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PubMed2001

Hypermethylation of the CD44 gene is associated with progression and metastasis of human prostate cancer.

BACKGROUND: CD44 is a metastasis suppressor gene for prostate cancer and the down-regulation of CD44 and its variants is associated with the progression of prostate cancer. Also, hypermethylation of the CpG islands of the CD44 gene is closely associated with transcriptional inactivation, resulting in the decreased expression of CD44. To clarify the exact role of methylation status of CpG islands of CD44 gene in the progression and metastasis of prostate cancer, we investigated the methylation status of this gene in primary and metastatic human prostate tumors obtained from surgery or autopsy. METHODS: We examined 97 samples from 40 Japanese patients with adenocarcinoma of the prostate. Tumor tissues were obtained from radical prostatectomy specimens from eight patients with stage B, 12 patients with stage C and three patients with stage D1 and at autopsy from 17 hormone-refractory metastatic cases, who had initially responded to the therapy and thereafter relapsed. Distant metastatic tissues were also obtained at autopsy (i.e., liver, lung, kidney, mammary gland, and pelvic lymph nodes) from 10 of 17 hormone-refractory cases. We analyzed the hypermethylation status of CD44 promotor region by PCR using genomic DNAs digested with the m(5)C-sensitive restriction enzyme HpaII. RESULTS: The correlation between the methylation status of CD44 gene and the stage progression of prostate cancer was statistically significant (P = 0.0438). In two of 10 hormone-refractory cases, a comparison of the methylation status of the CD44 gene in metastases to that in primary tumors revealed interfocal heterogeneity of CD44 methylation status. CONCLUSIONS: These results indicate an important role of CD44 methylation in the progression and metastasis of prostate cancer, although the amount of methylational heterogeneity is substantial among metastatic sites within the same patient.

Adenocarcinoma↗
PubMed1999

[The quantification of the magnetization transfer contrast (MTC) effect by calculating MT quotients: does it yield additional information for the differentiation of benign and malignant diseases of the locomotor apparatus?].

PURPOSE: To investigate the potential information of the amount of magnetization-transfer effect in musculoskeletal lesions and to compare MT ratios from benign and malignant musculoskeletal lesions. MATERIAL AND METHOD: 49 patients with malignant tumors (3 osteosarcoma, 3 malignant fibrous histiocytoma, 4 chondrosarcoma, 2 Ewing sarcomas) and benign lesions (8 chondroma, 2 fibrous dysplasia, 3 osteoid-osteoma, 6 ganglion cyst, 3 cyst, 3 osteomyelitis, 4 tendinitis, 3 rotator cuff tear, 5 scar tissue) were scanned using routine MRI protocols including T1- and T2-weighted spin echo as well as T2*-weighted gradient echo (FFE) sequences at 1.5 Tesla (ACS II, Philips Medical). Additionally MTC images were generated by combining the FFE sequence and the off-resonance MT technique (-1500 Hz off-resonance frequency, 1770 degrees flip angle and 50 ms pulse duration). MT ratios were calculated as Slo-Slm/Slo. RESULTS: The MT ratio of benign lesions was 26 +/- 15%, that of malignant lesions was 22 +/- 6%. The difference was statistically not significant. As expected muscle showed a high MT ratio of 50 +/- 8%. Scar tissue demonstrated an MT ratio of 39 +/- 16% which was significantly higher than the tumor MT ratios. CONCLUSION: MTC (MT ratios) failed to show significant differences between benign and malignant lesions as was expected due to basic differences in cellularity, rate of mitosis and chromatin content. MTC might however gain more importance in separating scar tissue from recurrent tumor in the future.

Adolescent↗
PubMed1988

Clinical-pathologic staging of large-bowel cancer. A report of the ASCRS Committee.

After surgical treatment in patients with large-bowel cancer, a prediction about the likelihood for cure remains uncertain despite the availability of several different types of staging systems. A committee of the American Society of Colon and Rectal Surgeons has reviewed the available data and concludes that future assessments of prognosis should be based on a combination of clinical and pathologic prognostic factors, using multivariate statistical techniques for the analysis. Although many important prognostic factors are known, there is much to learn about these and other items before a confident prediction of long-term outcome can be made. An extension of these methods should be possible to assist in prospective clinical decision-making based on clinical and investigational data. Such a system would be of particular value for patients with rectal cancer for whom cost-benefit relationships of alternative treatments can be so controversial. It is concluded that an accepted, standard nomenclature is required to reach both these objectives using large multicenter studies.

