Clinical safety of enamel matrix derivative (EMDOGAIN®) in the treatment of periodontal defects

Abstract The aim of the present clinical trial was to test tolerability during 2 treatments with EMDOGAIN® in a large number of patients. An open, controlled study design in 10 Swedish specialist clinics was chosen, with a test group of 107 patients treated with EMDOGAIN® in connection with periodontal surgery at 2 surgical test sites per patient. The procedures were performed 2 to 6 weeks apart on one-rooted teeth with at least 4 mm deep intraosseous lesions. A control group of 33 patients underwent flap surgery without EMDOGAIN® at I comparable site. In total 214 test and 33 control surgeries were performed. Serum samples were obtained from test patients for analysis of total and specific antibody levels. 10 of the patients had samples taken before and after the first surgery. 56 other samples were taken after one treatment with EMDOGAIN®, and 63 after 2 treatments. None of the samples, not even from allergy-prone patients after 2 treatments, indicated deviations from established baseline ranges. This indicates that the immunogenic potential of EMDOGAIN® is extremely low when applied in conjunction with periodontal surgery. Comparison between the test and control groups demonstrated the same type and frequency of post-surgical experiences, i.e., reactions caused by the surgical procedure itself. Clinical probing and radiographic evaluation was performed at baseline and 8 months postsurgery. About half of the patients (44 test and 21 control) were also evaluated after 3 years. There was a significant difference between the test and control results at 8 months post surgery. and this difference had increased further at the 3 year follow-up. The 2.5–3 mm increase in attachment and bone level after treatment with EMDOGAIN® was of the same magnitude as seen in the studies with split-mouth design aiming for lest of effectiveness of EMDOGAIN®.     

Three different pathogenic mechanisms for paraparesis in association with bacterial infections

Three different pathogenic mechanisms are apparent for paraparesis in association with a bacterial infection: a spinal cord compression caused by either an epidural abscess or a vertebral collapse due to spondylitis, an ischaemic spinal cord lesion as a result of septic thromboembolus in abdominal aorta, and a nonspecific, probably immunological, cause in association with reactive polyarthritis. An example of each of these mechanisms is described by means of case histories.     

The effect of comonomer composition, silane heating, and filler type on aqueous TEGDMA leachability in model resin composites

Experimental composites using either bisGMA/TEGDMA or UEDMA/ TEGDMA matrices, quartz or barium glass fillers, and 2 different filler silanization methods were evaluated regarding monomer leachability in distilled water. The leached amount was detected and quantified using gas chromatography. The results showed that twice as much TEGDMA is leached from a bisGMA/TEGDMA based composite than from an UEDMA/ TEGDMA based composite, when both contain 50 wt% TEGDMA. The hypothesis suggested that the higher degree of cure of UEDMA/TEGDMA based composites would be reflected in a lower monomer leaching value, and this hypothesis was supported by the findings. Whether such a correlation exists within groups of UEDMA/TEGDMA based matrices having different degrees of cure was not determined and needs to be investigated in future studies. Variables such as filler composition and silane treatment did not affect the leaching values of TEGDMA in water. That finding suggests that future studies should target differences in matrices, and that the need for considering effects of filler composition and silane treatment methods should not receive the same priority.     

Nuclear morphometry and DNA flow cytometry as prognostic factors in female breast cancer.

OBJECTIVE--To evaluate the predictive value of traditional prognostic factors, nuclear morphometry, and flow cytometric data in invasive breast cancer. DESIGN--Open study. SETTING--One university hospital in Finland. SUBJECTS--248 women with invasive breast cancer followed up for more than 11 years. MAIN OUTCOME MEASURES--Univariate and multivariate analysis of factors thought to indicate prognosis. RESULTS--Diameter of the tumour, lymph node status, S phase fraction. DNA index, the age of the patient, and the SD of nuclear perimeter were significant independent predictors in the whole series in a multivariate analysis. In node negative patients the SED of the nuclear perimeter and diameter of the tumour had independent prognostic value, whereas in node positive patients diameter of the tumour and the S phase fraction were independently related to survival. CONCLUSIONS--Diameter of the tumour is an important prognostic factor in breast carcinomas. Histoquantitative methods are superior to conventional histological techniques for the prediction of outcome in women with breast cancer.     

