCC. The study population consisted of 272 patients with a diagnosis of cSCC. Clinical data, such as age and tumor location, were extracted from pathology reports, and other information was gathered by contacting the patients via phone calls. All pathology slides were reviewed by an expert dermatopathologist, and the histopathological features and prognostic factors were evaluated. The highest number of tumors was found in the scalp and forehead (21.3%), while the lowest number was found in the trunk and thighs (3.31%). The highest mean tumor thickness was observed in the group with no inflammatory cells; on the other hand, the lowest tumor thickness was found in the group of lymphocytes and plasma cells. The group with severe eosinophilic infiltration had the highest mean tumor thickness, while the group with no eosinophilic infiltration had the lowest mean tumor thickness. Depending on the type of peritumoral inflammatory cells, the prognosis of cSCC may be predictable.

A combined spatial score of granzyme B and CD68 surpasses CD8 as an independent prognostic factor in TNM stage II colorectal cancer

BackgroundPrevious assessments of peritumoral inflammatory infiltrate in colorectal cancer (CRC) have focused on the role of CD8+ T lymphocytes. We sought to compare the prognostic value of CD8 with downstream indicators of active immune cell function, specifically granzyme B (GZMB) and CD68 in the tumour microenvironment.MethodsImmunohistochemical (IHC) staining was performed for CD8, GZMB, CD68 and CD163 on next-generation tissue microarrays (ngTMAs) in a primary cohort (n = 107) and a TNM stage II validation cohort (n = 151). Using digital image analysis, frequency of distinct immune cell types was calculated for tumour proximity (TP) zones with varying radii (10 μm-100 μm) around tumour cells.ResultsAssociations notably of advanced TNM stage were observed for low density of CD8 (p = 0.002), GZMB (p < 0.001), CD68 (p = 0.034) and CD163 (p = 0.011) in the primary cohort. In the validation cohort only low GZMB (p = 0.036) was associated with pT4 stage. Survival analysis showed strongest prognostic effects in the TP25μm zone at the tumour centre for CD8, GZMB and CD68 (all p < 0.001) in the primary cohort and for CD8 (p = 0.072), GZMB (p = 0.035) and CD68 (p = 0.004) in the validation cohort with inferior prognostic effects observed at the tumour invasive margin. In a multivariate survival analysis, joint analysis of GZMB and CD68 was similarly prognostic to CD8 in the primary cohort (p = 0.007 vs. p = 0.002) and superior to CD8 in the validation cohort (p = 0.005 vs. p = 0.142).ConclusionCombined high expression of GZMB and CD68 within 25 μm to tumour cells is an independent prognostic factor in CRC and of superior prognostic value to the well-established CD8 in TNM stage II cancers. Thus, assessment of antitumoral effect should consider the quality of immune activation in peritumoral inflammatory cells and their actual proximity to tumour cells.

Identification of PGC-related ncRNAs and their relationship with the clinicopathological features of Gastric Cancer.

Pepsinogen C (PGC) is considered to be the final product of mature differentiated gastric mucosa. The expression level of PGC in gastric mucosa is clearly decreased upon the development of gastric cancer (GC). However, the mechanism behind PGC's down-regulation remains unclear and needs to be clarified. This study aimed to identify PGC-related ncRNAs with the potential to be PGC post-transcriptional regulators and to further explore the association between these ncRNAs and the clinicopathological parameters of GC. Bioinformatic software was used to predict miRNAs binding specifically to PGC and circRNAs binding specifically to these candidate miRNAs. Dual-luciferase reporter assay was performed to validate the completely complementary pairing of PGC and PGC-related ncRNAs. qRT-PCR was applied to determine the expression levels of PGC and PGC-related ncRNAs in GC tissue. hsa-let-7c was predicted to bind to the PGC gene, which was confirmed by dual-luciferase reporter assay. hsa_circ_0001483 and hsa_circ_0001324 were identified to bind to hsa-let-7c by bioinformatic analysis and dual-luciferase reporter assay. In addition, the hsa_circ_0001483/hsa_circ_0001324 -hsa-let-7c-PGC axis was confirmed in tissue by qRT-PCR. The expression level of hsa_circ_0001483 was correlated with peritumoral inflammatory cell infiltration and lymphatic metastasis. hsa_circ_0001483, hsa_circ_0001324, and let-7c were newly identified and validated as PGC-related ncRNAs and showed associations with the clinicopathological features of GC. The hsa_circ_0001483/hsa_circ_0001324-hsa-let-7c-PGC axis in GC may account for the down-regulation of PGC in GC tissue.

