Prognostic role of serum cytokeratin 19 fragments in advanced non-small-cell lung cancer: association of marker changes after two chemotherapy cycles with different measures of clinical response and survival.

Prognostic implication of serum cytokeratin 19 fragments (CYFRA 21-1) was explored in 60 advanced NSCLC patients, whereas in 45 patients assessable for serological response a >or=35% CYFRA 21-1 decline after two chemotherapy cycles was strongly associated with non-progression (NP), defined as a sum of objective response (OR)+stable disease (P<0.0001) and survival (P=0.0002). Association of OR with survival was not significant. In multivariate survival analysis, >or=35% marker decline and radiological NP status were found as major determinants of prolonged survival with RR: 0.37 (P=0.01) and 0.63 (P=0.01), respectively. In advanced NSCLC patients, NP reflects therapeutic efficacy better than traditional OR. CYFRA 21-1 >or=35% decline seems to be a reliable surrogate marker of treatment efficacy in terms of survival.

Genetic testing of breast and ovarian cancer patients: clinical characteristics and hormonal risk modifiers.

OBJECTIVES: Carriers of the mutations 185delAG and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene have a substantial life-time risk for breast and ovarian cancers (BC and OC). The aim of the study was to identify the clinical features and the hormonal risk modifiers in mutation carriers and the implication in suggested guidelines for treatment decisions in BRCA1/2 carrier patients. STUDY DESIGN: Breast and/or ovarian cancer patients from the Oncology and Cancer Genetic clinics were tested for the three Ashkenazi founder mutations: 87 patients were identified as carriers of one of these mutations. Clinical presentation and age at onset were correlated with the mutations, in patients with bilateral BC or BC and OC, the length of time that elapsed between the diagnosis of the two cancers was recorded. We compared BC and OC patients with regard to ages at menarche, first pregnancy and menopause, number of pregnancies and deliveries, the use of oral contraceptives, hormonal replacement therapy and fertility treatments. RESULTS: The carriers of the three BRCA1/2 Ashkenazi founder mutations did not differ in clinical presentation nor age at onset. Forty-three patients (74.1%) of 58 BC patients were diagnosed between the ages 30 and 50, only four (6.9%) patients were diagnosed after age 60. Of BC patients diagnosed before age 35, 63.6% developed second BC as compared to 25.5% of those diagnosed after age 35. Ovarian cancer was diagnosed after age 45 in 89.7% of the patients, only one patient was diagnosed under the age of 40. Oral contraceptives use was documented in 61.3% of BC patients as compared to 11.8% of OC patients. Other hormonal factors did not differ between the two groups. CONCLUSIONS: The carriers of the three Ashkenazi founder mutations should be considered at the same risk for BC and for OC and treatment options should be the same. Mutation carriers diagnosed with BC before the age of 35 are at a very high risk for developing second breast cancer. Most ovarian cancers in carriers were diagnosed after age 45, and prophylactic oophorectomy should be postponed to the age of 45. Oral contraceptives might elevate the risk of BC in mutation carriers.

Prognostic value of CYFRA 21-1, TPS and CEA in different histologic types of non-small cell lung cancer.

The prognostic value of the tumor markers CYFRA 21-1, tissue polypeptide specific antigen (TPS) and carcinoembryonic antigen (CEA) was investigated in three histologic subtypes of non-small cell lung cancer. Pretreatment serum marker levels were measured in 38 patients with adenocarcinoma (AC), in 43 patients with squamous cell carcinoma (SQC) and in 35 patients with large cell carcinoma (LCC). Univariate analysis in AC showed significant lower survival of patients with elevated levels of TPS, CYFRA 21-1 and CEA. In LCC, elevated levels of TPS and CEA were found to predict lower survival, while in SQC--only TPS was a predictor. A multivariate analysis of survival identified CEA (Relative Risk-5.5; p = 0.004), CYFRA 21-1 (RR-3.4; p = 0.008) and TPS (RR-3.0; p = 0.02) as independent prognostic factors in AC. In SQC, only TPS (RR-2.3; p = 0.03) was such a factor whereas in LC--none of the markers studied retained statistical significance. Thereafter, the combinations of the two strongest prognostic factors in the AC group--CEA and CYFRA 21-1 were explored to divide this group into subsets with different prognosis. In cases where both markers were positive, the relative risk of death was 10.5 times higher as compared to cases where both markers were negative (p = 0.002).