Colonic Neoplasms↗
PubMed1965

BREAST CANCER AT THE ONTARIO CANCER CLINICS, 1938-1956: A STATISTICAL REVIEW.

In Ontario, breast cancer accounts for one death in every 27 among females. In 1938-1956 some 40% of all new cases were registered at the Ontario Cancer Foundation's regional clinics. The five-year crude survival rate for 11,393 women was 45.4%, and for 91 men, 36.3%. Survival rates were strongly affected by extent of disease; when this was allowed for, pregnancy and treatment method were also found to influence survival rate. Simple mastectomy with radiotherapy gave results that appeared comparable to those after radical mastectomy, alone or with radiotherapy. There was a 20% improvement in the crude five-year survival rate over the period of the survey. The need for great caution in interpreting these findings is stressed.

Breast Neoplasms↗
PubMed2005

[Histological criteria and metastasis of squamous cell carcinoma of the pinna].

INTRODUCTION: According to the guidelines for cancer of the skin in the head and neck region of the German association of Otolaryngology, Head and Neck surgery squamous cell carcinoma (SCC) of the pinna are classified by using the current TNM system of skin cancer. As soon as cartilage is infiltrated, irrespective of other criteria like tumour size, SCC of the thin skin of the pinna are classified as T4 category. As therapy considerably depends on the TNM stage a review of the prognostic value of cartilage infiltration as well as other histological criteria seems to be justified. METHODS: Medical records of all patients (n = 36) being operated for SCC of the pinna between August 1988 and January 2004 at our department were retrospectively analysed with regard to a statistical correlation of histological criteria, cervical lymph node metastases and prognosis. RESULTS: In 36 cases a histological re-evaluation could be performed on the original tumour samples (34 male symbol : 2 female symbol; average age was 76 years, with an age interval of 54 - 99 years). 26 SCC cases were smaller than 2 cm, 8 cases between 2 and 5 cm and 2 cases bigger than 5 cm of size. 36 % of SCC cases had infiltration of the auricular cartilage. Statistical analysis did not show a statistical correlation of either cartilage infiltration, tumour size bigger than 2 cm or 1 cm, tumour grading and tumour depth with regard to lymph node metastases. DISCUSSION: According to our results, cartilage infiltration as single criterion of inclusion into a T4 category should be analysed cautiously. The anatomical peculiarity of the pinna where cartilage lies directly beneath very thin skin should be taken into account. A survey of a bigger group of patients e. g. as a multicenter study would be desirable for such a rare malignancy.

Aged↗
PubMed1976

Prostatic carcinoma: some morphological features affecting prognosis.

Morphologic features in 146 cases of prostatic carcinoma were correlated with 5-year survival. Simple probability tests showed a significant prognostic difference of the presence or absence of cell borders, lymphocytic infiltration, pleomorphism of nuclei, and McNeal's typing. Further statistical analysis, with a probability test which was adjusted for the distribution of these factors, showed that only the presence or absence of cell borders and lymphocytic infiltration affected prognosis. It is very important for the pathologist reporting on prostate carcinoma to include mention of these factors in his report because of their prognostic importance. In particular it should be noted that if the tumor has indistinct cell borders and there is no lymphocytic infiltration, then it is likely to have a very poor prognosis.

Adult↗
PubMed2004

Report of a multicenter Canadian phase III randomized trial of 3 months vs. 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer.

