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Progress in gynecologic cancer detection and treatment.

Slow but steady progress has been made in the earlier diagnosis and better treatment of gynecological cancers, particularly over the last 50 years. Cervical cytology screening programs, where implemented, have led to a remarkable reduction in both the incidence and mortality from clinically invasive cervical cancer. This relatively simple technology has been truly one of the major success stories of modern medicine, but unfortunately this technique has not been uniformly applied to all women in the world, particularly to women in developing countries. New research into cervical cancer etiology, the role of HPV, and the development of vaccines against this virus offer a great hope particularly for developing countries. In addition, the combination of radiotherapy and chemotherapy has resulted in a marked improvement in outcome results for women with advanced cervical cancer. Ovarian cancer has seen the development of effective chemotherapy strategies for this disease. Currently this disease remains one of the major scourges in industrialized countries but the continued evolution of knowledge with regard to optimum sequencing of chemotherapeutic agents and surgery offers the prospect for better outcomes, less morbidity and a better quality of life. Ongoing research into the development of newer chemotherapeutic agents and a better understanding of the actual mechanisms regarding the efficacy of chemotherapy and drug resistance offers great promise for the future. Endoscopic surgery for staging and also for therapy shows promise for improved quality of life as well as outcomes for patients in the future and offers the challenge of trying to make this technology readily available to all women in the world. As we gain a better understanding of the molecular basis of disease and health we will truly be able to intervene in a preventive mode in the new millennium.

Breast Neoplasms↗

Early lung cancer detection and localization.

The Mayo Lung Project was established to develop and evaluate a screening program for early lung cancer in high-risk subjects. Men who are more than 45 years of age and who smoke one package of cigarettes or more daily are screened by the use of thoracic roentgenograms, three-day pooled sputum cytology, and lung health questionnaires at four-month intervals. These data are compared with data from similar subjects screened only on entry into the project. During the past three years, 34 patients who had no roentgenoraphic evidence of lung cancer were identified and examined because of carcinoma cells in sputum. Of these 34 patients, 27 have had bronchoscopic localization of their tumors and definitive treatment and 3 had upper respiratory tract neoplasms and also have been treated. Of the remaining four, one patient died suddenly after myocardial infarction and three patients have not had localization or treatment because of other severe complicating medical problems. Localization of roentgenographically occult lung cancer is reliable by the use of bronchofiberoscopy and meticulous, thorough sampling from the tracheobronchial tree. A search must be made for upper airway cancers in the same high-risk population, and the possibility of second primary bronchogenic tumors also must be considered. Although follow-up is short, 22 of the 27 treated lung cancer patients were found with stage I disease. The outlook for 19 of these 27 is encouraging an average of 16 months after surgical resection.

Aged↗

Polyps: an approach to large bowel cancer detection and prevention.

The evidence that an adenomatous polyp identifies a patient at higher than average risk for colonic cancer seems firm. There is also growing evidence that polypectomy with followup decreases the expected mortality from colonic cancer in patients with adenomatous polyps. Recent studies suggest inheritance of solitary adenomas and colonic cancer in some pedigrees. Further studies of adenoma etiology are suggested; the information to be gained from such studies should be of potential importance to colonic cancer screening efforts.

Colonic Neoplasms↗

Genetic changes in intraductal breast cancer detected by comparative genomic hybridization.

Ductal carcinoma in situ (DCIS) is considered a direct precursor of invasive ductal breast cancer (IDC). We combined tissue microdissection and comparative genomic hybridization to identify genetic changes in five DCIS lesions with no invasion and in two that were adjacent to IDC. Extensive genetic changes characterized pure DCIS cases with gains of 1q, 6q, 8q, and Xq as well as losses of 17p and chromosome 22 being most often involved. Except for the Xq gain, these changes are also common to IDC. Separate analysis of DCIS and IDC components in the same tumor revealed an almost identical pattern of genetic changes in one case, whereas substantial differences were found in another. We conclude that many of the common genetic changes in IDC may take place before development of invasive growth. However, a simple linear progression model may not always account for the DCIS-IDC transition.

Breast Neoplasms↗

Occult cancer detected by positron emission tomography/computed tomography image fusion.

A 60-year-old male in a high-risk group for lung cancer, who also had positive sputum cytology, underwent examination by chest plain radiography, chest computed tomography (CT) and bronchofiberscopy. However, initially no abnormal findings were detected with these diagnostic modalities. Furthermore, thin-section spiral chest CT disclosed only a slight thickness of the right side of the tracheal wall, while consequent re-examination by bronchofiberscopy revealed only a light ulcerative lesion in the same area. However, the existence of a primary tumor was not confirmed using these modalities. Therefore, FDG-PET (positron emission tomography with fluorodeoxyglucose) was performed and demonstrated accumulation corresponding to the anterior mediastinum, although the exact location of the tumor was unclear by FDG-PET alone. Therefore, FDG-PET/CT image fusion was performed and resulted in the detection of a tracheal carcinoma on the outside of the right side of the tracheal wall. The patient then underwent tracheal sleeve resection including the tumor and tracheoplasty accompanied with wrapping using the flap of the thymus right lobe. To the best of our knowledge, this is the first reported case of tracheal carcinoma detected by FDG-PET/CT image fusion with consequent radical resection.

