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Gad Singer

Publications and source records attributed to Gad Singer.

At least 19 recordsLinked to original sources
PubMed2007

Napoleon Bonaparte's gastric cancer: a clinicopathologic approach to staging, pathogenesis, and etiology.

BACKGROUND: Numerous hypotheses on the cause of Napoleon Bonaparte's death have been proposed, including hereditary gastric cancer, arsenic poisoning, and inappropriate medical treatment. We aimed to determine the etiology and pathogenesis of Napoleon's illness by a comparison of historical information with current clinicopathologic knowledge. INVESTIGATIONS: Evaluation of Napoleon's clinical history, original autopsy reports, and of historical documents. The clinicopathologic data from 135 gastric cancer patients were used for comparison with the data available on Napoleon. DIAGNOSIS: At least T3N1M0 (stage IIIA) gastric cancer. Napoleon's tumor extended from the cardia to the pylorus (>10 cm) without infiltration of adjacent structures, which provides strong evidence for at least stage T3. The N1 stage was determined by the presence of several enlarged and hardened regional (perigastric) lymph nodes, and the M0 stage by the absence of distant metastasis. Analysis of the available historical documents indicates that Napoleon's main risk factor might have been Helicobacter pylori infection rather than a familial predisposition. CONCLUSIONS: Our analysis suggests that Napoleon's illness was a sporadic gastric carcinoma of advanced stage. Patients with such tumors have a notoriously poor prognosis.

Famous Persons↗
PubMed2006

T4 category revision enhances the accuracy and significance of stage III breast cancer.

BACKGROUND: Because of the considerable heterogeneity in breast carcinoma with noninflammatory skin involvement (T4b/Stage IIIB), a revision was proposed of the TNM staging system that would classify these tumors exclusively based on their tumor size and lymph node status. In the current study, the authors evaluated how implementation of this proposal will affect Stage III noninflammatory breast cancer. METHODS: Two hundred seven patients who were classified with noninflammatory Stage III breast cancer were treated consecutively between 1990 and 1999 at the University Hospital Basel, Switzerland. To assess the extent of T4b/Stage IIIB tumors independent of the clinicopathologic feature of skin involvement, the reclassification was undertaken. RESULTS: Of 68 patients who had nonmetastatic T4b breast cancer, 37 patients (54.4%) had a tumor extent in accordance with Stage I/II and had improved disease-specific survival (DSS) compared with patients who had Stage III breast cancer (P = .008). Excluding those patients from Stage III led to a 17.9% reduction of the number of patients in this group (n = 170 patients). The 10-year DSS declined from 48.5% to 42.9%. CONCLUSIONS: Considerable numbers of patients who are classified with noninflammatory Stage IIIB breast cancer show only a limited disease extent. Through a revision of the T4 category, these low-risk patients were excluded from the highest nonmetastatic TNM stage, and overstaging could be avoided. This procedure decreased the degree of heterogeneity of the entire Stage III group and may result in a more precise assessment of this disease entity.

Breast Neoplasms↗
PubMed2006

Expression of peroxisome proliferator activated receptor gamma and cyclo-oxygenase 2 in primary and recurrent ovarian carcinoma.

AIM: Peroxisome proliferator-activated receptor gamma (PPARgamma) has emerged as a potential therapeutic target in several types of cancer. In ovarian carcinomas, limited and conflicting data on PPARgamma protein expression have been reported. METHODS: The immunoexpression of PPARgamma and its putative target cyclo-oxygenase 2 (COX2) was investigated in tumour tissues from 80 patients with primary and corresponding recurrent ovarian serous carcinomas after conventional platinum-based chemotherapy. RESULTS: PPARgamma expression was observed in 29% of primary and recurrent carcinomas. In the recurrent tumours, PPARgamma expression inversely correlated with COX2 overexpression in both chemosensitive (p = 0.02) and chemoresistant (p = 0.04) carcinomas. CONCLUSIONS: The data indicate that PPARgamma may represent a potential target for second-line treatment in ovarian cancers.