PURPOSE: To evaluate the effect of 3 months vs. 8 months of neoadjuvant hormonal therapy before conventional dose radiotherapy (RT) on disease-free survival using prostate-specific antigen PSA and biopsies as end points for clinically localized prostate cancer. METHODS AND MATERIALS: Between February 1995 and June 2001, 378 men were randomized to either 3 or 8 months of flutamide and goserelin before conventional-dose RT (66 Gy) at four participating centers. The median patient age was 72 years (range, 50-84 years). The stage distribution was 17% T1c, 35% T2a, 34% T2b-T2c, 13% T3-T4. The Gleason score (GS) was < or =6 in 51%, 7 in 38%, and 8-10 in 11%. The median baseline PSA level was 9.7 ng/mL (range, 1.3-189 ng/mL). Of the 378 men, 26% were low risk (Stage T1c-T2a, GS < or =6, PSA <10 ng/mL), 43% were intermediate risk (Stage T2b or GS 7 or PSA 10-20 ng/mL), and 31% were high risk (Stage T3 or GS 8-10 or PSA >20 ng/mL). The two arms were balanced in terms of age, GS, T stage, risk group, and presenting PSA level. The median follow-up was 44 months (range, 10-84 months), and 361 patients were available for evaluation. RESULTS: The 8-month arm achieved a lower PSA level before starting RT (0.37 vs. 0.74 ng/mL, p < or =0.001) and had a greater downsizing of the prostate (mean volume 26.6 cm(3) vs. 30.5 cm(3), p < or =0.001). However, the actuarial freedom from failure rate (biochemical by American Society for Therapeutic Radiology and Oncology definition, local or distant) for the 3-month vs. 8-month arms at 3 years was 66% vs. 68% and by 5 years was 61% vs. 62%, respectively (p = 0.36). No statistically significant difference was noted in the types of failure between the two arms (crude final status): biochemical, 22.2% vs. 22.3%; local, 10.2% vs. 6.5%; and distant, 3.4% vs. 4.4% (p = 0.61). Two-year post-RT biopsies were done in 57% (n = 205). Negative biopsies were obtained in 68% of the 3-month and 77% of the 8-month patients; 18% and 14% had indeterminate biopsies and 14% and 9% were positive for residual cancer (p = 0.34) in the two arms, respectively. The median PSA level for nonfailing patients was 0.50 ng/mL in both the 3-months and 8-month arms. A suggestion of improvement was found in the 8-month arm for disease-free survival at 5 years for high-risk patients (39% vs. 52%) but did not achieve statistical significance. CONCLUSION: A longer period of neoadjuvant hormonal therapy before standard-dose RT does not appear to confer a benefit in terms of disease-free survival or to alter failure patterns. Failure was delayed in the 8-month arm, but this advantage was lost by 5 years of follow-up. A suggestion of benefit was noted with a longer period of hormonal therapy for high-risk patients.

Aged↗
PubMed1976

Calculation of survival rates by the life table and other methods.

The last few years have seen the introduction of medical statistics into the curriculum for MB, BS and for the FFR. Also, an increasing number of clinical trials have considered statistics at the planning stage of the trial, rather than only at the end point. However, there is one particular aspect of medical statistics which has consistently been neglected, namely, technique in calculating survival rates for cancer patients. All too often, a direct method of calculation, see section 3.1, is used when a life table method would provide a better estimate. The life table, or actuarial method, was first described in a medical context by Greenwood (1926), and later by Merrell and Shulman (1955) and Cutler and Ederer (1958). It has however, not been explained in detail in a British journal. The objective of the present paper is to remedy, this fact so that it can be used more widely in the future in preference to a direct method.

Humans↗
PubMed1989

The size of clinical trials in cancer research--what are the current needs? Medical Research Council Cancer Therapy Committee.

Most randomised clinical trials of cancer treatment include a few hundred patients or less. Recent statistical papers advocate that sometimes thousands of patients should be entered. In this paper I show that for certain types of cancer trials the 'thousands policy' is not required while for others it is desirable but not feasible. In the latter case other strategies should be considered, such as two-stage phase III studies or parallel studies leading to overviews. There is, however, an important subset of trials for which application of the thousands policy is both necessary and feasible. The key to progress lies partly in the achievement of greater recruitment rates in trails of common cancers and partly in greater inter-group collaboration.

Clinical Trials as Topic↗
PubMed2005

Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials.

OBJECTIVE: To evaluate the efficacy and safety of 5% imiquimod cream compared with vehicle in the treatment of actinic keratosis (AK). DESIGN: Two phase 3 randomized, double-blind, parallel-group, vehicle-controlled studies. SETTING: Twenty-six ambulatory care offices, including dermatologists in private practice or research centers. PATIENTS: Four hundred ninety-two patients, 18 years and older, with 4 to 8 AK lesions in a 25-cm(2) treatment area on the face or the balding scalp were randomized; an additional 162 patients underwent screening but were ineligible. INTERVENTIONS: Patients applied 5% imiquimod (Aldara) or vehicle cream to the treatment area once daily, 3 times per week, for 16 weeks, followed by an 8-week posttreatment period. MAIN OUTCOME MEASUREMENTS: Complete clearance rate (proportion of patients at the 8-week posttreatment visit with no clinically visible AK lesions in the treatment area), partial clearance rate (proportion of patients at the 8-week posttreatment visit with a >/=75% reduction in the number of baseline AK lesions in the treatment area), and frequency and severity of adverse events and local skin reactions were measured. RESULTS: Complete and partial clearance rates for imiquimod-treated patients (48.3% and 64.0%, respectively) were clinically and statistically significantly higher than for vehicle-treated patients (7.2% and 13.6%, respectively). The median percentage reduction of baseline lesions was 86.6% for the imiquimod-treated group and 14.3% for the vehicle-treated group. CONCLUSION: The 5% imiquimod cream dosed 3 times weekly for 16 weeks is safe and effective for the treatment of AK.