Radioguided surgery with radiolabeled somatostatin analogs: not only in GEP-NETs.

Radioguided surgery (RGS) is a surgical technique that, using intra-operative probes, enables the surgeon to identify tissues preoperatively "marked" by a radiopharmaceutical. Somatostatin receptors (SSTRs) are present in the majority of neuroendocrine cells and may be over-expressed not only by tumor cells, but also by endothelial cells of peritumoral vessels, inflammatory cells and cells of the immune system, such as activated lymphocytes, monocytes and epithelioid cells. This extra neoplastic uptake is the rationale for the use of radiolabeled somatostatin analogs (SSAs) either in some tumors not expressing SSTRs or in various non-oncological diseases. The crucial point of RGS technique lays in the establishment of a favorable tumor-to-background ratio (TBR). A wide range of probe systems are available with different detectors and many radiopharmaceuticals have been experimented and utilized, mainly using g-detection probes; in order to widen RGS application field, newer approaches with b- or b+ emitting radioisotopes have also been proposed. Together with the consolidated clinical use, a promising and effective employment of RGS may be found in neuroendocrine tumors (NETs) using 111In-pentetreotide (OCT). RGS with OCT has been demonstrated useful in the management of patients with gastroenteropancreatic (GEP) tumors, lung, brain and breast cancer. Preoperative scintigraphy or PET with DOTA-peptides combined with RGS increases the rate of successful surgery. Preliminary studies with b- probes using 90Y-SSA suggest the possible interest of this approach in patients undergoing peptide receptor radiotherapy.

Abstract IA7: Innate immune signaling in the pancreatic tumor microenvironment

Abstract Pancreatic ductal adenocarcinoma (PDA) is a devastating disease in which mortality rates approach incidence rates. Invasive PDA is necessarily preceded by a robust intra-pancreatic inflammatory infiltrate which participates in intimate cross-talk with the at-risk or transformed epithelial compartment. However, specific peri-pancreatic inflammatory entities can have widely divergent effects on tumorigenesis by either combating transformation via innate or antigen-restricted tumoricidal immune responses or by promoting tumor growth by providing nutrient sustenance to tumors via the release of tumor-promoting cytokines or growth factors. Elements of the adaptive immune system have a central role in modulating tumorigenesis. We recently reported that antigen-restricted Th2 cells promote pancreatic cancer progression in mice. Accordingly, intratumoral CD4+ Th2 cell infiltrates correlate with reduced survival in human pancreatic cancer. CD4+CD25+Foxp3+ regulatory T cells also facilitate tumor immune escape in murine models and human pancreatic adenocarcinoma. Conversely, CD8+ T cells mediate tumor protection. Innate inflammatory cells also play a vital role in pancreatic tumorigenesis. We reported that immature myeloid cells proliferate in the transformed pancreas and in the pre-metastatic niche and can negate adaptive CD8+ T cells mediated anti-tumor immunity leading to accelerated cancer growth within the pancreas and in the metastatic liver. Similarly, dendritic cells can also promote inflammation and tumorigenesis within the pancreas by inducing the proliferation of Th2 cells. Innate immune receptors and specifically pattern recognition receptors link environmental stimuli to innate immune responses and inflammation. Toll-like receptors (TLRs) are the most well-studied family of pattern recognition receptors. TLRs bind specific molecular motifs derived from microbes, collectively denoted pathogen associated molecular patterns (PAMPs) and thus have a critical role in our capacity to mount an immune responses to invading micro-organisms. However, in addition to binding PAMPs, TLRs are activated by ligating non-pathogenic ‘danger molecules’ which include by-products of inflammatory injury and cellular necrosis, collectively denoted damage associated molecular patterns (DAMPs). Our preliminary work found that the pancreatic tumor microenvironment is rife with DAMPs including HMGB-1 and S100A9. We also found that gut-derived pathogens and PAMPs can access the pancreas. Moreover, Toll-like receptor expression is upregulated on transformed pancreatic ductal epithelial cells, peri-tumoral inflammatory cells, and pancreatic stellate cells in PDA. Based on these data we postulated the ligation of TLRs by peri-pancreatic DAMPs or PAMPs may induce tumor-promoting inflammation. We found that ligation of TLR4, TLR7, or TLR9 accelerates pancreatic cancer progression in an NF-κB and MAP Kinase dependent manner. TLR ligation resulted in activation of Notch and STAT3 signaling mechanisms in both epithelia and stromal compartments. Moreover, blockade of selective TLRs was protective against PDA development. Our work suggests that targeting TLRs may be an attractive strategy to prevent tumorigenesis in at-risk patients or to treat early pancreatic neoplasia. Citation Format: George Miller. Innate immune signaling in the pancreatic tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA7.

