Quantitative expression of the human kallikrein gene 9 (KLK9) in ovarian cancer: a new independent and favorable prognostic marker.

Many members of the human kallikrein gene family were found to be differentially expressed in various malignancies and some are useful cancer diagnostic/prognostic markers. KLK9 is a newly discovered human kallikrein gene that is expressed in several tissues including thymus, testis, spinal cord, salivary gland, ovary, and skin. Like other kallikreins, the KLK9 gene was found to be regulated by steroid hormones in cancer cell lines. Our purpose is to examine whether quantitative analysis of KLK9 expression has prognostic value in ovarian cancer. We studied the expression of KLK9 by quantitative reverse transcription-PCR in 168 consecutive ovarian tumors of different stages, grades, and histological types, and correlated the expression with clinicopathological parameters, response to chemotherapy, and patients' survival. We found that KLK9 expression was significantly higher in patients with early disease stages (I or II; P = 0.044) and in patients with optimal debulking (P = 0.019). Kaplan-Meier survival curves demonstrated that patients with KLK9-positive tumors have substantially longer progression-free and overall survival (P < 0.001 and P = 0.016, respectively). When the Cox proportional hazard regression analysis was applied to subgroups of patients, KLK9 expression was found to be a significant predictor of progression-free survival in the subgroup of patients with low-grade tumors [hazard ratio (HR), 0.13; P = 0.0015], early stage (HR, 0.099; P = 0.031); and those with optimal debulking (HR, 0.26; P = 0.012). After adjusting for other known prognostic variables, KLK9 retained its independent prognostic value in all of these subgroups of patients. A negative correlation was found between the expression levels of CA125 and KLK9 (rs, 0.350; P = 0.002). Our results indicate that KLK9 is under steroid hormone regulation in ovarian and breast cancer cell lines. Immmunohistochemically, human kallikrein protein (hK9) was localized in the cytoplasm, but not in the nuclei, of the epithelial cells of ovarian cancer tissues. We conclude that KLK9 is a potential new independent favorable prognostic marker for early stage, low-grade, optimally debulked ovarian cancer patients.

Abnormalities of the ARF-p53 pathway in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is associated with heavy smoking and drinking, but the molecular pathway of tumorigenesis is not understood. Inactivation of the p53 tumor suppressor gene is likely to play an important role since p53 mutation is frequently found. The p14ARF tumor suppressor gene is functionally linked to p53, because it is activated by oncogenes and causes p53-dependent growth arrest and apoptosis. The relationship between p14ARF and p53 inactivation has not been described for OSCC. We studied 25 cases of OSCC to determine if there is an inverse correlation between p53 mutation and p14ARF inactivation by homozygous deletion or mutation. p53 mutation was found in 16 of 25 cases (64%), including nine missense and seven truncating mutations. While all cases with missense mutations showed abnormal accumulation of p53 protein, there were also five carcinomas which showed increased p53 staining in the absence of mutation. p14ARF deletion or mutation was found in eight cases (32%), six of which also demonstrated p53 mutation. Our findings indicate that OSCC often involves loss of both p14ARF and p53 function and suggest that inactivation of these two tumor suppressor genes are not functionally equivalent during tumorigenesis.

Lymphoid cell infiltration into Epstein-Barr virus-positive nasopharyngeal carcinomas.

OBJECTIVES: A pilot study was designed to analyze lymphoid cell infiltration in Epstein-Barr virus-positive (EBV+) nasopharyngeal carcinomas (NPCs) and to determine whether this pattern of infiltration is consistent with non-EBV+ head and neck carcinomas or with solid EBV+ tumors in other locations. STUDY DESIGN: We performed a retrospective analysis of archived NPCs and oral cavity carcinomas. METHODS: Immunohistochemical staining of the archive material for various markers (CD3, CD8, UCHL-1, S-100, and intercellular adhesion molecule) was performed. Polymerase chain reaction techniques to establish the presence of the EBV genome were used. Cells in different locations were counted under a light microscope by 2 of the authors. RESULTS: The infiltration pattern of NPCs was different from that of oral cavity carcinomas. Stromal infiltration was significantly denser in oral cavity carcinomas. Tumor nest infiltration was more pronounced in NPCs. The pattern of infiltration was comparable with what has been described for other solid EBV+ tumors. CONCLUSIONS: The immune response to NPCs is likely to be strongly influenced by the presence of the EBV genome. The pattern of infiltration is similar to that of other non-head and neck EBV+ solid tumors and different from that of EBV- head and neck carcinomas.

Cyclin D1 gene amplification and protein expression in benign breast disease and breast carcinoma.