Administration, Topical↗
PubMed2001

Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer.

PURPOSE: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors. PATIENTS AND METHODS: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug. RESULTS: Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042). CONCLUSION: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.

Adult↗
PubMed2006

Micronucleus--an upcoming marker of genotoxic damage.

This study was conceived for the early detection of oral precancer and cancer lesions using a noninvasive reliable technique. Micronucleus assay was performed on oral exfoliated cells of chosen subjects having leukoplakia and squamous cell carcinoma (SCC) using fluorescent (Acridine Orange) and conventional (Feulgen) stainings. The results were analyzed using Mann-Whitney U test, Kruskal-Wallis test, Spearman's Correlation and SPSS statistical package. The frequency of mean percentage occurrence of micronucleated cells increased significantly in comparison to controls with leukoplakia and squamous cell carcinoma. Subjects with synergism of abnormal oral habits also showed increased micronucleated cells. Fluorescent staining was found to be more sensitive than the conventional one for micronucleus detection. The results clearly demonstrate that micronucleus assay in oral exfoliated cells can be used as a simple reliable marker to assess the genotoxicity and for the early diagnosis of premalignant and malignant lesions. Micronucleus assay is, thus, an easy tool for early detection of cancer.

Adolescent↗
PubMed1984

Growth and vascular structure of human melanoma xenografts.

The growth and the vascular structure of five human melanomas grown in athymic nude mice were studied. Four growth parameters (tumour volume doubling time, fraction of cells in S-phase, growth fraction, cell-loss factor) were analysed against each of four vascular parameters (length of vessels with diameters in the range 5-15 micron, total vessel length, total vessel surface, total vessel volume--all per unit of histologically intact tumour volume). Statistically significant linear correlations between the parameters were found for any of the combinations. However, there was a consistent trend in the data: the tumour volume doubling time and the cell-loss factor tended to decrease while the fraction of cells in S-phase and the growth fraction tended to increase with increasing vascular density, whichever vascular parameter was considered. This finding indicates that the vascular density is among the factors which are decisive for the growth rate of tumours. However, the present work does not exclude the possibility that intrinsic properties of the tumour cells may also be important.

Animals↗
PubMed1999

Farnesylthiosalicylic acid inhibits the growth of human Merkel cell carcinoma in SCID mice.

Merkel cell carcinoma (MCC) is a neuroendocrine malignancy showing poor response to a variety of therapeutic strategies. We evaluated the antitumor activity of S-trans, trans-farnesylthiosalicylic acid (FTS), a new inhibitor of Ras signal transduction, in a newly established SCID mouse xenotransplantation model for human MCC (seven animals per group). FTS injected intraperitoneally at 5 mg/kg per day for 2 weeks up-regulated the tumor suppressor p53 and induced tumor cell apoptosis in established MCCs growing subcutaneously in SCID mice. These effects led to a statistically significant inhibition of MCC growth (P<0.002). The mean tumor weights following FTS or control treatment were 0.32+/-0.15 g and 1.08+/-0.29 g, respectively. There was no evidence of FTS related toxicity at the effective dose used. Our findings stress the notion that FTS may qualify as a novel and rational treatment approach for MCC and possibly for other tumors that rely on tyrosine kinase signaling.

Aged↗
PubMed2005

Dynamic contrast-enhanced magnetic resonance imaging: a non-invasive method to evaluate significant differences between malignant and normal tissue.

PURPOSE: An ever recurring challenge in diagnostic radiology is the differentiation between non-malignant and malignant tissue. Based on evidence that microcirculation of normal, non-malignant tissue differs from that of malignant tissue, the goal of this study was to assess the reliability of dynamic contrast-enhanced Magnetic Resonance Imaging (dcMRI) for differentiating these two entities. MATERIALS AND METHODS: DcMRI data of rectum carcinoma and gluteus maximus muscles were acquired in 41 patients. Using an fast T1-mapping sequence on a 1.5-T whole body scanner, T1-maps were dynamically retrieved before, during and after constant rate i.v. infusion of a contrast medium (CM). On the basis of the acquired data sets, PI-values were calculated on a pixel-by-pixel basis. The relevance of spatial heterogeneities of microcirculation was investigated by relative frequency histograms of the PI-values. RESULTS: A statistically significant difference between malignant and normal tissue was found for the mean PI-value (P < 0.001; 8.95 ml/min/100 g +/- 2.45 versus 3.56 ml/min/100 g +/- 1.20). Additionally relative frequency distributions of PI-values with equal class intervals of 2.5 ml/min/100 g revealed significant differences between the histograms of muscles and rectum carcinoma. CONCLUSION: We could show that microcirculation differences between malignant and normal, non-malignant tissue can be reliably assessed by non-invasive dcMRI. Therefore, dcMRI holds great promise in the aid of cancer assessment, especially in patients where biopsy is contraindicated.

