Lack of Association between Membrane-Type 1 Matrix Metalloproteinase Expression and Clinically Relevant Molecular or Morphologic Tumor Characteristics at the Leading Edge of Invasive Colorectal Carcinoma.

Colorectal cancer (CRC) is one of the leading causes of death from cancer in the western world, but tumor biology and clinical course show great interindividual variation. Molecular and morphologic tumor characteristics, such as KRAS/BRAF mutation status, mismatch repair (MMR) protein expression, tumor growth pattern, and tumor cell budding, have been shown to be of key therapeutic and/or prognostic relevance in CRC. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a membrane-anchored zinc-binding endopeptidase that is expressed at the leading edge of various invasive carcinomas and promotes tumor cell invasion through degradation of the extracellular matrix. The aim of this study was to investigate possible associations between MT1-MMP expression and molecular tumor characteristics as well as morphologic features of tumor aggressiveness in a consecutive series of 79 CRC tissue samples. However, although MT1-MMP was expressed in 41/79 samples (52%), there was no significant association between MT1-MMP expression and KRAS/BRAF mutation status, MMR protein expression, presence of lymphovascular invasion, tumor growth pattern, tumor-infiltrating lymphocytes, or tumor cell budding in our sample cohort (P > 0.05). Thus, we conclude that although MT1-MMP may play a role in CRC invasion, it is not of key relevance to the current models of CRC invasion and aggressiveness.

Role of reflux-induced epithelial-mesenchymal transition in periprosthetic leakage after prosthetic voice rehabilitation.

BACKGROUND: Gastroesophageal reflux (GER) contributes to periprosthetic leakage after prosthetic voice rehabilitation. However, underlying mechanisms are unclear, and markers predicting anti-reflux therapy response are missing. METHODS: We assessed epithelial-mesenchymal transition in 148 consecutive biopsies from 44 patients with/without fistula enlargement under dual-probe pH monitoring before and after proton-pump inhibitor (PPI) therapy applying immunohistochemistry. Results were correlated with reflux intensity and clinical and histologic findings. RESULTS: Epithelial-mesenchymal transition correlated with GER in all samples, and patients with fistula enlargement showed higher epithelial-mesenchymal transition scores. Contrary to patients without enlargement, epithelial-mesenchymal transition scores did not regress during therapy in this group. Furthermore, pretherapeutic epithelial-mesenchymal transition scores were lower in therapy responders than in nonresponders without reaching significance (p = .07). CONCLUSION: We demonstrate that epithelial-mesenchymal transition correlates with severity of GER and presence of periprosthetic fistula enlargement in patients who underwent prosthetic voice rehabilitation, but epithelial-mesenchymal transition seems to be reversible upon PPI treatment in early stages only.

Expression and Y435-phosphorylation of Abelson interactor 1 (Abi1) promotes tumour cell adhesion, extracellular matrix degradation and invasion by colorectal carcinoma cells.

BACKGROUND: The Abelson tyrosine kinase (c-Abl) inhibitor STI571 (Glivec®) has been shown to effectively inhibit colorectal cancer cell migration and invasion. The c-Abl substrate abelson interactor 1 (Abi1) is a key regulator of actin reorganization and upregulated in colorectal carcinoma. The specific role of Abi1 in relation to extracellular matrix degradation and effects of targeting Abi1 phosphorylation have not yet been examined. Here, we investigated the role of Abi1 in relation to invasive properties in colorectal cancer. METHODS AND RESULTS: In 56 primary human colorectal carcinoma samples, we found overexpression of Abi1 in 39% at the invasive edge of the tumour, associated with an infiltrative phenotype and high-grade tumour cell budding (p = 0.001). To explore the role of Abi1 in vitro, we employed the Abi1 expressing and KRAS-mutated CHD1 model and performed matrix degradation assays that showed Abi1 localization at specific sites of matrix degradation. Moreover, quantification of matrix dissolution demonstrated suppression after RNAi knockdown of Abi1 by 95% (p = 0.001). Importantly, treatment with STI571 did abolish Abi1 Y435-phosphorylation, suppressed the matrix dissolution, decreased fibronectin attachment, and suppressed cell invasion through reconstituted extracellular matrix. CONCLUSION: Our data indicate that phosphorylated Abi1 contributes to the invasive properties of colorectal cancer.

