Teleradiology with satellite units - six years experience at the norwegian radium hospital.

UNLABELLED: Norway has played a leading role in Europe in applying telemedicine in health care services over the past two decades and is still in the forefront of developing telemedicine services both nationally and internationally. Today support for telemedicine comes mainly from the wish to meet the challenges of rising costs in health care. Critical obstacles for implementation of telemedicine techniques may by overcome easier by referring to the experience from other medical centers. A case in point is the six year experience of telemedicine at The Norwegian Radium Hospital, in distributing radiotherapy services to two satellite hospitals hundred kilometers far off. The main lesson learned is: the most serious obstacles are not technological but socio-psychological challenges and that staff up-dating, prior to implementation, is crucial. Case selections, routines, work flows and administrative solutions are described for the daily operations between the main clinic and the satellite units. IN CONCLUSION: radiotherapy service by telemedicine is feasible and cost effective. Standardization and quality assurance of radiotherapy at the quality level of a comprehensive cancer center can be offered to a much larger population and may play a role in improved cancer survival outcome.

The influence of resection and aneuploidy on mortality in oral leukoplakia.

BACKGROUND: Although the standard treatment of oral leukoplakia ranges from watchful waiting to complete resection, the value of these approaches is unknown. METHODS: We studied the relations among resection, ploidy status, and death from cancer in 103 patients with diploid dysplastic oral leukoplakia, 20 patients with tetraploid lesions, and 27 patients with aneuploid lesions. Data on cancer-specific mortality and treatment were obtained from the Cancer Registry of Norway, Statistics Norway, and chart reviews. RESULTS: Primary oral carcinoma developed in 47 of the 150 patients with leukoplakia (31 percent)--5 with diploid, 16 with tetraploid, and 26 with aneuploid leukoplakia--during a mean follow-up of 80 months (range, 4 to 237). The margin status of the initial leukoplakia resection had no relation to the development of oral cancer (P=0.95). Twenty-six of the 47 patients in whom cancer developed (4 with prior tetraploid and 22 with prior aneuploid lesions) had recurrences (55 percent); the recurrences were more frequently multiple and distant (within the oral cavity) among patients with aneuploid lesions than among those with tetraploid or diploid lesions. All 47 patients underwent a standard regimen of surgery and radiation, followed by chemotherapy in the 26 with recurrent cancer. Only patients with aneuploid leukoplakia died of oral cancer; the five-year rate of death from cancer was 72 percent. Aneuploidy-related first carcinomas were diagnosed at a more advanced stage than were carcinomas originating from diploid or tetraploid leukoplakia (P=0.03) and were more likely to be lethal regardless of the stage. CONCLUSIONS: Complete resection of aneuploid leukoplakia does not reduce the high risk of aggressive carcinoma and death from oral cancer.

Risk markers of oral cancer in clinically normal mucosa as an aid in smoking cessation counseling.

PURPOSE: Quitting smoking may prevent oral cancer. Behavioral intervention to quit smoking may be more efficient if persons are assigned an individual risk of cancer. PATIENTS AND METHODS: In this prospective study, we provided counseling and behavioral intervention toward smoking cessation, supplemented by genetic analyses in clinically normal oral mucosa of heavy smokers. Measurement of serum cotinine was used to assess changes in smoking habits. RESULTS: In cytologic scrapings from 275 heavy smokers with clinically normal mucosa, we found tetraploidy in four and aneuploidy in 19 persons (23 of 275; 8%). Twenty one (91%) of 23 persons with aneuploidy had quit or reduced their smoking habits at the 3-month follow-up, 20 (87%) of 23 persons had done so at 12 months, and 21 (91%) of 23 persons had done so at 24 months. Fifty-one (20%) of the 252 persons without genetic changes in their mucosa had quit or reduced their tobacco habits at the 3-month follow-up, 23 (9%) had done so at 12 months, and 17 (7%) had done so at 24 months (P < .001). After 24 months, normalization of DNA content to diploidy was observed in two of four persons with tetraploid (50%), and in 11 of 19 persons (58%) with aneuploid scrapings. One patient developed an oral carcinoma in the floor of the mouth: this patient had an aneuploid scraping obtained 43 months earlier and developed a leukoplakia 28 months before the carcinoma. CONCLUSION: Risk markers of oral cancer are present in clinically normal mucosa of heavy smokers, and such findings enhance the adherence to smoking cessation on counseling. Cytogenetic aberrations may normalize after quitting smoking.