Cytokeratin markers in malignant pleural mesothelioma.

Previously available serum tumor markers had a low clinical value in malignant pleural mesothelioma (MPM). The recently developed tissue polypeptide-specific antigen (TPS) and CYFRA 21-1 assays identify the soluble cytokeratin 18 and 19 fragments, respectively. In MPM these cytokeratins are expressed and may therefore be used as serum tumor markers. In this preliminary study, TPS and CYFRA 21-1 assays were evaluated to determine their potential for management of patients with MPM. Carcinoembryonic antigen (CEA) was evaluated as an additional marker. The study group consisted of 95 patients with benign lung and pleural diseases (BLPD), 14 patients with MPM, 41 patients with adenocarcinoma of lung (AC), and 40 patients with squamous cell carcinoma of lung (SQC). The utilized cutoff points corresponded to a 95% specificity for patients with BLPD. In MPM, TPS showed greater sensitivity (64.3%) than CYFRA 21-1 (50.0%), while CEA showed no sensitivity. In SQC, the marker CYFRA 21-1 had the highest sensitivity (52.5%), whereas in AC the most sensitive marker was CEA (56.1%). Significantly lower levels of CEA were found in MPM compared with BLPD (p < 0.001) or AC and SQC (p < 0.0001). Conversely, TPS levels in MPM were significantly higher than in SQC (p < 0.05). Close correlation of various individual pretreatment marker levels was observed only between TPS and CYFRA 21-1, both in MPM (r = 0.84; p < 0.001) and in non-small cell lung cancer (NSCLC) (r = 0.71; p < 0.001). In serial determinations of the markers during chemotherapy of MPM (n = 10), TPS and CYFRA 21-1 were shown to demonstrate more or less the same pattern of reactivity, although the changes in the TPS levels better reflected the clinical response to therapy. In conclusion, TPS seems to be a more sensitive marker than CYFRA 21-1.

Evaluation of tissue polypeptide specific antigen, CYFRA 21-1, and carcinoembryonic antigen in nonsmall cell lung carcinoma: does the combined use of cytokeratin markers give any additional information?

BACKGROUND: Recently developed tissue polypeptide specific antigen (TPS) and CYFRA 21-1 assays determine the soluble cytokeratin 18 and 19 fragments, respectively, in serum. The authors compared the value of TPS, CYFRA 21-1, and carcinoembryonic antigen (CEA) for the diagnosis, staging, prognosis, and monitoring of patients with nonsmall cell lung carcinoma (NSCLC). METHODS: The study included 85 patients with benign lung diseases and 94 patients with NSCLC. TPS, CYFRA 21-1, and CEA serum levels were measured with commercial kits. RESULTS: The following were demonstrated: 1) CYFRA 21-1 and TPS levels, but not CEA levels, differed significantly between NSCLC patients with operable disease (Stages I-IIIA) and those with inoperable disease (Stages IIIB-IV). 2) The correlation coefficient between CYFRA 21-1 and TPS increased with the progression of NSCLC from Stages I-IIIA (r = 0.41, P = 0.04) to Stages IIIB-IV (r = 0.70, P < 0.001). 3) Multivariate analysis identified TPS and CYFRA 21-1 as significant predictors of survival, with relative risks of 2.57 (P = 0.001) and 2.05 (P = 0.01), respectively. For cases in which both cytokeratin markers were positive, the relative risk was 6.4 (P < 0.0001) compared with cases in which both were negative. 4) For the group with inoperable disease, the combined use of TPS and CYFRA 21-1 allowed for the definition of 3 sets of patients with significantly different median survival times (14.3 months vs. 7.4 months vs. 2.6 months). 5) The percentages of marker evaluations concordant with results of clinical assessments of response to therapy were 75.0%, 72.2%, and 61.1% for CYFRA 21-1, TPS, and CEA, respectively. CONCLUSIONS: These findings suggest that, for NSCLC patients, CYFRA 21-1 and TPS are significant prognostic factors and effective monitors of therapy. The combined use of these cytokeratin markers may provide additional information for prognosis.