Invasion pattern and histologic features of tumor aggressiveness correlate with MMR protein expression, but are independent of activating KRAS and BRAF mutations in CRC.

KRAS/BRAF mutation testing and mismatch repair (MMR) protein immunohistochemistry have an established role in routine diagnostic evaluation of colorectal carcinoma (CRC). However, since the exact impact of these molecular characteristics on tumor morphology and behavior is still subject to research, the aim of our study was to examine associations between molecular and morphologic features that had not been analyzed in this combination before. KRAS (codons 12, 13, and 61) and BRAF (codon 600) mutation status and MMR protein expression were analyzed in a consecutive series of 117 CRC samples using DNA pyrosequencing and immunohistochemistry. Tumor cell budding, infiltration pattern, and peritumoral lymphocytic (PTL) reaction was assessed applying established criteria. Molecular and morphological findings were correlated applying chi-square and Fisher's exact test. We found KRAS or BRAF mutations in 40 and 8 % of samples, while loss of MMR protein expression was observed in 11 %. Tumor budding was significantly associated with infiltrative growth, absence of PTLs, and blood and lymph vessel infiltration. Neither KRAS nor BRAF mutations were associated with a certain growth pattern or budding intensity of CRC, but loss of MMR protein expression was found in context with BRAF mutation, expanding growth, and presence of PTLs. Our results confirm an association between loss of MMR protein expression, presence of activating BRAF mutation, expanding growth, and PTL reaction as well as between tumor budding, infiltrative growth pattern, and tumor aggressiveness; however, there was no such association between the presence of an activating KRAS or BRAF mutation and a distinct invasion pattern or tumor aggressiveness in CRC.

Dose-dependent uptake of 3'-deoxy-3'-[(18) F]fluorothymidine by the bowel after total-body irradiation.

PURPOSE: The aim of this study is to non-invasively assess early, irradiation-induced normal tissue alterations via metabolic imaging with 3'-deoxy-3'-[(18) F]fluorothymidine ([(18) F]FLT). PROCEDURES: Twenty-nine male C57BL/6 mice were investigated by [(18) F]FLT positron emission tomography for 7 days after total body irradiation (1, 4, and 8 Gy) versus 'sham' irradiation (0 Gy). Target/background ratios were determined. The imaging results were validated by histology and immunohistochemistry (Thymidine kinase 1, Ki-67). RESULTS: [(18) F]FLT demonstrated a dose-dependent intestinal accumulation post irradiation. Mean target/background ratio (±standard error) 0 Gy: 1.4 (0.2), 1 Gy: 1.7 (0.1), 4 Gy: 3.1 (0.3), 8 Gy: 4.2 (0.6). Receiver operating characteristic analysis (area under the curve, p value): 0 vs. 1 Gy: 0.81, 0.049; 0 vs. 4 Gy: 1.0, 0.0016; and 0 vs. 8 Gy: 1.0, 0.0020. Immunohistochemistry confirmed the results. CONCLUSIONS: [(18) F]FLT seems to provide dose-dependent information on radiation-induced proliferation in the bowel. This opens the perspective for monitoring therapy-related side-effects as well as assessing, e.g., radiation accident victims.

Combined PET/MRI improves diagnostic accuracy in patients with prostate cancer: a prospective diagnostic trial.