Bronchi↗

c-myc copy number gains in bladder cancer detected by fluorescence in situ hybridization.

Amplification and overexpression of c-myc have been suggested as prognostic markers in human cancer. To assess the role of c-myc gene copy number alterations in bladder cancer, 87 bladder tumors were examined for c-myc aberrations by fluorescence in situ hybridization. Dual labeling hybridization with a repetitive pericentromeric probe specific for chromosome 8 and a probe for the c-myc locus (at 8q24) was performed to analyze c-myc copy number in relation to chromosome 8 copy number on a cell by cell basis. A clear-cut c-myc amplification (up to 40 to 150 copies per cell) was found in 3 tumors. There was a low level c-myc copy number increase in 32 of the remaining 84 tumors. There was no association of low level c-myc copy number increase with c-myc protein overexpression. This suggests that a c-myc gene copy number gain as detected by fluorescence in situ hybridization does not necessarily reflect a disturbed c-myc gene function but may indicate a structural chromosome 8 abnormality including gain of distal 8q. The strong association of low level c-myc (8q) gains with tumor grade (P < 0.0001), stage (P < 0.0001), chromosome polysomy (P < 0.0001), p53 protein expression (P = 0.0019), p53 deletion (P = 0.0403), and tumor cell proliferation (Ki67 labeling index; P = 0.0021) is consistent with a role of chromosome 8 alterations in bladder cancer progression.

Chromosomes, Human, Pair 8↗

Quantitative real-time PCR for cancer detection: the lymphoma case.

Advances in the biologic sciences and technology are providing molecular targets for diagnosis and treatment of cancer. Lymphoma is a group of cancers with diverse clinical courses. Gene profiling opens new possibilities to classify the disease into subtypes and guide a differentiated treatment. Real-time PCR is characterized by high sensitivity, excellent precision and large dynamic range, and has become the method of choice for quantitative gene expression measurements. For accurate gene expression profiling by real-time PCR, several parameters must be considered and carefully validated. These include the use of reference genes and compensation for PCR inhibition in data normalization. Quantification by real-time PCR may be performed as either absolute measurements using an external standard, or as relative measurements, comparing the expression of a reporter gene with that of a presumed constantly expressed reference gene. Sometimes it is possible to compare expression of reporter genes only, which improves the accuracy of prediction. The amount of biologic material required for real-time PCR analysis is much lower than that required for analysis by traditional methods due to the very high sensitivity of PCR. Fine-needle aspirates and even single cells contain enough material for accurate real-time PCR analysis.

Biomarkers, Tumor↗

[Combined use of PSA density and free to total PSA ratio for cancer detection from patients with PSA elevations].

Prostate specific antigen (PSA) has been used an excellent diagnostic indicator, but its low cancer specificity has been pointed out. In this study, we investigated whether or not the use of Prostate specific antigen density (PSAD) in combination with free/total (F/T) ratio could improve biopsy indication in patients with abnormal PSA levels. Investigated were 428 patients undergoing prostate biopsy in our institution between January 2001 and September 2004, in which PSA levels were 4-20 ng/ml, and F/T ratio and prostate volume (hereinafter 'PV') could also be measured. At the cut-off values of 0.15 for PSAD and 0.25 for F/T ratio, the specificity and sensitivity were 37.7% and 85.5%, respectively, with PSAD alone; 20.1% and 91.8%, respectively, with F/T ratio alone; and 46.5% and 100%, respectively, with PSAD and F/T ratio. These results indicated that PSAD in combination with F/T ratio could also be an excellent biopsy indicator.

Biomarkers, Tumor↗

Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array.