The relevance of cell type- and tumor zone-specific VEGFR-2 activation in locally advanced colon cancer.

BackgroundFor the successful therapeutic use of inhibitors of the vascular endothelial growth factor receptor (VEGFR) pathway detailed knowledge of the mechanisms leading to tumor progression is indispensable. The main goal of this study was to determine the relevance of the VEGFR-2 activating pathway for colon carcinoma (CC) metastasis. The initial event is ligand-induced receptor activation through tyrosine autophosphorylation.MethodsVEGFR-2, its ligands VEGF-C and VEGF-D and the phosphorylated (activated) receptor forms pVEGFR-2Tyr1175 and pVEGFR-2Tyr1214 were investigated immunohistochemically in different tumor compartments (intratumoral (zone 1) - invasive front (zone 2) – extratumoral soft tissue (zone 3)) and various cell types (tumor cells, inflammatory cells, macro- and microvasculature) in 84 non-metastatic, lymphogenous-metastatic and haematogenous-metastatic CC.ResultsVEGF-D produced by tumor cells has an autocrine affinity for its receptor VEGFR-2. In tumor budding regions VEGF-D-induced receptor activation by autophosphorylation at Tyr1214 seems to be a possible initial event of the VEGFR-2-mediated signaling pathway, but without effect on metastatic behaviour. In inflammatory cells of almost all CC VEGFR-2 phosphorylation at Tyr 1175 and Tyr 1214 was detectable without accompanying receptor expression, suggesting receptor activation without cell surface expression. Peritumoral inflammatory cells also expressed paracrine acting VEGF-C. The autocrine VEGF-D/VEGFR-2 signaling axis and receptor autophosphorylation at Tyr1214 appear to be main events for capillaries in all three tumor zones and for small vessels in zone 1 and 2. Independent of the metastatic status a large number of cases with capillary immunopositivity in the angiogenically active invasive front was documented, especially for VEGF-D, VEGFR-2 and pVEGFR-2Tyr1214. VEGFR-2 positive extratumoral capillaries were significantly more common in distant metastatic CC. In all tumor compartments the investigated biomolecules were also detected in different frequencies in the macrovasculature, which is responsible for sufficient tumor vascularization. In addition, vascular paracrine-acting VEGF-C production was widely detected, but without zone and vessel-type dependence.ConclusionsThe VEGFR-2 activating pathway is closely involved in tumor cell-associated, vessel-mediated and immuno-inflammatory processes in colon carcinoma and appears to contribute to tumor survival and growth as well as maintenance of the infiltrative phenotype rather than to promote metastasis.

Programmed death ligand-1 (PD-L1) expression in penile squamous cell carcinoma.