Adult↗
PubMed2006

Correlation and significance of histopathological and clinical features in breast cancer with skin involvement (T4b).

A retrospective review was performed to investigate the prognostic significance and validity of the pathological and clinical TNM staging of noninflammatory skin involvement in breast cancer. In 128 tumors with histologically proven skin involvement and a size up to 5 cm (64% of the entire group), we distinguished clearly between group A) cases showing the classical clinical signs (cT4b) and those that do not, and between group B) carcinomas infiltrating the epidermis (pT4b) and those infiltrating only the dermis. We found only moderate concordance (kappa = 0.44) between the pathological and clinical TNM staging system. In the analysis of 80 patients with a tumor size from 2.1 to 5.0 cm, neither the appearance of classical clinical signs nor the histological diagnosis of infiltration of the epidermis was shown to be a relevant factor. In comparison to the control groups, similar clinicopathologic entities without significant differences in long-term outcome were observed. After regrouping of the patients having tumor infiltration of the papillary dermis from the control group into the study group (pT4), the study group showed a significant higher number of involved axillary lymph nodes (P = .014) and a more extensive lymph node involvement (pN3; P = .025). The combination epidermis-papillary dermis seems to be more a functional unit than the epidermis alone that is defined as the crucial and delineating factor in the TNM Classification. Our results challenge the validity of the TNM rules and recommendations concerning T4b breast cancer because it leads, in the majority of cases, to tumors of comparable extent and prognosis being placed in different categories.

Adenocarcinoma↗
PubMed2006

Epithelial growth factor receptor status in primary and recurrent ovarian cancer.

Success of epidermal growth factor receptor (EGFR) targeting agents in different cancer types is related to EGFR gene mutations and/or copy number gains. We investigated the EGFR gene status and protein expression by DNA mutational analysis, fluorescence in situ hybridization (FISH), and immunohistochemistry in tumor tissues from 80 patients with primary and corresponding recurrent ovarian serous carcinomas. The patients were classified into six groups with ascending EGFR gene copy numbers. EGFR amplification and high polysomy (FISH+) was present in a significant fraction of the primary (20%) and recurrent (22%) ovarian carcinomas. On mutational analysis, only one tumor with a silent EGFR mutation was observed, and this was the only carcinoma with high-level amplification. EGFR protein immunoexpression was seen in 28% of primary and 33% of recurrent carcinomas and correlated to amplification in the primary tumors (P = 0.003). In recurrent carcinoma, moderate and strong EGFR expression was associated with amplification (P = 0.034). These molecular events potentially have impact on the responsiveness to EGFR targeting agents in ovarian cancer.

Adult↗
PubMed2006

A new approach in breast cancer with non-inflammatory skin involvement.

The widely accepted image of breast cancer with non-inflammatory skin involvement (T4b) is determined by the tenet that all these tumors are locally advanced (Stage IIIB). The study addresses the question whether this view is justified. Data from 453 non-metastatic breast cancer patients were collected retrospectively. Eighty-one patients had T4b disease. To assess the malignant potential of tumors independent of the feature skin involvement, a reclassification only considering tumor size was undertaken. We compared the clinical course of three study groups (A: Stage II; B: Stage IIIA; C: Stage IIIC) with control groups of 372 patients without skin involvement. In the study groups, we found a broad distribution among the stages (A:36.2%; B:33.7%; and C:27.7%) with significant differences in disease-specific survival (DSS) (A/B: p = 0.032; B/C: p = 0.048). There were no significant differences in DSS between the study and the corresponding control group. In multivariate analysis, skin involvement was not a significant predictor of DSS. Heterogeneity of the T4b category and a lack of prognostic significance expand the widely accepted image of breast cancer with non-inflammatory skin involvement. The highest T category, or Stage III, is not the appropriate classification for a considerable number of patients having this clinicopathologic entity.