Leptomeningeal metastases: evaluation by gadolinium enhanced spinal magnetic resonance imaging.

BACKGROUND: Leptomeningeal metastases are common in patients with metastatic systemic cancer or certain primary brain tumors. They may be unsuspected clinically and may be missed by cerebrospinal fluid (CSF) cytology. We undertook a retrospective study of the diagnostic value of gadolinium enhanced spinal MR imaging in patients with known or at high risk for leptomeningeal metastases (LM). MATERIAL AND METHODS: Ninety-six gadolinium enhanced MR examinations of the whole spine were performed in 61 patients (26 primary central nervous system tumors, 20 solid tumors and 15 lymphoproliferative neoplasms). All patients had detailed neurological evaluation and concomitant CSF examination. RESULTS: Sixty-one MR's (62%) were positive, mostly in the lumbar spine. MR's were positive in 92% of patients with positive initial CSF cytology and in 60% of patients with negative CSF cytology. The MR examination was positive in 49% of those without clinical findings related to the spinal region. It showed disease beyond the symptomatic level in 42% of patients with spinal symptomatology. Multi-level spinal involvement was present in 57% of positive MR exams. CONCLUSION: Enhanced spinal MR is sensitive for the detection of neoplastic spinal seeding. It detects LM in about 50% of high risk patients with negative initial CSF cytology or no spinal symptoms.

The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.

The mutations 185delAG, 188del11, and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene were analyzed in 199 Ashkenazi and 44 non-Ashkenazi Jewish unrelated patients with breast and/or ovarian cancer. Of the Jewish Ashkenazi women with ovarian cancer, 62% (13/21) had one of the target mutations, as did 30% (13/43) of women with breast cancer alone diagnosed before the age 40 years and 10% (15/141) of those with breast cancer diagnosed after the age 40 years. Age at ovarian cancer diagnosis was not associated with carrier status. Of 99 Ashkenazi patients with no family history of breast and/or ovarian cancer, 10% carried one of the mutations; in two of them the mutation was proved to be paternally transmitted. One non-Ashkenazi Jewish ovarian cancer patient from Iraq carried the 185delAG mutation. Individual mutation frequencies among breast cancer Ashkenazi patients were 6.7% for 185delAG, 2.2% for 5382insC, and 4.5% for 6174delT, among ovarian cancer patients; 185delAG and 6174delT were about equally common (33% and 29%, respectively), but no ovarian cancer patient carried the 5382insC. More mutations responsible for inherited breast and ovarian cancer probably remain to be found in this population, since 79% of high-incidence breast cancer families and 35% of high-incidence breast/ovarian cancer families had none of the three known founder mutations.

[Genetic counseling for families at high cancer risk].

About 5-10% of the most common cancers, such as breast, colon and melanoma, result from mutations in inherited predisposition genes. Recently some of these genes have been mapped or even cloned. These advances in cancer genetics have made more precise genetic counseling possible for cancer patients and their families. In our clinic for specific genetic counseling 180 families with a history of cancer were seen during a 10-month period. In counseling sessions, the family history was confirmed and interpreted, personal risk was estimated and the availability of molecular genetic testing was presented. Blood samples for DNA testing were drawn from those with certain criteria who wished to be tested. Instructions for early detection were also given, depending on the personal risk of cancer as compared to that of the general population.