393 Background: PD-1 protein is a co-inhibitory receptor expressed on B cells, T cell, and NK cells. Its ligand PD-L1 (B7-H1) leads to inhibition of T cell proliferation and cytokine production and is not expressed on normal tissues other than macrophages, but is expressed on various human carcinomas. Expression of PD-L1 in the HPV-associated disease penile carcinoma is unknown. Methods: Formalin-fixed paraffin-embedded tumor specimens were obtained from 19 patients. PD-L1 staining was done with an E1L3N rabbit monoclonal antibody with the summary of a positive score using H-score membrane staining, which considers both intensity and percentage of cells, with &gt;5% score as a positive. HPV status was also evaluated using FISH or p16 immunohistochemical staining to evaluate for correlation with PD-L1. Results: 23 samples between primaries and lymph nodes were collected from the 19 patients with 5/23 samples (22%) positive for anti-PDL1 staining. 6 samples (26%) were positive for HPV by at least one method of testing with 2/6 (33%) HPV positive patients having positive PD-L1 membrane staining. In both of these samples, there was equivocal peritumoral inflammatory infiltration of PD-L1 cells. Conclusions: This analysis shows that PD-L1 is expressed in penile squamous cell carcinomas and may indicate a role for future anti-PD-L1/PD-1 drugs as therapeutic options. Further analyses of correlated clinical features, survival, and separate PD-L1 staining in peritumoral inflammatory cells are underway.

MMP-7, MMP-8, and MMP-9 in oral and cutaneous squamous cell carcinomas

Oral squamous cell carcinoma (OSCC) and cutaneous squamous cell carcinoma (CSCC) are epithelial neoplasms, of which OSCC has a worse prognosis. Matrix metalloproteinases (MMPs) are involved in the initiation, invasion, metastasis, and defense of cancer. This study aimed to compare differences in MMP expression in these cancers. Sixty-one patients with early-stage (T1-T2 N0 M0) cancers, of which 36 were OSCC and 25 CSCC, were enrolled into this study. Immunohistochemical staining was performed with MMP-7, MMP-8, and MMP-9 antibodies. MMP-7 expression was stronger in OSCC than in CSCC, mainly in the invasive front. MMP-8 was absent and MMP-9 was mildly expressed in OSCC and CSCC cells. However, MMP-8 and MMP-9 were positive in peritumoral inflammatory cells in both cancers. In addition, MMP-7, MMP-8, and MMP-9 were not associated with the overall survival of patients with OSCC and CSCC patients. The increased expression of MMP-7 in the invasive front may partly explain the aggressiveness of OSCC.

HIF-1alpha Expression Profile in Intratumoral and Peritumoral Inflammatory Cells as a Prognostic Marker for Squamous Cell Carcinoma of the Oral Cavity

The HIF-1 transcriptional complex is responsible for controlling transcription of over 100 genes involved in cell hypoxia response. HIF-1alpha subunit is stabilized in hypoxia conditions, creating the HIF-1 nuclear transcription factor. In inflammatory cells, high HIF-1alpha expression induces lymphocytic immunosuppression, decreasing tumoral antigen recognition, which promotes tumor growth. The present work investigated the relationship between HIF-1alpha expression in lymphocytes populating the intratumoral and peritumoral region of 56 patients with oral cancer. Our data indicates a prognostic value for this expression. High HIF-1alpha expression in peritumoral inflammatory cells is significantly related to worse patient outcome, whereas high expression in the intratumoral lymphoid cells correlates with a better prognosis. A risk profile indicating the chance of disease relapse and death was designed based on HIF-1alpha expression in tumoral inflammatory cells, defining low, intermediate and high risks. This risk profile was able to determine that high HIF-1alpha expression in peritumoral cells correlates with worse prognosis, independently of intratumoral expression. Low HIF-1alpha in tumor margins and high expression in the tumor was considered a low risk profile, showing no cases of disease relapse and disease related death. Intermediate risk was associated with low expression in tumor and tumor margins. Our results suggest that HIF-1alpha expression in tumor and peritumoral inflammatory cells may play an important role as prognostic tumor marker.