Adult↗
PubMed2006

Comparison of gene expression profiles in core biopsies and corresponding surgical breast cancer samples.

INTRODUCTION: Gene expression profiling has been successfully used to classify breast cancer into clinically distinct subtypes, and to predict the risk of recurrence and treatment response. The aim of this study was to investigate whether the gene expression profile (GEP) detected in a core biopsy (CB) is representative for the entire tumor, since CB is an important tool in breast cancer diagnosis. Moreover, we investigated whether performing CBs prior to the surgical excision could influence the GEP of the respective tumor. METHODS: We quantified the RNA expression of 60 relevant genes by quantitative real-time PCR in paired CBs and surgical specimens from 22 untreated primary breast cancer patients. Subsequently, expression data were compared with independent GEPs obtained from tumors of 317 patients without preceding CB. RESULTS: In 82% of the cases the GEP detected in the CB correlated very well with the corresponding profile in the surgical sample (rs > or = 0.95, p < 0.001). Gene-by-gene analysis revealed four genes significantly elevated in the surgical sample compared to the CB; these comprised genes mainly involved in inflammation and the wound repair process as well as in tumor invasion and metastasis. CONCLUSION: A GEP detected in a CB are representative for the entire tumor and is, therefore, of clinical relevance. The observed alterations of individual genes after performance of CB deserve attention since they might impact the clinical interpretation with respect to prognosis and therapy prediction of the GEP as detected in the surgical specimen following CB performance.

Aged↗
PubMed2005

Breast carcinoma with noninflammatory skin involvement (T4b): time to abandon an historic relic from the TNM classification.

BACKGROUND: In this study, the authors evaluated the clinical presentation of patients with T4b breast carcinoma, analyzed the impact of noninflammatory skin involvement on long-term survival, and addressed the question whether the T4 tumor category still has any justification. METHODS: The clinical course of a study group of 119 patients with skin involvement was compared with the outcome of a control group of 299 consecutive patients who had tumors of the same size but without skin involvement. All tumors were stratified into 1 of 4 subsets according to greatest tumor dimension, as follows: Group A, < or = 3.0 cm; Group B, 3.1-5.0 cm; Group C, 5.1-10.0 cm; and Group D, > 10.0 cm. RESULTS: The study group distribution of patients within the size subsets were as follows: Group A, 26.1%; Group B, 24.3%; Group C, 26.1%; and Group D, 23.5%. Differences in disease-specific survival between the tumor size subsets were significant (Groups A and B vs. Groups C and D; P < 0.0001). In contrast to large tumors (> 5.0 cm), carcinomas < or = 5.0 cm showed no statistical significant differences in disease-specific survival between study group patients and control group patients (Group A: P = 0.17; Group B: P = 0.31). CONCLUSIONS: There is a broad range of clinicopathologic breast carcinoma entities within the T4b category. For > 50% of patients with T4b breast carcinoma, the feature noninflammatory skin involvement had no significant prognostic impact. Approximately 25% of patients had an extent of disease similar to that observed in patients with Stage I-II disease and, thus, falsely were considered to have more advanced disease. Heterogeneity and a lack of prognostic significance suggest that a revision of the T4 category, a relic of historic tumor classifications, is necessary.

Adult↗
PubMed2005

Placental site trophoblastic tumor of the mediastinum.

Choriocarcinoma has been described as the most frequent subtype of mediastinal germ cell tumors showing trophoblastic differentiation. We report a unique case of a placental site trophoblastic tumor, which developed in the mediastinum of a 14-year-old boy 2 years after the resection of a mature teratoma. The recurrent tumor was composed of a grossly hemorrhagic and necrotic mass. Histologically, diffusely infiltrating large polygonal cells with focal nodular growth and a teratomatous part containing mature intestinal, respiratory, and squamous epithelium with adjacent cutaneous adnexal structures were found. The typical morphologic features included vessel wall infiltration by the neoplastic cells with fibrinoid deposits and geographic necroses within the tumor masses. Characteristic diffuse positivity for melanoma cell adhesion molecule and human leucocyte antigen G was found on immunohistochemical investigation, confirming the diagnosis of placental site trophoblastic tumor. The patient died 1 year later after polychemotherapy. The outcome of this rare tumor is similar to the reported poor clinical outcome in patients with mediastinal choriocarcinomas.