Cyclin D1 plays a critical role in regulating cell-cycle progression. Gene amplification and protein overexpression of cyclin D1 have been detected in breast cancer but little is known concerning whether these changes occur in normal breast tissue and in breast lesions associated with increased risk of development of invasive breast cancer. We looked for cyclin D1 gene amplification and protein overexpression in 30 cases of benign breast disease (16 epithelial hyperplasias without atypia and 14 atypical ductal hyperplasias) and 18 ductal carcinomas in situ by use of differential PCR and immunohistochemical staining. We compared the resulting frequencies to those in 15 cases of normal breast tissue and 17 invasive ductal carcinomas. We found cyclin D1 gene amplification in 15% of those with normal breast tissue, 19% of those with epithelial hyperplasia without atypia, 27% of those with atypical ductal hyperplasia, 35% of those with ductal carcinoma in situ, and 25% of those with invasive ductal carcinoma; corresponding figures for protein overexpression were 13, 13, 57, 50, and 64%. These results suggest that cyclin D1 amplification and protein overexpression can occur before histologic alterations are seen but that the frequencies of these changes are higher in histologic lesions with cellular atypia (atypical hyperplasia and ductal carcinoma in situ), reaching frequencies similar to those observed in invasive carcinoma.

Immunohistochemical detection of c-erbB-2 and p53 in benign breast disease and breast cancer risk.

BACKGROUND: We studied the associations between c-erbB-2 protein overexpression and p53 protein accumulation in benign breast tissue and the risk of subsequent breast cancer. METHODS: We conducted a case-control study nested within the cohort of 4888 women in the National Breast Screening Study (NBSS) who were diagnosed with benign breast disease during active follow-up. Case subjects were the women who subsequently developed breast cancer (ductal carcinoma in situ [DCIS] or invasive carcinoma). Control subjects were matched to each case subject on NBSS study arm, screening center, year of birth, and age at diagnosis of benign breast disease. Histologic sections of benign and cancerous breast tissues were analyzed immunohistochemically. Information on potential confounding factors was obtained by use of a self-administered lifestyle questionnaire. RESULTS: Accumulation of p53 protein was associated with an increased risk of progression to breast cancer (adjusted odds ratio [OR] = 2.55; 95% confidence interval [CI] = 1.01-6.40), whereas c-erbB-2 protein overexpression was not (adjusted OR = 0.65; 95% CI = 0.27-1.53). The findings for c-erbB-2 and p53 did not differ among strata defined by menopausal status, allocation within the NBSS, history of breast disease, and whether the benign breast disease was detected at a scheduled screen or between screens. The results were also similar after exclusion of case subjects whose diagnosis of breast cancer occurred within 1 year of their diagnosis of benign breast disease and after exclusion of subjects with DCIS. CONCLUSIONS: p53 protein accumulation, but not c-erbB-2 protein overexpression, appears to be associated with an increased risk of progression to breast cancer in women with benign breast disease.

Elevated levels of plasma triglycerides are associated with histologically defined premenopausal breast cancer risk.

Lipids and lipoproteins have been associated with breast cancer risk; however, published results have been inconsistent. To clarify these associations, we measured fasting lipids in women undergoing breast biopsies. A case-control study examined the association of fasting levels of lipids with histologically defined breast cancer risk. Four groups of premenopausal women were assembled on the basis of histological appearance of breast tissue: 1) no epithelial proliferation (n = 102), 2) proliferation without atypia (n = 53), 3) atypical hyperplasia or carcinoma in situ (n = 53), and 4) node-negative invasive cancer (n = 102). A postoperative fasting blood specimen was analyzed for cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. Demographics, risk factors, diet, physical activity, fasting weight, and skin-fold thickness were measured. Triglyceride levels were significantly higher in women with node-negative invasive cancer (0.94 +/- 1.04 mg/ml) than in those with no epithelial proliferation (0.83 +/- 1.04 mg/ml, p = 0.03). This association persisted after adjustment for age, body size, lipids, reproductive and familial risk factors, and previous benign breast problems (p < 0.01), in keeping with an independent association of elevated triglycerides with breast cancer risk.

[Demonstration of pneumonia in swine as a constant problem: culture and immunofluorescence microscopic studies of bronchioalveolar lavage (BAL) and serological findings]. / Nachweis von Pneumonieerregern bei Schweinen aus Problembeständen: Kulturelle und immunfluoreszenzmikroskopische Untersuchungen der bronchoalveolären Lavage (BAL) und serologische Befunde.

