Mutations in Rb1 pathway-related genes are associated with poor prognosis in anaplastic astrocytomas.

Anaplastic astrocytoma (AA, WHO grade III) is, second to Glioblastoma, the most common and most malignant type of adult CNS tumour. Since survival for patients with AA varies markedly and there are no known useful prognostic or therapy response indicators, the primary purpose of this study was to examine whether knowledge of the known genetic abnormalities found in AA had any clinical value. The survival data on 37 carefully sampled AA was correlated with the results of a detailed analysis of the status of nine genes known to be involved in the development of astrocytic tumours. These included three genes coding for proteins in the p53 pathway (TP53, p14(ARF)and MDM2), four in the Rb1 pathway (CDKN2A, CDKN2B, RB1 and CDK4) and PTEN and EGFR. We found that loss of both wild-type copies of any of the three tumour suppressor genes CDKN2A, CDKN2B and RB1 or gene amplification of CDK4, disrupting the Rb1 pathway, were associated with shorter survival (P=0.009). This association was consistent in multivariate analysis, including adjustment for age (P=0.013). The findings suggest that analysis of the genes coding for Rb1 pathway components provides additional prognostic information in AA patients receiving conventional therapy.

Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females: clinical observations and histopathologic features.

BACKGROUND: Because the clinical and histopathologic features of vulvar melanoma had not been characterized completely in a large, homogeneous population, the authors retrospectively analyzed all such patients recorded in Sweden during a 25-year period. METHODS: The Swedish National Cancer Registry opened its records to the authors for review of all 219 females with primary vulvar melanoma reported from 1960 to 1984. Histopathologic specimens and clinical histories of the 198 patients who qualified for this study were reanalyzed and the tumors rigorously subtyped. RESULTS: Macroscopically amelanotic tumors were observed in 27% of patients, predominantly in glabrous skin; the clitoral area and labia majora were the most common primary sites. Of all melanomas, 46% emerged in glabrous skin, 12% emerged in hairy skin, and 35% extended to both areas. On average, approximately 2.5 times more melanomas appeared in the vulva than on the whole body surface. Overall, 57% were of the mucosal lentiginous (MLM) type, 22% were nodular melanomas (NMs), 12% were unclassified, and only 4% were superficial spreading melanomas (SSMs); this was the reverse of the order observed for cutaneous melanoma. Almost all vulvar melanomas underwent a vertical growth phase; other common features were marked thickness and ulceration, particularly in the glabrous skin. Preexisting nevi occurred in 11 cases, all in hairy skin, and 71% in conjunction with SSM but only 4% with MLM. CONCLUSIONS: Several clinical and histopathologic features indicated that the natural history of vulvar melanomas is at variance with that of cutaneous melanomas. Because preexisting nevi, which are often considered a precursor to melanoma, were significantly linked to SSM and only in the vulvar hairy skin, melanomas in the glabrous skin apparently emerged de novo.

Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females: predictors of survival.

BACKGROUND: In an epidemiologic study of 219 Swedish females with vulvar melanoma, the authors previously established the incidence of this disease as 0.19 per 100,000 women, with a 3% annual decrease from 1960 to 1984 and a 5-year relative survival rate of 47%. After reviewing the medical histories of all of the 219 patients, the authors documented their precise clinical and histopathologic features, which, along with treatment, are assessed herein as predictors of survival. METHODS: Of 219 consecutive cases of vulvar melanoma collected from the Swedish National Cancer Registry, 21 were excluded because of inadequate data. Clinical and histopathologic materials from the remaining 198 cases were then reexamined. With a clinical three-stage system, lesion types and treatment modalities were assessed as survival factors in univariate and multivariate analyses. RESULTS: In univariate analysis, significant predictors of survival for patients at Stage I were tumor thickness, ulceration, number of mitoses, macroscopic amelanosis, preexisting nevi, extent of tumor invasion (lateral labia majora), and patient age. The mode of treatment was not significant. In multivariate analysis, staging (Stage I vs. II and III) and tumor thickness were independent predictors of survival. For Stage I only, tumor thickness, ulceration, and clinical amelanosis independently predicted survival time. CONCLUSIONS: To the authors' knowledge, this is the largest series of patients with vulvar melanoma ever reviewed, and an ethnically homogeneous and nationwide female population is represented. In this series, clinical stage, macroscopic amelanosis, and tumor characteristics such as tumor thickness and ulceration, rather than treatment mode, were the best factors for predicting the outcome of these patients.