Tumour Src kinase family member expression correlates with peritumoral inflammatory cell infiltrate in a cohort of early breast cancer patients

Tumour Src kinase family member expression correlates with peritumoral inflammatory cell infiltrate in a cohort of early breast cancer patients

Macrophage migration inhibitory factor and oral cancer

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with pro-inflammatory functions and involved in tumorigenesis. The aim of this study was to evaluate the expression and localization of the macrophage MIF in oral squamous carcinoma (OSC). In addition, the relationship between MIF expression and clinicopathological parameters such as survival data, tobacco use, alcohol habits, TNM stage, tumor graduation, and peritumoral inflammatory infiltrate were evaluated. Using immunohistochemistry, expression and localization of MIF was detected in 44 specimens of OSC. The absolute number and relative proportions of MIF-positive cells detected were also determined separately for tumor parenchyma vs. stroma. All counts were determined from 10 consecutive high-power fields using an integration graticule. Moreover, some parameters were analyzed separately for lip and intra-oral cancers. Migration inhibitory factor-positive cells were observed in both the tumor parenchyma and in inflammatory cells of all specimens. In contrast, MIF expression was not detected in tumoral nests associated with poorly differentiated tumors. In specimens of lip cancer, a greater number of MIF-positive stromal immune cells were detected than in intra-oral cancer specimens (Mann-Whitney test, P = 0.049). Oral squamous carcinoma cells consistently express MIF independent of their location. Lip tumors presented more MIF-positive peritumoral inflammatory cells, similar to control, suggesting that immunological differences in leukocyte activation exist between in lip and intra-oral cancers.

CD45/CD8 myeloid histioid antigen and plasma cell antibody immune response in a case of malignant melanoma

The immune response in metastatic melanoma is not well established and therefore is of particular interest to test for recruitment of immune cells to the tumor. A 46-year-old Caucasian female was evaluated for an asymptomatic right forearm mass. The lesion had been present for at least 4 years and had become painful 4 months ago. Biopsies for hematoxylin and eosin (H and E) staining, as well as immunohistochemical analysis were performed on the primary tumor and on sentinel lymph nodes. The H and E staining was consistent with metastatic melanoma. Positive staining was noted on the tumor cells with S-100, Mart-1/Melan A/CD63, PNL2, HMB45, and tyrosinase. Peritumoral and intratumoral inflammatory cells stained positive for CD8, CD45, PCNA, myeloid histoid antigen, antihuman plasma cell antibody, and focal BRCA1. The staining patterns of CD8/CD45, myeloid histoid antigen and plasma cell antibody on inflammatory cells around the melanoma cells suggest an unusual type of immune response.

Peri-Tumoral Inflammatory Cell Infiltration in OSCC: A Reliable Marker of Local Recurrence and Prognosis? An Investigation Using Artificial Neural Networks

The presence of inflammatory reaction in peri-tumoural connective tissue is generally considered as a defense mechanism against cancer, but inflammation tissue in malignant transformation and early steps of oncogenesis has been recently proven to play a supporting and aggravating role in some carcinomas. Aims of this retrospective study were to evaluate in OSCCs the independent association of peri-tumoral inflammatory infiltrate (PTI) with local recurrence (LR) or survival outcome, and to verify whether PTI can be considered a marker of prognosis. Data from 211 cases of OSCC, only surgically treated between 1990 and 2000, were collected and retrospectively analyzed for PTI and the event LR (5 yrs follow-up at least) by means of univariate-multivariate and neural networks analyses. Patients (mean age 65.3 ± 12.4 yrs, M/F = 2.98) showed presence of PTI in 68.2% (144/211): (+) in 27.0%, (++) in 25.6%, (+++) 15.6%; PTI was found reduced in 24.7% of cases and absent in 7.1%. In overall PTI+ve group (n=144), 66 were TNM Stage I, 33 Stage II, 45 Stage III, none Stage IV. LR (mean 6 ± 4 months) was present in 87/211 (41.2%) patients, of which 43/144 (29.8%) in OSCCs with PTI [23 (+), 13 (++) and 7 (+++)] vs. 44/67 (65.7%) in OSCC with PTI -/+ or PTI-ve ones. By univariate analysis, PTI+ve cases showed a significant lower risk to have LR (p <0.0001; OR= 0.2297; CI= 0.1277:0.4134) vs PTI -/+ or -ve ones, especially among cases with higher PTI value (+++) (OR= 0.1718; CI= 0.0749:0.3939). Multivariate analyses (Logit model and neural networks) confirmed the same datum: presence of PTI was an independent predictive variable accounting for a better tumoural outcome without LR (Logit and neural networks values: OR' 0.226; CI= 0.113:0.454; ROC Area = 0.66, respectively). In terms of prognostic significance, elevated PTI was found to have an independent association with the poorest overall survival rate (P = 0.056). Our findings strongly suggest the importance to investigate routinely PTI in OSCCs, as useful marker of tumoral behavior and prognosis, and warrant further studies.