[Retraction of: Diagnostics and treatment of early stages of oral cancer]. / Tilbaketrekking av: Diagnostikk og behandling av forstadier til munnhulekreft.

The undersigned, who are co-authors of the article Diagnostics and treatment of early stages of oral cancer, wish to retract it. The reason is that the basis for the review article has been shown to be false. A review committee, that has assessed the research activity of the main author, has concluded that the data in this article are fabricated. We can no longer stand behind the article and hereby retract it.

Gross genomic aberrations in precancers: clinical implications of a long-term follow-up study in oral erythroplakias.

PURPOSE: Gross genomic aberrations are increasingly seen as a cause rather than a consequence of carcinogenesis. Carcinomas may be prevented by systemically acting agents when used in high-risk individuals. If gross genomic aberrations could be shown to be predictive markers in precancers, they could serve as a tool for identifying high-risk individuals to be included in chemopreventive trials. PATIENTS AND METHODS: To investigate the predictive power of gross genomic aberrations in several types of oral premalignancies, we analyzed 57 biopsies from oral erythroplakias of 37 patients, both histologically and for DNA content. DNA content was measured by high-resolution image cytometry, and distribution histograms of DNA content were generated and interpreted according to established protocols. The primary end point was cancer-free survival. RESULTS: Fifty-seven dysplastic oral red lesions from 37 patients were investigated. Forty-one lesions from 25 patients were classified with aberrant DNA content (DNA aneuploidy), of which 23 patients (92%) later developed an oral carcinoma (after a median observation time of 53 months; range, 29 to 79 months). Of 12 patients having altogether 16 lesions with normal DNA content, none developed a carcinoma (median observation time, 98 months; range, 23 to 163 months; P <.001). In multivariate analysis, DNA content was a significant prognostic factor (P <.001), whereas histologic grade, sex, use of tobacco, size and location of lesions, and the presence multiple of lesions were not. CONCLUSION: Gross genomic aberrations are highly predictive for the subsequent occurrence of carcinomas from a wide range of oral premalignancies.

Biphasic chromatin structure and FISH signals in reflect intranuclear order.

BACKGROUND AND AIM: One of the two parental allelic genes may selectively be expressed, regulated by imprinting, X-inactivation or by other less known mechanisms. This study aims to reflect on such genetic mechanisms. MATERIALS AND METHODS: Slides from short term cultures or direct smears of blood, bone marrow and amniotic fluids were hybridized with FISH probes singly, combined or sequentially. Two to three hundred cells were examined from each preparation. RESULTS AND SIGNIFICANCE: A small number of cells (up to about 5%), more frequent in leukemia cases, showed the twin features: (1) nuclei with biphasic chromatin, one part decondensed and the other condensed; and (2) homologous FISH signals distributed equitably in those two regions. The biphasic chromatin structure with equitable distribution of the homologous FISH signals may correspond to the two sets of chromosomes, supporting observations on ploidywise intranuclear order. The decondensed chromatin may relate to enhanced transcriptions or advanced replications. CONCLUSIONS: Transcriptions of only one of the two parental genomes cause allelic exclusion. Genomes may switch with alternating monoallelic expression of biallelic genes as an efficient genetic mechanism. If genomes fail to switch, allelic exclusion may lead to malignancy. Similarly, a genome-wide monoallelic replication may tilt the balance of heterozygosity resulting in aneusomy, initiating early events in malignant transformation and in predicting cancer mortality.

Cyclooxygenase-2 (COX-2) expression in high-risk premalignant oral lesions.