The impact of tumour angiogenesis, p53 overexpression and proliferative activity (MIB-1) on survival in squamous cervical carcinoma.

Tumour angiogenesis (antifactor VIII-related antigen antibody), p53 overexpression (DO-1) and proliferative activity (MIB-1) were immunohistochemically analysed for the prediction of long-term survival in 113 patients with squamous cervical carcinoma. The median follow-up time was 82 months (range 72-99). In early stages (IB-IIA), neovascularisation was significantly related to tumour size. Significantly more patients in stage IIA had high tumour vascularity compared to stage IB (P < 0.01) but no significant difference was found between early and advanced stages (IIB-IVB) of cervical carcinoma. p53 overexpression was correlated to the stage of disease (P < 0.01). No relationship was found between tumour angiogenesis, p53 overexpression or MIB-1 and pelvic lymph node metastases, histological subtype or differentiation. Tumours with more than 50% p53 overexpression was significantly correlated with survival in the univariate analysis, but no independent predictive value was found. It is concluded that immunohistochemically detectable p53 overexpression as measured by DO-1 and proliferative activity as measured by MIB-1 seems of no clinical value for the prediction of long-term survival in squamous cervical carcinoma. The predictive value of tumour angiogenesis for survival outcome has still to be determined in squamous cervical carcinoma.

Leucocyte doubling time is a useful predictor of progression-free survival in chronic lymphocytic leukaemia.

OBJECTIVE: To assess leucocyte doubling time (LDT) in relation to progression-free survival in patients with chronic lymphocytic leukaemia (CLL). In addition, to define the impact of a second LDT in both untreated and treated patients. DESIGN: Retrospective study of LDT in previously untreated patients with CLL. SUBJECTS AND SETTING: Sixty patients diagnosed over a 13-year period at a county hospital. In forty-five of the 60 patients, an LDT could be defined. These patients were included in the final analysis. MAIN OUTCOME MEASURES: LDT below and above 12 months, progression-free and overall survival. RESULTS: Patients in Binet stages B and C had a median LDT of 4 months as compared to 26 months in stage A patients (P < 0.01). The projected progression-free survival at 3 years was 24% in patients with an LDT of < 12 months. The corresponding figure for the remaining patients was 68% (P < 0.01). The overall 5-year survival did not differ significantly between patients with an LDT below and above 12 months, respectively. In seven untreated patients, a second LDT could be calculated which was shorter than the first recorded LDT. A second LDT was also identified in five patients post treatment that was consistently shorter than their first LDT. CONCLUSIONS: Measurement of LDT is a simple complement in predicting progression-free survival in patients with CLL. Thus, monitoring of LDT may add to the clinical evaluation and therapeutic decision making for the many elderly patients with this often indolent disease.

Prognostic significance of pretreatment serum levels of squamous cell carcinoma antigen and CA 125 in cervical carcinoma.

Serum levels of squamous cell carcinoma antigen SCC, carcinoembryonic antigen CA 125, and tissue polypeptide antigen were determined in 142 patients with primary cervical carcinoma, 60 patients with precancerous lesions and in 129 healthy women. With regard to elevated tumour marker levels, specificity ranged from 94.6% to 97.7%. Sensitivity was highest (44.4%) for SCC. A stage relation was found for all tumour markers except for carcinoembryonic antigen. In stage Ib, SCC levels increased according to tumour volume. SCC, CA 125 or both markers were elevated in 7 of 8 patients with pelvic lymph node metastases compared with only 17 of 58 patients with negative nodes (P = 0.005). In a multivariate analysis, pretreatment serum levels of SCC and CA 125 were found to be significantly related to patient survival, in addition to stage. In cervical SCC, the risk of a fatal outcome increased 16 times with SCC levels > or = 4.5 ng/ml, compared with SCC levels < or = 1.3 ng/ml. We conclude that pretreatment serum levels of SCC may be of value as an adjunct to clinical staging. In addition, serum determinations of SCC and CA 125 seem to be useful in predicting the risk of pelvic lymph node metastases and as prognostic risk factors for disease outcome.