Tumor size, nuclear morphometry, mitotic indices as prognostic factors in axillary-lymph-node-positive breast cancer.

The biopsy specimens from the primary tumors of 234 women with axillary-lymph-node-positive breast carcinomas (followed up for a mean of 10.9 years) were subjected to interactive morphometric analysis of nine nuclear factors. The proliferative activity of the tumors was estimated by determining two different mitotic indices. Morphometrically determined nuclear factors and mitotic indices showed a significant correlation to the histological grading (p less than 0.0001). Mitotic activity index (MAI; p = 0.018) and volume-corrected mitotic index (M/V index; p = 0.005) accurately predicted the tumor recurrence. Recurrence-free survival was related to the M/V index (p = 0.0003), MAI (p = 0.0024) and tumor size (p = 0.0144). Disease-related survival was determined by the tumor size (p less than 0.0001), M/V index (p = 0.0142) and MAI (p = 0.0492) in that order. On the other hand, the nuclear factors analyzed and the histological grading used had no predictive value (i.e. tumor recurrence, recurrence-free survival or tumor-related survival) in these women. The results indicate that mitotic indices can be successfully applied in place for subjective grading and nuclear morphometry in predicting the disease outcome in patients with axillary-lymph-node-positive breast carcinomas. The mitotic indices provide independent prognostic information in addition to tumor size. The major clinical implications of these results would be to accurately disclose among these women the high-risk patients (i.e. those with high mitotic indices), who might benefit from more agressive adjuvant therapies.     

Immune response against P815X2 mastocytoma growing in syngeneic DBA/2 mice. V. Spleen immunoreactivity and cell mediated cytotoxicity

The in vitro cytotoxicity assay and the histological in vivo analysis were used to study cell-mediated immunity in the spleen of DBA/2 mice bearing subcutaneously developing P815X2 mastocytoma. Mononuclear cells separated from the spleen showed P815X2 specific cytotoxic activity between days 10 (12) and 16 following tumor inoculation. Maximal cytotoxicity was detected on days 13 and 14. In the T cell area of the spleen white pulp (C-PALS), an increase in the proportions of T lymphocytes and mononuclear phagocytes was observed on days 10 and 12 after the injection of P815X2 cells. On day 14, the T cell level in C-PALS dropped below control values, and the cellular density in the T cell area was reduced. Tumor metastases were seen in the spleen from day 14 onwards. The results indicate, that the T cell reaction in vivo was detectable in C-PALS one to two days earlier than the in vitro cytotoxicity of the spleen cells. By the time of maximal cytotoxic activity, the in vivo reaction had disappeared.     

Characterization of a novel breast carcinoma xenograft and cell line derived from a BRCA1 germ-line mutation carrier

A human tumor xenograft (L56Br-X1) was established from a breast cancer axillary lymph node metastasis of a 53-year-old woman with a BRCA1 germ-line nonsense mutation (1806C>T; Q563X), and a cell line (L56Br-C1) was subsequently derived from the xenograft. The xenograft carries only the mutant BRCA1 allele and expresses mutant BRCA1 mRNA but no BRCA1 protein as determined by immunoprecipitation or Western blotting. The primary tumor, lymph node metastasis, and xenograft were hypodiploid by DNA flow cytometry, whereas the cell line displayed an aneuploidy apparently developed via polyploidization. Cytogenetic analysis, spectral karyotyping, and comparative genomic hybridization of the cell line revealed a highly complex karyotype with numerous unbalanced translocations. The xenograft and cell line had retained a somatic TP53 missense mutation (S215I) originating from the primary tumors, as well as a lack of immunohistochemically detectable expression of steroid hormone receptors, epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER-2), and keratin 8. Global gene expression analysis by cDNA microarrays supported a correlation between the expression profiles of the primary tumor, lymph node metastasis, xenograft, and cell line. We conclude that L56Br-X1 and L56Br-C1 are useful model systems for studies of the pathogenesis and new therapeutic modalities of BRCA1-induced human breast cancer.     