PURPOSE: The pretherapeutic assessment of prostate cancer is challenging and still holds the risk of over- or undertreatment. This prospective trial investigates positron emission tomography (PET) with [(18)F]fluoroethylcholine (FEC) combined with endorectal magnetic resonance imaging (MRI) for the assessment of primary prostate cancer. EXPERIMENTAL DESIGN: Patients with prostate cancer based on needle biopsy findings, scheduled for radical prostatectomy, were assessed by FEC-PET and MRI in identical positioning. After prostatectomy, imaging results were compared with histologic whole-mount sections, and the PET/MRI lesion-based semiquantitative FEC uptake was compared with biopsy Gleason scores and postoperative histology. RESULTS: PET/MRI showed a patient-based sensitivity of 95% (36/38; 95% confidence interval (CI), 82%-99%). The analysis of 128 prostate lesions demonstrated a sensitivity/specificity/positive predictive value/negative predictive value/accuracy of 67%/35%/59%/44%/54% (P = 0.8295) for MRI and 85%/45%/68%/69%/68% (P = 0.0021) for PET, which increased to 84%/80%/85%/78%/82% (P < 0.0001) by combined FEC-PET/MRI in lesions >5 mm (n = 98). For lesions in patients with Gleason >6 tumors (n = 43), MRI and PET achieved 73%/31%/71%/33%/60% (P = 1.0000) and 90%/62%/84%/73%/81% (P = 0.0010), which were improved to 87%/92%/96%/75%/88% (P < 0.0001) by combined PET/MRI. Applying semiquantitative PET analysis, carcinomas with Gleason scores >6 were distinguished from those with Gleason ≤ 6 with a specificity of 90% and a positive predictive value of 83% (P = 0.0011; needle biopsy 71%/60%, P = 0.1071). CONCLUSIONS: In a prospective diagnostic trial setting, combined FEC-PET/MRI achieved very high sensitivity in the detection of the dominant malignant lesion of the prostate, and markedly improved upon PET or MRI alone. Noninvasive Gleason score assessment was more precise than needle biopsy in this patient cohort. Hence, FEC-PET/MRI merits further investigation in trials of randomized, multiarm design.

Overexpression of p16(INK4a) in urothelial carcinoma in situ is a marker for MAPK-mediated epithelial-mesenchymal transition but is not related to human papillomavirus infection.

BACKGROUND: The role of human papillomavirus (HPV) in bladder carcinogenesis remains controversial. Overexpression of p16(INK4a), a surrogate marker for infection with oncogenic HPV in other tumours, has been described for urothelial carcinoma in situ (UCIS). Our goal was therefore to evaluate whether overexpression of p16(INK4a) is associated with HPV infection and to identify mechanisms of p16(INK4a) upregulation in UCIS. MATERIALS AND METHODS: In 60 tissue specimens from a total of 45 patients (UCIS and controls), we performed p16(INK4a) immunohistochemistry followed by detection and subclassification of HPV DNA. In a subset of samples, we tested for gene amplification of p16(INK4a) applying fluorescence in situ hybridization (FISH). RAS/MAPK signalling and epithelial-mesenchymal transition (EMT) was assessed using immunohistochemistry. Finally, we transfected urothelial carcinoma cells with KRAS and examined the expression of p16(INK4a) as well as markers of EMT. RESULTS: We found overexpression of p16(INK4a) in 92.6% of UCIS and in all cervical intraepithelial neoplasia (CIN) controls. In contrast, we detected high-risk HPV DNA in 80% of CIN, but none in UCIS. There was no gene amplification of p16(INK4a). High levels of phosphorylated kinases and urokinase plasminogen activator (uPA) and loss of membraneous E-cadherin were detected in UCIS. KRAS transfection of urothelial carcinoma cells led to upregulation of p16(INK4a) and uPA accompanied by loss of E-cadherin that could be inhibited by application of the kinase-inhibitor Sorafenib. CONCLUSIONS: Our results show that overexpression of p16(INK4a) in UCIS is neither associated with HPV infection nor p16(INK4a) gene amplification but is a consequence of enhanced RAS/MAPK signalling that promotes EMT, possibly due to Sorafenib-sensitive paracrine secretion of the EMT activator uPA. These findings might open a novel therapeutic option for localized but aggressive urothelial cancer.

Fatal thromboembolism to the left pulmonary artery by locally applied hemostatic matrix after surgical removal of spinal schwannoma: a case report.