Adenocarcinoma↗
PubMed2002

Screening with low PSA cutoff values results in low rates of positive surgical margins in radical prostatectomy specimens.

BACKGROUND: In the literature, positive margins in radical prostatectomy specimens, the rate of which ranges between 7% and 46%, are associated with adverse patient survival. The aim of the present study was to determine the predictive value of preoperative serum prostate specific antigen (PSA) values for the rate of positive margins in radical retropubic prostatectomy. METHODS: The study included a cohort of 845 patients who underwent radical retropubic prostatectomy between October of 1993 and December of 1999. All patients were stratified in groups on the basis of their preoperative PSA values: PSA group I, 0-1.99 ng/ml; PSA group II, 2-3.99 ng/ml; PSA group III, 4-5.99 ng/ml; PSA group IV, 6-7.99 ng/ml; PSA group V, 8-9.99 ng/ml; and PSA group VI, >10 ng/ml. For each group, the pathologic stage, Gleason score, and the incidence of positive margins were analyzed. For statistical analysis, the Mann Whitney U-test was used. RESULTS: Our data show a significantly higher rate of organ-confined prostate cancers and a significantly lower rate of positive surgical margins in patients with preoperative total PSA values of less than 4 ng/ml compared with patients with higher preoperative total PSA levels. CONCLUSION: As tumor stage and surgical margin status after radical prostatectomy are important predictors of the likelihood of PSA recurrence, which necessitates additional therapy, these findings support the concept of PSA screening by using low PSA cutoff levels.

Adult↗
PubMed2000

Signs and symptoms of melanoma in older populations.

We conducted a descriptive study to assess the relationship between increasing age and the reporting of melanoma signs/symptoms in 634 hospital-based and 624 population-based incident cases of melanoma. Multivariate logistic regression was used to evaluate the relationship between older age (> or = 50 years) and the reporting of melanoma signs/symptoms. Older patients were less likely to report itching and change in elevation of their lesions (P < 0.05). Change in color was also less likely to be reported by older patients, although not statistically significant. Ulceration of the lesion was reported significantly more by older patients (P < 0.05). Older individuals may be less likely to report itching and change in elevation/color of their lesions, but more likely to report ulceration, a symptom associated with advanced disease and poor prognosis. Further research is necessary to provide a better understanding of the development of melanoma in older populations so that new strategies can be explored to improve early detection in this age group.

Adult↗
PubMed2006

Are melanocytic nevi influenced by pregnancy? A dermoscopic evaluation.

BACKGROUND: Dermoscopic data of melanocytic nevi (MN) in pregnancy are very limited and related to small groups of women. OBJECTIVE: This study systematically analyzes dermoscopic parameters in a wide series of MN during and after pregnancy. METHODS: Eighty-six MN on the back of 47 women were studied. Dermoscopic parameters, total dermoscopic score (TDS) according to Stolz's ABCD rule, and the sizes of the nevi were evaluated over time. RESULTS: Progressive lightening of the nevi resulted at the end of pregnancy (p<.05) and after delivery (p<.001). Pigment network showed a progressive reduction in prominence and thickness (end of pregnancy, p<.05; after delivery, p<.01). At the end of pregnancy, vessels increased (p<.05) and a higher TDS was observed, with a significant reduction in both after delivery (vessels, p<.05; TDS, p<.01). Area changes were not statistically significant. CONCLUSIONS: At the end of pregnancy, both vascular structures and TDS increased. These modifications were transient as the nevi recovered their prior appearance after delivery. The results indicate that an intrinsic influence of pregnancy may induce structural modifications without influencing the size of the nevi. Behavioral factors during the observational period, like a reduced exposure to sunlight reported by most of the women, may have influenced other characteristics, like global pigmentation and pigment network. The authors thank the Fondazione Cassa di Risparmio di Ferrara for its financial support, which enabled them to acquire the instrumentation necessary for this study.

Adult↗