Emerging data indicate a link between genetic instability and up-regulation of cyclooxygenase-2 (COX-2). To see if individuals at high risk of oral cancer are candidates for treatment with selective COX-2 inhibitors (coxibs), levels of COX-2 expression in healthy, premalignant and cancerous oral mucosa were compared with the occurrence of DNA ploidy status as a genetic risk marker of oral cancer. COX-2 gene product was evaluated immunohistochemically in 30 healthy persons, in 22 patients with dysplastic lesions without previous or concomitant carcinomas, and in 29 patients with oral carcinomas. The immunohistochemical findings were verified by western blotting. COX-2 expression was correlated to DNA content as a genetic risk marker of oral cancer. COX-2 was up-regulated from healthy to premalignant to cancerous oral mucosa. Thus, COX-2 expression was found in 1 case of healthy oral mucosa (3%). All specimens from healthy mucosa had a normal DNA content. In patients with premalignancies. In 29 patients with oral carcinomas, cyclooxygenase-2 expression was observed in 26 (88%), and aneuploidy was observed in 25 cases (94%, P=0.04). Notably, of 22 patients with dysplastic lesions, COX-2 was exclusively expressed in a subgroup of nine patients (41%) identified to be at high risk of cancer by the aberrant DNA content of their lesions. Seven of these patients were followed for 5 years or more. An oral carcinoma developed in six of them (85%; P=0.02). These findings emphasize the need to determine whether coxibs can reduce the risk of oral cancer in patients with high-risk precancerous lesions.

Molecular based treatment of oral cancer.

Given the increase in the age distribution of the population, an increase in cancer incidence rates are to be expected. Oral cancer is a disfiguring disease that continues to increase in incidence, particularly in the young, and to an extent that cannot be fully explained by increased exposure to known risk factors. Despite extensive research on treatment modalities towards oral cancer, the 5-year survival rate of this disease has not been improved over the last 4-5 decades. These facts strongly favour chemoprevention-systemic medication to revert, stop, or delay the carcinogenic process-as an approach to treating oral cancer. A chemopreventive approach to oral cancer most likely should encompass a combination of drugs targeting metabolic pathways relevant to oral carcinogenesis. Candidate drugs are retinoids and selective inhibitors of cyclooxygenase-2, epidermal growth factor receptor (EGFR), and peroxisome proliferator activated receptors (PPARs). Chemopreventive trials so far have used surrogate intermediate biomarkers as measurement of treatment effect. However, the efficiency of any drug for chemopreventive use should be assessed through a prospective randomized trial and evaluated by the only definitive end point for prevention of cancer, the incidence rates of new carcinomas.

Information technology in action: the example of Norway.

In Europe, Norway has played since the 1990 a pioneering role in applying telemedicine in healthcare services. 4.5 millions occupy a country nearly as large as the former West Germany with a coast line as long as the equator and stretching 2500 km from the south to the north. The most northern counties are very sparsely populated. Therefore the government decided to build a national research centre for telemedicine at the regional hospital of Tromsø north of the polar circle with the aim of exploring the new telemedicine techniques in the different branches of medicine. Later political support was based on the wish to increase quality and safety of diagnostic and therapeutic procedures and of saving costs.

The evolution of predictive oncology and molecular-based therapy for oral cancer prevention.

More than 300,000 new cases worldwide are being diagnosed with oral squamous cell carcinoma annually. This aggressive epithelial malignancy is associated with a high mortality and severe morbidity among the long-term survivors. The ability to intervene prior to this advanced stage may improve treatment results. This requires the early identification of molecular events that represent early phases of malignant transition, which is possible through measurement of DNA ploidy in epithelial cells of oral leukoplakia. Recently, we showed that patients with aneuploid dysplastic oral lesions had a 96% rate of oral cancer (26 of the 27 patients received the diagnosis) with a 70% rate within three years, an 81% rate of subsequent cancer (22 of 27), a 74% rate of death from cancer (21 of 27) and virtually no help from complete resection-all hallmarks of biologically aggressive cancer. Standard treatment of oral leukoplakia-a precursor lesion of oral cancer-varies from watchful waiting to complete resection. We have recently demonstrated that complete resection of aneuploid oral leukoplakia does not prevent the occurrence of clinically aggressive and highly lethal oral cancer. Oral carcinogenesis is a complex multifocal process of multiclonal field carcinogenesis and intraepithelial clonal spread. The multifocal nature of early oral carcinogenesis may hinder local treatment modalities. Inhibitors of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR), either alone or in combination, may be used for reversing or stopping the oral carcinogenesis at an early stage of disease. The failure of standard treatment to control aneuploid oral leukoplakia justifies clinical trials with new treatment modalities, such as systemic therapy with molecular targeting agents, which in patients with aggressive leukoplakia is tantamount to cancer therapy.