Locally applied hemostatic agents, mostly consisting of gelatinous granules with admixed human or bovine thrombin, are used in various surgical procedures. In our case, a 78-year-old woman underwent neurosurgical removal of an extraforaminal schwannoma of the L5 dorsal root ganglion. During the procedure, the hemostatic matrix consisting of a meshwork of bovine gelatinous granules admixed with human thrombin was locally applied to control diffuse paravertebral bleeding. Eight hours after surgery, the patient developed dyspnea with right heart failure and finally died. At autopsy, we found complete occlusion of the left pulmonary artery with a large thromboembolus. Histologically, that thromboembolus consisted of gelatinous granules with only a thin rim of surrounding, classic parietal thrombus. To our knowledge, this is the first description of fatal pulmonary embolization of a major lung artery with this material. The report depicts a possible life-threatening complication associated with the local application of hemostatic agents.

Expression of Abelson interactor 1 (Abi1) correlates with inflammation, KRAS mutation and adenomatous change during colonic carcinogenesis.

BACKGROUND: Abelson interactor 1 (Abi1) is an important regulator of actin dynamics during cytoskeletal reorganization. In this study, our aim was to investigate the expression of Abi1 in colonic mucosa with and without inflammation, colonic polyps, colorectal carcinomas (CRC) and metastases as well as in CRC cell lines with respect to BRAF/KRAS mutation status and to find out whether introduction of KRAS mutation or stimulation with TNFalpha enhances Abi1 protein expression in CRC cells. METHODOLOGY/PRINCIPAL FINDINGS: We immunohistochemically analyzed Abi1 protein expression in 126 tissue specimens from 95 patients and in 5 colorectal carcinoma cell lines with different mutation status by western immunoblotting. We found that Abi1 expression correlated positively with KRAS, but not BRAF mutation status in the examined tissue samples. Furthermore, Abi1 is overexpressed in inflammatory mucosa, sessile serrated polyps and adenomas, tubular adenomas, invasive CRC and CRC metastasis when compared to healthy mucosa and BRAF-mutated as well as KRAS wild-type hyperplastic polyps. Abi1 expression in carcinoma was independent of microsatellite stability of the tumor. Abi1 protein expression correlated with KRAS mutation in the analyzed CRC cell lines, and upregulation of Abi1 could be induced by TNFalpha treatment as well as transfection of wild-type CRC cells with mutant KRAS. The overexpression of Abi1 could be abolished by treatment with the PI3K-inhibitor Wortmannin after KRAS transfection. CONCLUSIONS/SIGNIFICANCE: Our results support a role for Abi1 as a downstream target of inflammatory response and adenomatous change as well as oncogenic KRAS mutation via PI3K, but not BRAF activation. Furthermore, they highlight a possible role for Abi1 as a marker for early KRAS mutation in hyperplastic polyps. Since the protein is a key player in actin dynamics, our data encourages further studies concerning the exact role of Abi1 in actin reorganization upon enhanced KRAS/PI3K signalling during colonic tumorigenesis.

Progressive multifocal leukoencephalopathy developing in advanced pulmonal sarcoidosis.

Coincidence of pulmonal sarcoidosis and progressive multifocal leukoencephalopathy (PML) rarely occurs. So far an entire course has been recorded in only very few cases. We demonstrate the case of a 49-year-old male developing an infratentorial localized PML in the setting of advanced pulmonal sarcoidosis. PML was not included in the diagnostic considerations in the first instance. Regarding the diagnosis of pulmonal sarcoidosis proved by lung biopsy, the neurological impairment was first thought to be due to a neurosarcoidosis. But magnetic resonance tomography (MRI) clearly showed a demyelination process in the cerebellum. Because of the inconsistency of the radiological findings with a neurosarcoidosis the diagnosis of an acute disseminated encephalomyelitis (ADEM) was favoured. Therefore, the patient was initially treated with corticosteroids. Because of increasing deterioration further diagnostic testings were performed. In the cerebrospinal fluid (CSF) as well as in the paraffin-embedded tissue of a stereotactical brain biopsy JCV-DNA was successfully demonstrated by PCR. Cidofovir was administered. The progression of the disease could not be influenced. The patient died 5 months after the first neurological symptoms. This report stresses the diagnostic difficulties considering patients with sarcoidosis and neurological symptoms.