BACKGROUND: Alternative splicing is a mechanism for increasing protein diversity by excluding or including exons during post-transcriptional processing. Alternatively spliced proteins are particularly relevant in oncology since they may contribute to the etiology of cancer, provide selective drug targets, or serve as a marker set for cancer diagnosis. While conventional identification of splice variants generally targets individual genes, we present here a new exon-centric array (GeneChip Human Exon 1.0 ST) that allows genome-wide identification of differential splice variation, and concurrently provides a flexible and inclusive analysis of gene expression. RESULTS: We analyzed 20 paired tumor-normal colon cancer samples using a microarray designed to detect over one million putative exons that can be virtually assembled into potential gene-level transcripts according to various levels of prior supporting evidence. Analysis of high confidence (empirically supported) transcripts identified 160 differentially expressed genes, with 42 genes occupying a network impacting cell proliferation and another twenty nine genes with unknown functions. A more speculative analysis, including transcripts based solely on computational prediction, produced another 160 differentially expressed genes, three-fourths of which have no previous annotation. We also present a comparison of gene signal estimations from the Exon 1.0 ST and the U133 Plus 2.0 arrays. Novel splicing events were predicted by experimental algorithms that compare the relative contribution of each exon to the cognate transcript intensity in each tissue. The resulting candidate splice variants were validated with RT-PCR. We found nine genes that were differentially spliced between colon tumors and normal colon tissues, several of which have not been previously implicated in cancer. Top scoring candidates from our analysis were also found to substantially overlap with EST-based bioinformatic predictions of alternative splicing in cancer. CONCLUSION: Differential expression of high confidence transcripts correlated extremely well with known cancer genes and pathways, suggesting that the more speculative transcripts, largely based solely on computational prediction and mostly with no previous annotation, might be novel targets in colon cancer. Five of the identified splicing events affect mediators of cytoskeletal organization (ACTN1, VCL, CALD1, CTTN, TPM1), two affect extracellular matrix proteins (FN1, COL6A3) and another participates in integrin signaling (SLC3A2). Altogether they form a pattern of colon-cancer specific alterations that may particularly impact cell motility.

Algorithms↗

Colon cancer: detection and prevention.

Recent data have advanced our ability to detect, survey, and manage patients with colonic neoplasia. Current studies and consensus statements increasingly support the role of colonoscopic screening over less invasive testing such as FOBT or FS for appropriately selected individuals. There are many issues, however, that remain unresolved. What is the appropriate surveillance of an individual with a single family member who had colon cancer at an early age? How should family members of suspected HNPCC kindreds be managed? There has yet to be a prospective cohort validation of the Bethesda criteria in directing clinical practice, with the endpoint of mortality reduction. Questions regarding prophylaxis with dietary supplements and medications are exciting areas that are currently under study. As newer technologies become clinically available for molecular diagnostics and screening, and virtual colonoscopy with computed tomography and magnetic resonance disseminates, there will undoubtedly be new questions to be answered regarding their ability to aid in the detection and management of colon cancer.

Chemoprevention↗

Amplification of c-myc, K-sam, and c-met in gastric cancers: detection by fluorescence in situ hybridization.

Gene amplifications of c-myc, K-sam, and c-met were examined in cancer nuclei isolated from 154 primary gastric adenocarcinomas by fluorescence in situ hybridization (FISH) using cosmid probes for 8q24 (c-myc locus) and 7q31 (c-met), as well as a DNA probe for K-sam synthesized by PCR. The results were compared with those of Southern blot analysis. Dual-color FISH using gene locus and chromosome-specific probes detected gene amplifications of c-myc in 24 tumors (15.5%), c-met in 6 tumors (3.9%), and K-sam in 3 tumors (2.9%). The six tumors with c-myc amplification had also been found to have amplified c-erbB-2 in our previous study, and coamplification of c-myc and c-met was found in two other tumors. This technique also differentiated the amplified genes on the homogeneous staining region (HSR) and on double minute chromosomes (DMs) in metaphase spreads and interphase nuclei of cell lines established from poorly differentiated adenocarcinomas, KATO III, SNU 16, and HSC 39. Examination of FISH images of these cell lines suggested that the high-level amplifications of c-myc found in primary tumors occurred mainly on DM in four tumors and on HSR in one, and those of K-sam occured on DM in two tumors and on HSR in one. No high-level amplification of c-met was found. These high-level amplifications were also detected in formalin-fixed, paraffin-embedded tissues from primary gastric tumors and metastatic lymph nodes, in some of which heterogeneity of gene amplification was demonstrated within the same tumor. We conclude that FISH is an important tool for examining the proto-oncogene aberrations in intact cells in solid tumors.

Blotting, Southern↗

Disseminated bone marrow metastases from primary breast cancer: detection and follow-up by radioimmune bone marrow scintigraphy.

Bone scintigraphy of a 40-yr-old patient suffering from primary breast cancer suggested the possibility of diffuse metastases. Bone marrow scintigraphy using 99mTc-labeled monoclonal antibodies (BW 250/183) demonstrated diffuse destruction of bone marrow due to metastatic disease and consecutive bone marrow extension. Bone marrow scintigraphy was highly sensitive in detecting progression of disease in this asymptomatic patient.

Adult↗

[MR diagnosis for metastasis or non-metastasis of mediastinal and hilar lymph nodes in cases of primary lung cancer: detectability, signal intensity, and MR-pathologic correlation].