Relationship between metalloprotease expression in tumour and stromal cells and aggressive behaviour in prostate carcinoma: Simultaneous high-throughput study of multiple metalloproteases and their inhibitors using tissue array analysis of radical prostatectomy samples

The aim of this study was to detect a potential association between clinicopathological factors of prostate cancer aggressiveness and the expression of matrix metalloproteases and their inhibitors in tumour and stromal cells. A tissue array technique and immunochemistry with specific antibodies against matrix metalloproteinases (MMPs)-1, 2, 7, 9, 11, 13, 14, and their tissue inhibitors (TIMPs)-1, 2 and 3 were used to analyse the surgical specimens of 133 patients treated by radical prostatectomy. For each antibody preparation, the cellular location of immunoreactivity was determined. The expression of MMP-2 was negatively associated with high tumour grade. With regard to stromal fibroblasts, TIMP-3 expression was positively associated with histological grade. MMP-7 expression was negatively associated with pretreatment serum levels of PSA, whereas MMP-13 was positively associated with higher levels of the antigen. TIMP-2 expression by mononuclear inflammatory cells correlated significantly and negatively with tumour grade. The expression of TIMP-3 by fibroblasts was associated with a higher Gleason score. An increased expression of MMP-13 by fibroblasts was associated with a greater preoperative level of PSA. In contrast, MMP-2 expression by tumour as well as TIMP-2 expression by peritumoral inflammatory cells was associated with less aggressive prostate carcinoma characteristics.

Endometrial Giant Cell Carcinoma: A Case Series and Review of the Spectrum of Endometrial Neoplasms Containing Giant Cells

Poorly differentiated endometrial carcinomas of specific type include the rarely reported endometrial carcinoma with a malignant giant cell component [endometrial giant cell carcinoma (GCC)]. Since the initial description in 1991, there has only been 1 subsequent case report of this entity. We report another 5 cases. The patients ranged in age from 53 to 83 years, presenting with vaginal bleeding, anemia, or a pelvic mass. Four of the 5 tumors contained areas of endometrial adenocarcinoma of usual type, with a variable giant cell component. The conventional cell types present included 1 case with clear cell carcinoma (30% of tumor volume), 2 with high-grade endometrioid carcinoma (50% and 70% of tumor volume, respectively) and 1 with serous histology (10% of tumor volume). One was composed exclusively of giant cell carcinoma. The giant cell component in all cases consisted of poorly cohesive nests of bizarre multinucleated giant cells with mononuclear tumor cells. A striking peritumoral and intratumoral inflammatory cell infiltrate composed of lymphocytes, plasma cells and focal eosinophils, and neutrophils was present and emperipolesis was noted in 4 of the 5 cases. The giant cells showed focal staining for epithelial markers (AE1/AE3 and CAM 5.2). Three of the patients presented with stage 1A disease, 1 with stage 1B disease, and 1 tumor was advanced, presenting as stage IIIC2. One patient in whom the tumor was exclusively of the giant cell type, developed lung metastasis 4 years after diagnosis and 1 patient is disease free after 14 years. The remaining 3 patients showed no evidence of disease with 15 to 32 months of follow-up. As histotype supplemented by staging information is critical in selection of treatment modalities and in prognostication in uterine malignancies, accurate classification is mandated. Here, we present a series of endometrial carcinomas containing a component of GCC and discuss the spectrum of giant cell-containing uterine neoplasms. At this time, however, the cumulative data on endometrial GCC are limited and the prognostic significance of the presence and the extent of a giant cell component in endometrial carcinoma remains uncertain.