[DNA ploidy and proliferative activity in salivary gland tumours]. / DNA-Ploidie und proliferative Aktivität bei Speicheldrüsentumoren.

DNA ploidy and S-Phase fraction (SPF) of 279 salivary gland tumours were analysed using high-resolution DNA flow cytometry. All 229 benign neoplasms were diploid while 12 of 50 malignant tumours showed cell populations with aneuploid DNA content. The SPF values of diploid malignancies were significantly higher if compared with pleomorphic adenomas but did not differ from that of the zystadenolymphoma (Warthin tumour) group. While aneuploidy represents a distinct indicator of malignancy SPF values are of minor relevance for dignity assessment in salivary gland tumours.

Biological response to a new composite polymer augmentation device used for cruciate ligament reconstruction.

A resorbable composite augmentation cord braided of poly(L-lactide) and poly(L-lactide-co-glycolide) fibers was designed for the temporary protection of repaired cruciate ligaments. This study examined the biocompatibility of the new device and the influence of augmentation duration on ligament healing in a sheep model. The anterior cruciate ligament (ACL) was cut close to the femoral insertion and reinserted with sutures. The repaired ACLs were augmented with the slowly degrading new composite cord and alternatively with a faster degrading polydioxanone cord (PDS). A tendon graft group (gold standard) served as control. Histological evaluation and biomechanical testing were performed after 6 months. The composite cord showed no signs of degradation, whereas the PDS was intra-articularly resorbed. Both devices showed only minor foreign body reactions, proving their good biocompatibility. However, 9 of 11 composite cords had ruptured too early because of fatigue at the bone tunnel entrances. All operated knees were less stable than the nonoperated collateral joints. Knees equipped with the composite cord showed the largest anterior instabilities, whereas the PDS-augmented group exhibited in some cases knee instabilities comparable with that of the tendon group. A positive effect of a longer mechanical protection by a slowly degrading augmentation could not yet be shown. The fatigue strength of the device still needs improvement.

Correlation between DNA ploidy by flow cytometry and chromosome 3 aberration in oral squamous cell carcinoma.

Although flow cytometric DNA ploidy has turned out as a significant predictor of survival in oral squamous cell carcinoma, little is known about the underlying karyotypic structure of gross aneuploidy. We therefore analysed one diploid and 9 aneuploid carcinomas with relative DNA contents between 1.1 and 2.8 by fluorescence in situ hybridization with topologic markers for the centromere (3cen) and the terminal regions (3p, 3q) of chromosome 3. Progressing deviation of aberrant DNA contents from the normal diploid value correlated with increasing 3cen copy numbers per cell. A pronounced marker heterogeneity suggested that DNA-aneuploid cell populations consisted of karyotypically different clones. Monosomy of 3p was the only chromosomal alteration in the DNA diploid tumour. A significant 3p underrepresentation was a recurrent finding also in 7 of 9 aneuploid carcinomas while a subset of cells in each of 2 other cases showed a complete loss of one sister chromosome 3. In contrast, 7 of 9 aneuploid tumours exposed corresponding 3q and 3cen copy numbers, 2 showed a substantial 3q overrepresentation. It appears that amplification of chromosome 3 plays a role in the development of aneuploidy and the concurrent overexpression of 3q target genes. Acquired loss of the short arm of chromosome 3 in DNA-diploid tumour cells may contribute to the manifestation of recurrent 3q deletions in aneuploid cell populations.

Flow cytometric DNA ploidy in salivary gland tumours.