Bronchoalveolar lavage was performed in 128 pigs from five fattening units showing acute pneumonia (48 animals), subclinical purulent pneumonia (17 animals), and chronic purulent pneumonia (63 animals). These samples were investigated for bacteria. Additionally immunofluorescence microscopy as well as serological investigations were performed to detect antibodies against several bacteria and viruses. Pasteurella multocida could be detected in more than a half of the samples of pigs with acute pneumonia. Bordetella bronchiseptica and mycoplasmas were isolated in a lower amount. Probably these bacteria infected the pigs of at least one herd after a primary infection with influenza virus because (i) influenza virus could be detected in three of four animals investigated for influenza virus by culture methods, (ii) the virus could be detected in one third of the animals investigated for by immunofluorescence microscopy, and (iii) antibodies against influenza virus could be detected in almost all animals. From pigs with subclinical purulent pneumonia Bordetella bronchiseptica as the only bacterial lung pathogen could be isolated exclusively from nearly each sample. From the samples of pig suffering from chronic purulent pneumonia first of all Bordetella bronchiseptica, Pasteurella multocida and different mycoplasma species could be detected. Using cultural methods Actinobacillus pleuropneumoniae could be isolated from six samples only, in contrast to frequent positive reactions against Actinobacillus pleuropneumoniae antigens obtained by immunofluorescence microscopy and CFT.

Incidence and types of non-palpable thyroid nodules in thyroids removed for palpable disease.

The purpose of this study was to determine the number, size and types of non-palpable and ultrasound undetected thyroid nodules in thyroid glands removed for a single palpable nodule. Twenty patients undergoing partial (hemi- and subtotal) thyroidectomy and 40 patients having a total thyroidectomy were analyzed. Patients had no more than one palpable nodule, no cervical adenopathy and no history of previous thyroid surgery. An ultrasound was performed routinely within four months of surgery. Forty-six nodules were detected by final pathology in the partial thyroidectomy group but only 42% were detected by palpation and 59% by ultrasound. The median diameter of non-palpable and ultrasound undetected partial thyroidectomy nodules was 0.5 cm and all were benign except for one case of lymphoma. Pathology detected 186 nodules in the total thyroidectomy group although palpation only detected 22% of these and ultrasound 42%. The median diameters of the benign and malignant non-palpable nodules were 0.4 cm and 0.25 cm respectively. Most of the undetected nodules in the total thyroidectomy group were benign but there were 20 non-palpable and 18 ultrasound undetected papillary carcinomas.

Ureteral fibroepithelial polyp with positive urinary cytology.

We report on a patient with two fibroepithelial polyps of the upper ureter in whom the correct diagnosis was confused by finding voided urine as well as ureteral wash, and brush biopsy cytologies positive for malignancy. Fibroepithelial polyps and causes of falsely positive urinary cytology are reviewed.

Selected ultrastructural aspects of urothelial and prostatic tumors.

Ultrastructural techniques have been widely applied in the study of urothelial and prostatic tumors. In the common proliferative diseases affecting the lower urogenital tract, electron microscopy has provided us with a greater understanding of the pathobiology and morphology of these disease processes. Specific diagnostic application, however, has been limited. In the unusual tumors affecting urothelium and prostate such as neuroendocrine carcinoma, carcinosarcoma, and sarcomas, electron microscopy has provided some practical diagnostic information of value in patient management. This paper provides a survey of the fundamental and practical contributions of ultrastructural studies in the prostatic and urothelial areas.

Mucosal changes associated with adenomatous colonic polyps.

In order to assess the presence of morphologically recognizable colonic nonneoplastic mucosal alterations that may be associated with adenomatous transformation the authors undertook a retrospective analysis of 984 colonic polyps removed between 1979 and 1983. There were 708 adenomatous and 276 nonadenomatous polyps, all colonoscopically removed. In addition to adenomatous mucosa, three different mucosal patterns were recognized and labeled as transitional, eosinophilic, and, hyperplastic. Each polyp, but not the polyp's shoulder, was scored by two pathologists for the presence of these changes. Analysis of the data (Pearson's chi-square test) demonstrated a strong association between eosinophilic and transitional mucosa as well as between eosinophilic mucosa and adenomas. There was also a strong negative association between both eosinophilic and transitional mucosa and hyperplastic mucosa. On the basis of these data, it is postulated that transitional mucosa, representing a nonspecific reactive mucosal phenomenon, may precede eosinophilic mucosa, which subsequently may represent fertile soil for adenomatous transformation.

Effectiveness of a dental school program in the prevention of infective endocarditis and other related infections.

Dental records of 99 patients for whom a medical consultation was required to establish or eliminate the need for infective endocarditis prophylaxis were examined. The purpose of the review was to determine if the consultative process was effective and if patients requiring antibiotic prophylaxis were managed according to the current American Heart Association guidelines. The record review indicated that the consultative process is effective in determining need but that there are deficiencies in management documentation. An analysis of the consultation replies revealed that dental staff members must be thoroughly familiar with the current American Heart Association recommendations for the prevention of infective endocarditis.