Adolescent↗
PubMed2005

Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation.

The infrequent association of serous borderline tumors (SBTs) with invasive serous carcinoma has led to the view that SBTs are unrelated to invasive serous carcinoma. Nonetheless, mortality associated with SBTs is generally attributed to malignant transformation, and traditionally these tumors have been designated as "carcinomas of low malignant potential." Previous immunohistochemical studies evaluating p53 expression and molecular genetic studies evaluating mutational status have reported that p53 overexpression and mutations are infrequent in SBTs and occur in as many as 50% to 80% of invasive serous carcinomas. The different methodologies for determining p53 status and the failure to correlate the findings with tumor grade make these studies difficult to interpret. The current study was undertaken to overcome these deficiencies and to reconcile the relationship of SBTs to invasive serous carcinoma by performing a morphologic, immunohistochemical, and molecular genetic analysis comparing SBTs with low- and high-grade serous carcinoma. The molecular genetic analysis used a highly stringent, carefully designed nucleotide-sequencing method. A total of 96 sporadic serous tumors including 25 SBTs (11 atypical proliferative serous tumors and 14 intraepithelial low-grade serous carcinomas [noninvasive micropapillary serous carcinomas, MPSCs]), 12 low-grade serous carcinomas (invasive MPSCs), and 59 high-grade serous carcinomas were analyzed for their p53 mutational status of exons 5 to 9. Functional mutations, defined as mutations resulting in the alteration of the structure of the encoded protein, were detected in 30 of 59 (50.8%) high-grade serous carcinomas and 1 (8.3%) of 12 low-grade invasive serous carcinomas compared with 2 (8%) of 25 SBTs, both of these in intraepithelial low-grade serous carcinomas (noninvasive MPSCs). The similar frequency of p53 mutations in SBTs and low-grade invasive serous carcinomas in contrast to the significantly higher frequency of p53 mutations in high-grade serous carcinomas (P < 0.0005) suggests a common lineage for SBTs and low-grade invasive serous carcinomas and supports the view that SBTs are unrelated to the usual type of invasive serous carcinoma, which is a high-grade neoplasm. Mutational status was also correlated with p53 immunoreactivity. Although p53 immunoreactivity is generally higher in those specimens containing mutant p53, immunostaining is neither sufficiently specific nor sensitive enough to predict p53 mutations. The molecular genetic findings confirm our hypothesis of dual pathways of serous carcinogenesis based on previous analyses of KRAS and BRAF mutations on the same set of cases in which KRAS and BRAF mutations were found in 60% of SBTs and low-grade serous carcinoma but not in high-grade serous carcinomas. Based on these studies, we have proposed a model of serous carcinogenesis in which SBTs are the precursors of low-grade serous carcinomas whereas the usual type of invasive serous carcinoma is a high-grade neoplasm that develops "de novo" from in situ alterations in epithelial inclusion cysts.

Base Sequence↗
PubMed2004

Different types of microsatellite instability in ovarian carcinoma.