This study on 279 tumours of the salivary glands was conducted to analyse whether the assessment of DNA ploidy by flow cytometry may assist histopathology in discriminating benign from malignant types of tumours. The group of benign tumours included 164 pleomorphic adenomas, 51 Warthin's tumours, 7 basal cell adenomas, 2 lipomas as well as 5 other different tumours. All of the 229 benign tumours were diploid. The malignant tumours consisted of 18 adenoid cystic adenomas, 10 mucoepidermoid carcinomas, 5 acinic cell carcinomas, 5 carcinoma in pleomorphic adenoma as well as of 12 other malignancies belonging to 7 different tumour entities. Twelve of 50 malignant salivary gland tumours were aneuploid. There was no significant relationship between the DNA ploidy status and histopathological grading, lymph node metastasis and local recurrence development, respectively. In three cases which initially were taken for pleomorphic adenomas by routine histological examination, aneuploid cell populations exposed by DNA flow cytometric analysis gave rise to a closer inspection of the suspect lesions. Examination of consecutive slides actually revealed small assemblies of carcinoma cells that required a final diagnosis as non-invasive carcinoma in pleomorphic adenoma. The most obvious value of DNA flow cytometry in salivary gland tumours is thus its contribution to assist histopathology in identifying potentially malignant lesions.

Follicular dendritic cell sarcoma of the tonsil: report of a rare case.

Follicular dendritic cell tumors are extremely rare. Only 17 cases have been previously described in the literature, and only three of them involved primary tumours of the oral cavity. We describe a new case of the latter, which occurred in a 51-year-old man who sought evaluation for a painless enlargement of his left palatine tonsil. The tonsil was excised, and histologic examination revealed that the tumor was a primary sarcoma that had arisen from the dendritic reticulum cells of the palatine tonsil. Postoperatively, the tumor site was treated with percutaneous irradiation (total dose: 70 Gy). After more than 5 years of follow-up, the patient showed no evidence of recurrence. We also discuss the salient features of the immunohistochemical examination.

Endoreduplication in conjunction with tumor progression in an aneuploid laryngeal squamous cell carcinoma.

We report the case of a 58-year-old man who presented with a squamous cell carcinoma pT1a G2 of the left vocal cord. Six months after histologically verified complete resection, the patient experienced an endolaryngeal and extralaryngeal local recurrence pT4 pN2b G2. We applied DNA flow cytometry (FCM) and comparative genomic hybridization (CGH) on both primary and recurrent tumor. The primary tumor and the endolaryngeal compartment of the relapse was an aneuploid cell clone with a FCM DNA index of 1.42 and 1.44, respectively. The extralaryngeal compartment showed a shift featuring a DNA index of 2.78. In the primary tumor and in both compartments of the recurrence there was an identical pattern of complex chromosomal imbalances as detected in CGH (CGH karyotype: rev ish enh [8q24.2-q24.3, 10q26.1-q26.3, 11q24-q25, 12q24.2-q23.33,X], dim [4q, 13q14.3-q31], amp[1p36.1-p36.2]). Hence, the recurrence was not associated with further gains and losses of chromosomal material. However, in the anterior part of the recurrence, the aneuploid tumor cell genome had completely doubled, obviously due to endoreduplication. Immunohistochemical analysis of several cell-cycle regulators revealed altered expression of checkpoint proteins, pointing to a complex disturbance in cell-cycle regulation.

Are postoperative complaints and complications influenced by different techniques in fashioning and fixing the mesh in transperitoneal laparoscopic hernioplasty? Results of a prospective randomized trial.

It is unknown at present what the best method is among mesh implantation, central incision, reconstructing the deep inguinal ring, or a non-incised mesh implant in laparoscopic hernia surgery. Further, it is unproven to what extent a circular enclosure of the cremasteric structures by an incised mesh implant could cause postoperative complications and complaints. To evaluate the possible effects of different configurations and fixation techniques of mesh implants in transperitoneal repair of inguinal hernias, a randomized trial (phase IIIa study) was conducted to compare incised versus non-incised mesh and clip fixation versus suturing the mesh. A total of 360 male patients with unilateral primary hernias were randomized to 3 groups. Postoperative complaints were documented by means of a visual analog scale. These values showed no significant differences between study arms. At the first postoperative control, on day 3, patients after repair of Nyhus type II hernias had significantly fewer complaints than those after Nyhus type IIIa and IIIb repair. To gain additional facts, a duplex flow examination of testicular vessels was performed pre- and postoperatively. Testicular perfusion was not influenced by mesh configurations in the trial. There were no statistical differences in postoperative complications and recurrence rates between groups. In conclusion no influence on postoperative complaints and complications could be demonstrated by different mesh fashioning and fixation alternatives studied in this trial.