Search for large genomic alterations of the BRCA1 gene in a Finnish population

Mutations in the BRCA1 and BRCA2 genes are known to predispose to breast cancer. In Finland, however, only 21% of all breast cancer families have mutations in these genes. Recent studies have shown that large genomic alterations of BRCA1 are common in many countries. Because such alterations will be missed in conventional mutation screening strategies, we decided to screen Finnish breast and ovarian cancer families for genomic alterations by using a multiplex polymerase chain reaction method. The most characteristic features of BRCA1-related breast cancer were used to select patients, namely (1) both breast and ovarian cancer in the family (48 patients), (2) four or more breast cancers in family (22 patients), or (3) young age (< or =40 years) of onset (58 patients). A total of 128 patients were included in the study. All exons of BRCA1 were analyzed but no alterations were found. This study excludes the frequent occurrence of large genomic alterations in the BRCA1 gene in Finland. Here, again, Finland differs from other countries with a mixed population structure. Our results are in agreement with the common hypothesis that there are still unknown breast cancer susceptibility gene(s) that are responsible for breast cancer predisposition.     

Human papillomavirus testing with the hybrid capture 2 assay and PCR as screening tools

The recognition of high-risk human papillomaviruses (HPVs) as etiological agents of cervical cancer has increased the demands to use testing for HPV for the detection of abnormal cervical smears and for cervical cancer screening. The present study compared the performance of the Hybrid Capture 2 (HC2) assay with that of PCR for the detection of significant cervical lesions in 1,511 women with different risks for HPV infections in three New Independent States of the former Soviet Union. The results showed that the level of agreement between the HC2 assay and PCR was substantial, with a kappa (Cohen) value of 0.669 (95% confidence interval [CI], 0.629 to 0.709). Of the 228 samples with discrepant results, 92 were positive by the HC2 assay but negative by PCR, whereas 136 samples were PCR positive but HC2 assay negative. The positive predictive values (PPVs) of the HC2 assay and PCR in detecting high-grade intraepithelial lesions (HSILs) were 4.5% (95% CI, 3.5 to 5.5%) and 3.6% (95% CI, 2.7 to 4.5%), respectively, and the negative predictive values (NPVs) were 99.6% (95% CI, 99.3 to 99.9%) and 99.3% (95% CI, 98.9 to 99.7%), respectively. The sensitivities of the HC2 assay and PCR for the detection of HSILs were 85.2 and 74.0%, respectively, and the specificities were 67.2 and 64.1%, respectively. In receiver operating characteristic (ROC) analysis, the performance of the HC2 assay for the detection of HSILs was excellent (P = 0.0001); the area under the ROC analysis curve was 0.858 (95% CI, 0.811 to 0.905), and the optimal balance between sensitivity (86.5%) and specificity (80%) was obtained with an HC2 assay cutoff level of 15.6 relative light units/positive control. Use of this cutoff would increase the specificity of the HC2 assay to 80.0% without compromising sensitivity. In conclusion, the results of PCR and the HC2 assay were concordant for 85% of samples, resulting in substantial reproducibility. Both tests had low PPVs, equal specificities, and equal (almost 100%) NPVs for the detection of HSILs; but the sensitivity of the HC2 assay was slightly better.     

HPV infections and tonsillar carcinoma

Since human papillomavirus (HPV) was first linked to laryngeal/oral carcinomas in 1983, several studies have confirmed its causal role in a subgroup of upper aerodigestive tract tumours. Of the non-genital cancers, tonsillar carcinomas (TCs) have the strongest association with HPV. By the end of 2002, 432 TCs had been analysed for HPV DNA. Overall detection rate was 51%, with HPV-16 being the most prevalent (84%). The original proposal that HPV-33 would be the most frequent HPV in TCs has not been confirmed, being present in only 4.6% of cases. HPV copy numbers are similar to those found in genital carcinomas (10-300 copies/cell), although HPV is mainly episomal in TC. The importance of this observation is unclear, although a role for subepithelial proliferative lymphatic tissue has been speculated. Patients with HPV-16 positive tumours have better overall and disease specific survival than HPV negative patients. They are also younger and the association with conventional risk factors-smoking and drinking-is less significant than in HPV negative patients. Thus, recent data suggest a distinct pattern for HPV-16 positive TCs.