Microsatellite instability at mono- and dinucleotide repeats is the hallmark of the hereditary non-polyposis cancer syndrome (HNPCC) and is related to deficient DNA mismatch repair. In contrast, a distinct form of microsatellite instability at selective tetranucleotide repeats (EMAST or elevated microsatellite alterations at selected tetranucleotides) was described in several non-HNPCC cancer types. EMAST is probably unrelated to mismatch repair defects. We investigated the frequency of microsatellite instability at mononucleotide, dinucleotide and tetranucleotide repeats in a series of 75 ovarian carcinomas (53 serous and 22 non-serous). Microsatellite analysis was carried out using 5 mono- and dinucleotide markers from the National Cancer Institute Consensus Panel and 6 tetranucleotide markers, which have been reported as frequently unstable in the literature. High frequency of microsatellite instability (MSI-H) at mono- and dinucleotide repeats was observed in 9% and a low frequency (MSI-L) in 21% of serous carcinomas. MSI-H was detected in 4% and MSI-L in 18% of non-serous carcinomas. Nine percent of serous carcinomas showed instability at multiple and 9% at single tetranucleotide loci. All non-serous carcinomas were stable at tetranucleotide loci. In summary, EMAST (e.g., tumors with tetranucleotide instability without concomitant MSI-H) was observed in 13% of ovarian serous carcinomas. All EMAST positive tumors were of advanced stage. We conclude that EMAST occurs as a distinct form of microsatellite instability in ovarian cancer. EMAST seems to be particularly frequent in advanced serous carcinomas. Its clinical significance needs to be investigated.

Carcinoma↗
PubMed2004

Loss of SFRP1 is associated with breast cancer progression and poor prognosis in early stage tumors.

Aberrant activation of the Wnt signaling pathway plays an important role in the development of solid tumors such as breast and colon cancer. Secreted Frizzled-related protein 1 (SFRP1) is a negative regulator of the Wnt pathway. It has been described that SFRP1 mRNA is strongly down-regulated in breast cancer and a putative tumor suppressor function has been postulated. We have generated and characterized an SFRP1 specific antibody to analyze its expression on protein level and to investigate the association of SFRP1 expression with clinicopathological parameters and patient survival. Analysis of >2000 invasive breast tumors and 56 carcinoma in situ revealed similar frequencies of SFRP1 loss in these tumors (46% and 43% respectively). Therefore, we propose that loss of SFRP1 expression is an early event in breast tumorigenesis. SFRP1 expression was inversely correlated with tumor stage (p<0.001) but not with tumor grade (p=0.14) or lymph node status (p=0.84). Performing a multivariate analysis we could confirm the association between tumor stage and SFRP1 expression (p=0.029). In particular, loss of SFRP1 expression in early stage breast tumors (pT1) was associated with poor prognosis (p=0.04). In conclusion, expression of SFRP1 is commonly lost in breast cancer. SFRP1 expression might be useful as a novel prognostic marker in early stage breast cancer.

Biomarkers, Tumor↗
PubMed2003

HLA-G is a potential tumor marker in malignant ascites.

PURPOSE: Molecular approaches as supplements to cytological examination of malignant ascites may play an important role in the clinical management of cancer patients. HLA-G is a potential tumor-associated marker and that one of its isoforms, HLA-G5, produces a secretory protein. This study is to assess the clinical utility of secreted HLA-G levels in differential diagnosis of malignant ascites. EXPERIMENTAL DESIGN: We used ELISA to assess whether secretory HLA-G (sHLA-G) could serve as a marker of malignant ascites in ovarian and breast carcinomas, which represent the most common malignant tumors causing ascites in women. RESULTS: On the basis of immunohistochemistry, 45 (61%) of 74 ovarian serous carcinomas and 22 (25%) invasive ductal carcinomas of the breast demonstrated HLA-G immunoreactivity ranging from 2 to 100% of the tumor cells. HLA-G staining was not detected in a wide variety of normal tissues, including ovarian surface epithelium and normal breast tissue. Revese transcription-PCR demonstrated the presence of HLA-G5 isoform in all of the tumor samples expressing HLA-G. ELISA was performed to measure the sHLA-G in 42 malignant and 18 benign ascites supernatants. sHLA-G levels were significantly higher in malignant ascites than in benign controls (P < 0.001). We found that the area under the receiver-operating characteristic curve for sHLA-G was 0.95 for malignant versus benign ascites specimens. At 100% specificity, the highest sensitivity to detect malignant ascites was 78% (95% confidence interval, 68-88%) at a cutoff of 13 ng/ml. CONCLUSIONS: Our findings suggest that measurement of sHLA-G is a useful molecular adjunct to cytology in the differential diagnosis of malignant versus benign ascites.