Role of methylation of the hMLH1 gene promoter in the development of gastric and colorectal carcinoma in the elderly

The occurrence of malignant neoplasms increases with advancing age. Although aging and carcinogenesis are basically different processes, they share phenomena such as the accumulation of DNA damage and abnormal proteins. Recent advances in molecular biology have shown an accumulation of genetic and epigenetic changes in both aging and carcinogenesis, as well as the alteration of metabolism, immunosenescence and shortened telomeres. DNA methylation is a representative epigenetic phenomenon and is frequently involved in controlling gene functions during development and tumorigenesis. We herein focused on methylation of genes in the development of gastrointestinal carcinomas in the elderly. The proportion of gastric and colorectal carcinomas with hypermethylation of the hMLH1 promoter increases with age, reaching 25-30% of all carcinomas of the stomach and large intestine in elderly patients. These tumors have clinicopathological and molecular characteristics such as loss of hMLH1 expression, microsatellite instability, poorly differentiated histology, peritumoral inflammatory cell infiltration, low incidence of lymph node metastasis and favorable prognosis. However, methylation-related carcinogenesis accounts for up to approximately one-third of tumors, and other mechanisms; for example chromosomal instability as a result of telomere dysfunction, are responsible for the development of most carcinomas in the elderly.

Comparison of Synchrotron Images of DCIS of the Breast with Their Pathologic Findings.

Abstract Background: Synchrotron radiation x-ray imaging have opened a new door to explore breast tissue below the micron scale providing detailed internal structures of the samples with a great magnification and an excellent resolution. Using phase contrast technique, we got monochromated synchrotron images of DCIS (Ductal Carcinoma In Situ) of the breast tissue section. To figure out relation with their optical microscopic features, we compared the synchrotron images of the DCIS with their histopathologic findings of the same stained section.Material and Methods: A x-ray microscope was installed on 1B2 beamline of Pohang Light Source, a third generation synchrotron radiation facility with operating energy of 2.5 GeV in Pohang, Korea. The x-ray energy was set at 11.1 keV, and the x-ray beam was monochromatized by a W/B4C monochromator. Zernike phase-shifter was adapted for phase contrast x-ray microscopy. Formalin-fixed 5µm-thick breast tissue sample was attached onto the Kapton film, and positioned 25 m away from the beam source. The synchrotron image of sample was converted into a visual image on the CsI(TI) scintillation crystal, and this visual image was captured by a full frame CCD camera. After scanning, we patched these images one and another to show the large area of the tissue section. For the comparative analysis with their synchrotron image, synchrotron-scanned breast tissue sections were stained, and the histopathologic findings of the samples were captured by image analyzer. The magnifying power of this microscope was 100x.Results: The monochromated x-ray microscopic images of DCIS of the breast tissue were obtained with a good resolution. These images revealed various structures of DCIS lesion with a good contrast and high visibility by phase contrast technique. They include prominent and intact periductal basement membrane - a hallmark of DCIS lesion, and stippled fine microcalcifications which were indistinct in the histologic section, and a shadow of intense peritumoral inflammatory cell infiltration. But the minute changes of each cancer cell showing the features of cancer tissue such as, cellular differentiation and nuclear grade, were not identified well.Discussion: The x-ray microscopic imaging of DCIS of the breast tissue section with synchrotron radiation showed a good correspondence with the histopathologic findings of their stained tissue sections. And the synchrotron image of DCIS had some unique radiologic features differentiating from histopathogic findings. Therefore the synchrotron images of the DCIS lesion appear to have a new possibility of use for the clinical and research purposes in near future. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5015.