Volume-related sequence of tumor distribution pattern in prostate carcinoma: importance of posterior midline crossover in predicting tumor volume, extracapsular extension, and seminal vesicle invasion.

AIM: To evaluate intraprostatic distribution of prostate carcinoma as a function of increasing tumor size and its potential clinical relevance. METHODS: Forty-six prostates with different tumor extent were three dimensionally reconstructed and analyzed with emphasis on number of separate tumors (multifocality) and its distribution on both sides of the urethral midline (laterality). RESULTS: Three tumor distribution patterns were identified: multiple bilateral without posterior midline crossover, multiple bilateral with crossover, and single bilateral (global) tumors. Unilateral tumors were rare (2%). The pattern of tumor distribution was associated with total tumor volume, presence and volume of high grade component, presence of extracapsular extension, and seminal vesicle involvement. Bilateral tumors with crossover were larger than bilateral tumors without crossover (Spearman's rho=0,728, P<0.001) and were associated with adverse pathological features including capsular penetration, seminal vesicle invasion, and surgical margin involvement. However, only high-grade volume was independently and highly associated with seminal vesicle involvement (OR=2.64, 95%, CI=1.181-5.340, P<0.001). Total (OR=2.53 [1.23-3.74], P<0.001) and index tumor (OR=2.54 [1.31-4.93], P<0.001) volumes were independently associated with capsular penetration. CONCLUSIONS: The distribution of bilateral prostatic carcinomas with and without crossover may have clinical relevance because of their relation to total and high-grade volume.

Which putatively pre-malignant oral lesions become oral cancers? Clinical relevance of early targeting of high-risk individuals.

Oral squamous cell carcinomas continue to be a group of diseases with high mortality and increasing incidence rates, particularly among young individuals. This is a paradox finding, since most oral cancers are preceded - even by several years - by readily detectable mucosal changes, most often white or red patches (leukoplakias and erythroplakias, respectively). However, only a small fraction of leukoplakias or erythroplakias are related to cancer development, and the challenge has been to identify the high-risk lesions. From the vast literature on molecular markers in oral pre-cancer, no reliable prognostic marker for risk assessment in putatively pre-malignant lesions has emerged. For this reason, a wait-and-see approach has been adopted for this group of lesions. Recently published data point to gross genomic aberrations (DNA aneuploidy) as a tool for targeting patients at particular risk for future cancerous lesions in the oral cavity. Thus, DNA aneuploidy signalled a very high risk for subsequent development of carcinomas in a wide range of lesions from the oral mucous membrane, ranging from oral leukoplakias to oral erythroplakias and even including lesions that had been explicitly defined as being without a malignant potential by a group of trained pathologists. As an extension of research in oral pre-malignancies, the enzyme cyclooxygenase-2 (COX-2) seems to be enhanced specifically in high-risk oral lesions, as defined by the aberrant DNA content of their lesions. These data strongly indicate that COX-2 inhibitors (coxibs) should be investigated as chemopreventive agents in patients identified to be at high risk of developing oral cancer.

Impact of genomic instability in risk assessment and chemoprevention of oral premalignancies.

Head-and-neck cancer is a disfiguring disease with increasing incidence rates even in young people, whose exposure to known risk factors is limited. This emphasizes the importance of early identification, on an individual basis, of precursor lesions that will develop into carcinomas. The clinical value of identifying individuals at high risk of oral cancer is emphasized by the fact that these patients are likely to benefit from available chemopreventive measures, largely without adverse effects.