Ascites↗
PubMed2003

The RASSF1A tumor suppressor gene is commonly inactivated in adenocarcinoma of the uterine cervix.

PURPOSE: Development of adenocarcinoma (AC) of the uterine cervix, as well as squamous cell carcinoma (SCC), is strongly linked to infection by high-risk human papillomavirus (HPV) types. Human HPV E6 and E7 proteins inactivate the tumor suppressor genes p53 and retinoblastoma, respectively. However, additional genetic alterations may be required to maintain a malignant phenotype. Allelic loss at the short arm of chromosome 3 is one of the most frequent genetic changes found in cervical cancer and various other types of human cancer, including lung, breast, and ovarian cancer. This implies that a resident tumor-suppressor gene in this region is involved in the genesis of these tumors. RASSF1A, which is located at 3p21.3, is rarely inactivated by mutations but has been suggested as a target tumor suppressor gene on the basis of its frequent inactivation through promoter hypermethylation and loss of heterozygosity in a variety of primary human cancers. In the present study, we sought to determine whether epigenetic silencing of RASSF1A caused by hypermethylation of the promoter region plays a role in the development of uterine cervical cancer. EXPERIMENTAL DESIGN: We studied 51 uterine cervical carcinoma samples. These 51 cases were comprised of 31 SCCs and 20 ACs. Real-time methylation-specific PCR system was used for the detection and quantitation of the bisulfite-converted methylated version of the RASSF1A promoter region. The 20 cases of cervical AC were also analyzed for the presence of oncogenic HPV 16 DNA using a PCR-based method. RESULTS: We found complete methylation of the RASSF1A promoter in 45% (9 of 20 samples) of AC cases. There was no promoter methylation observed in any of the 31 cases of SCC. We also correlated RASSF1A promoter hypermethylation to oncogenic HPV 16 infection. HPV 16 DNA was found in 3 of 9 (33%) AC tumors with RASSF1A promoter hypermethylation and 5 of 11 (45%) AC tumors without RASSF1A promoter hypermethylation. We could not demonstrate an inverse correlation between RASSF1A methylation and HPV 16 infection in AC of the uterine cervix. CONCLUSIONS: Hypermethylation of the RASSF1A promoter region is common in AC of the uterine cervix and rare in squamous carcinoma of uterine cervix. HPV infection does not correlate with RASSF1A methylation status in AC of the uterine cervix, but the absence of RASSF1A methylation in SCC of the uterine cervix coupled with the high incidence of HPV 16 infection in this subtype is in accord with previous reports. Our results suggest that epigenetic silencing of RASSF1A may play a role in the development of AC of the uterine cervix.

Adenocarcinoma↗
PubMed2003

Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.

Activating mutations in KRAS and in one of its downstream mediators, BRAF, have been identified in a variety of human cancers. To determine the role of mutations in BRAF and KRAS in ovarian carcinoma, we analyzed both genes for three common mutations (at codon 599 of BRAF and codons 12 and 13 of KRAS). Mutations in either codon 599 of BRAF or codons 12 and 13 of KRAS occurred in 15 of 22 (68%) invasive micropapillary serous carcinomas (MPSCs; low-grade tumors) and in 31 of 51 (61%) serous borderline tumors (precursor lesions to invasive MPSCs). None of the tumors contained a mutation in both BRAF and KRAS. In contrast, none of the 72 conventional aggressive high-grade serous carcinomas analyzed contained the BRAF codon 599 mutation or either of the two KRAS mutations. The apparent restriction of these BRAF and KRAS mutations to low-grade serous ovarian carcinoma and its precursors suggests that low-grade and high-grade ovarian serous carcinomas develop through independent pathways.