The detectability and signal intensity on MR imaging of mediastinal and hilar lymph nodes were studied in cases of lung cancer. Additionally, short inversion time inversion recovery (STIR) images and pathologic findings were compared. In the detection of resected metastatic mediastinal and hilar lymph nodes (n = 146), the STIR image (82%) was superior to the T1-weighted image (71%) and the T2-weighted image (60%). On STIR imaging, 212 (60%) of 412 resected non-metastatic mediastinal nodes and 38 (33%) of 116 resected non-metastatic hilar lymph nodes were detected. Characteristics of signal intensities of metastatic nodes were mainly low on T1-weighted images, high on T2-weighted images, and very high on STIR images. The rate of these characteristics of signal intensity of metastatic nodes was 59%. However, the rate of very high signal intensity of metastatic nodes on STIR imaging was 81%. Pathologically, lymph nodes with high or very high signal intensities on STIR images were metastatic, reactive and hyperplastic, or non-metastatic. Lymph nodes with slightly high signal intensity or high intensity with a low focus on STIR images were anthracotic, anthrasilicotic, caseous necrotic, calcified, or fibrotic. Thus, when the signal intensity of a lymph node was decreased on the STIR image, there was no definite evidence of metastasis excluding micro-metastasis or coagulation necrosis of a metastatic tumor. We conclude that the signal characteristics on STIR imaging are useful for distinguishing between macro-metastatic and non-metastatic lymph nodes when enlarged nodes are detected by various other types of medical imaging.

Adenocarcinoma↗

Breast cancer detection and outcomes in a disability beneficiary population.

Women with disabilities may be at higher risk of late-stage breast cancer. Using the 1991-93 Medicare-Surveillance Epidemiology and End Results (SEER)-linked data set, the authors compared stage at diagnosis and mortality, for Social Security Disability Insurance (SSDI)-qualifying women and similarly aged non-SSDI qualifying women. Disabled patients were diagnosed at a later American Joint Committee on Cancer stage. Disabled patients had higher all-cause mortality rates but had similar breast cancer-specific mortality. Disabled women belonging to Medicare HMOs tended to have earlier stage diagnosis and better survival compared to Medicare fee-for-service (FFS) insurance. In conclusion, disabled patients tended to be diagnosed with breast cancer at a later stage and to have higher mortality. These findings were more pronounced in Medicare FFS than in Medicare HMOs.

Aged↗

Estrogen receptors in gallbladder cancer: detection by an improved immunohistochemical assay.

Although gallbladder carcinoma is the most common malignancy of the extrahepatic biliary tract, patients with this disease have a very poor prognosis. Previous investigations have documented the presence of estrogen receptors (ER) in gallbladder cancers for possible therapeutic benefit; however, the methods used for detection were largely imprecise, which led to a wide range of results. In light of these unclear results obtained with inferior techniques, we have attempted to determine more accurately the prevalence of ER positivity in gallbladder cancer using an improved, more specific immunohistochemical assay (IHA) for estrogen receptors. The IHA, which used a pronase pretreatment and the H222 monoclonal antibody, was performed on archival tumor specimens of 25 patients. There were no strongly or moderately positive specimens. Three specimens stained weakly positive, and 22 specimens (88%) were negative. The three specimens that were weakly positive showed neither statistical significance nor any identifiable trends with respect to patient sex, tumor stage, or histologic type. We conclude that, contrary to previous reports, weak estrogen receptor staining occurs in a very small percentage of gallbladder carcinomas. Furthermore, although the minimum concentration of ER required for potential therapeutic benefit is unclear, the addition of hormonal therapy in patients with gallbladder cancer is not likely to alter the outcome of this malignancy.

Aged↗

Diaphanoscopy and diaphanography for breast cancer detection in clinical practice.

Transillumination of the female breast has during the past few years been reintroduced as an aid in the diagnosis of breast lesions. A series of 259 women with symptoms from the breast were examined by mammography, clinical examination by two independent surgeons, diaphanoscopy by one of the surgeons, diaphanography, and fine needle aspiration biopsy of material taken from palpable tumours. The results were evaluated in order to ascertain the contribution made by transillumination procedures to the diagnosis of malignancy. Carcinoma of the breast was confirmed in 26 women. The malignancy was correctly suggested in 21 and 23 women, respectively, at clinical examination, in 19 by mammography, in 20 by diaphanoscopy, in 16 by diaphanography and in 20 by aspiration cytology. The number of false positive cases was high, especially with the transillumination procedures. All malignancies detected by diaphanoscopy were also believed to be carcinoma at the clinical examination. The three cancers falsely classified as benign at clinical examination were correctly identified as malignant only by mammography or cytology or both.

Adult↗