Cell proliferation and p27Kip1 expression in endophytic schneiderian papillomas.

OBJECTIVE: To clarify epithelial cell proliferation and p27Kip1 expression along the stepwise histological changes from endophytic schneiderian papillomas to associated carcinomas. STUDY DESIGN: Retrospective investigation involved surgical specimens from 58 patients. METHODS: Immunohistochemical assessment involved the nuclear Ki67 antigen expressed in proliferating cells. Further, the cyclin-dependent kinase (cdk) inhibitor p27Kip1 was assessed. Binding of p27Kip1 to the cyclin E-cdk2 complex inhibits this kinase, which results in cell cycle arrest. The expression rates of both proteins were compared between nonpapillomatous nasal mucosa, endophytic schneiderian papillomas, carcinoma in situ, and invasive squamous cell carcinomas. Statistics involved the Wilcoxon and Mann-Whitney u tests. Significance was set at P <.05. RESULTS: Comparable cell proliferation rates were observed between non-papillomatous nasal mucosa and cylindrical cell papillomas. Significant increases in cell proliferation were found along the stepwise series of histological changes involving non-papillomatous nasal mucosa, columnar epithelium in inverted papillomas, transitional and squamous metaplasia in inverted papillomas, and dysplastic inverted papillomas (P <.05, respectively). A tendency toward increased cell proliferation in carcinoma in situ compared with dysplastic inverted papillomas was present; however, this was not statistically significant. The expression rates of p27Kip1 were comparable between non-papillomatous nasal mucosa and all histological subtypes within nondysplastic endophytic schneiderian papillomas. Significantly reduced p27Kip1 expression was found in surface cells in dysplastic compared with non-dysplastic inverted papillomas, as well as in the total number of cells in carcinoma in situ compared with dysplastic inverted papillomas (P <.05, respectively). CONCLUSIONS: Inverted papillomas but not cylindrical cell papillomas show increased cell proliferation compared with nonpapillomatous nasal mucosa. Stepwise increases in cell proliferation accompany the consecutive histological changes within inverted papillomas. Among them, increased cell proliferation along with the development of dysplasia and carcinoma in situ is associated with reduced p27Kip1 expression.

Fas/Fas ligand system and apoptosis induction in testicular carcinoma.

BACKGROUND: Tumor-infiltrating, Fas ligand (FasL)-expressing lymphocytes are able to eliminate Fas-bearing tumor cells by apoptosis induction. Activated cytotoxic T-cells that express Fas may enter apoptosis in the presence of FasL tumor cells. To date, no studies of patients with testicular carcinoma have correlated the differential expression of Fas and FasL in both cell types with the corresponding apoptotic index (AI). METHODS: Fas and FasL were investigated immunohistochemically in paraffin embedded tissue sections from 25 patients with nonseminomatous testicular tumors. The percentages of positive cells and the ratios of Fas cells to FasL cells were correlated with the AI of tumor cells and lymphocytes, respectively, using Spearman correlations. RESULTS: No association was found between the rate of FasL positive cells and AI of the other cell type or between the rate of Fas positive cells and the AI of the same cell type. Ratios between Fas positive cells and FasL positive cells were not correlated with the AI; however, a significant positive correlation was found between the AI of tumor cells and the AI of lymphocytes. CONCLUSIONS: It seems unlikely that the Fas/FasL system is responsible for immune escape of the tumor in testicular carcinoma. Rather, the significant positive correlation between the AIs of tumor cells and lymphocytes implicate a previously unknown mechanism of apoptosis induction in both cell types.