Codon↗
PubMed2003

Mutational analysis of K-ras segregates ovarian serous carcinomas into two types: invasive MPSC (low-grade tumor) and conventional serous carcinoma (high-grade tumor).

We previously proposed a dualistic model for ovarian serous carcinogenesis. One pathway involves the stepwise development of invasive micropapillary serous carcinoma (MPSC) from serous borderline tumor (atypical proliferative serous tumor) to noninvasive and then invasive MPSC. The carcinomas that develop in this fashion are characterized by low-grade nuclei and frequent K-ras mutations. They generally pursue an indolent course. In the other pathway conventional serous carcinoma (CSC) develops from the ovarian surface epithelium without what appears to be intermediate stages. These tumors display high-grade nuclei, wild-type K-ras, and are very aggressive. Some of these CSCs display micropapillary architecture and simulate invasive MPSCs. This raises the possibility that these CSCs develop from an invasive MPSC. To address this question we reviewed 31 moderately and poorly differentiated CSCs and identified 7 with morphological features of invasive MPSC. These seven tumors exhibited micropapillary architecture in at least 25% of the tumor but contained high-grade nuclei. The 31 tumors were assessed for K-ras mutations using digital polymerase chain reaction-based analysis. Despite their micropapillary architecture, all 7 CSCs with micropapillary features contained wild-type K-ras as did the other 24 pure CSCs. The results indicate that CSCs with micropapillary features are not derived from invasive MPSCs. The molecular findings also support the view that ovarian serous carcinomas should be graded as low- and high-grade tumors.

Cystadenocarcinoma, Serous↗
PubMed2002

Assessment of plasma DNA levels, allelic imbalance, and CA 125 as diagnostic tests for cancer.

BACKGROUND: Allelic imbalance (AI), the loss or gain of chromosomal regions, is found in many cancers. AI can be detected in genomic tumor DNA released into the blood after necrosis or apoptosis. We evaluated plasma DNA concentration, allelic status in plasma DNA, and serum CA 125 level as screening tests for ovarian and other cancers. METHODS: Plasma samples were obtained from 330 women (44 normal healthy control individuals, 122 patients with various cancers, and 164 control patients with non-neoplastic diseases). Plasma DNA concentration was determined in all samples. Allelic status was determined by digital single nucleotide polymorphism (SNP) analysis with eight SNP markers in plasma DNA from 54 patients with ovarian cancer and 31 control patients. CA 125 was determined in 63 samples. Receiver-operating characteristic (ROC) curves were plotted, and the areas under the ROC curves--a measure of the overall ability of a diagnostic test with multiple cutoffs to distinguish between diseased and nondiseased individuals--were determined. RESULTS: The area under the ROC curve for plasma DNA concentration was 0.90 for patients with neoplastic disease versus healthy control individuals and 0.74 for patients with neoplastic diseases versus control patients with non-neoplastic diseases. For control subjects given a specificity of 100% (95% confidence interval [CI] = 92% to 100%), the highest sensitivity achieved was 57% (95% CI = 49% to 67%). AI in at least one SNP was found in 87% (95% CI = 60% to 98%) of patients with stage I/II ovarian cancer and 95% (95% CI = 83% to 99%) of patients with stage III/IV ovarian cancer, but AI was not found in 31 patients with non-neoplastic diseases (specificity = 100%, 95% CI = 89% to 100%). The area under the ROC curve assessing AI was 0.95. Combining the serum CA 125 level with the plasma DNA concentration increased the area under the ROC curve from 0.78 (CA 125 alone) to 0.84. CONCLUSION: Plasma DNA concentration may not be sensitive or specific enough for cancer screening or diagnosis, even when combined with CA 125. AI was detected with high specificity in plasma DNA from patients with ovarian cancer and should be studied further as a screening tool.

Adult↗