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Evaluating the breast screening programme: the need for surgical audit.

It is to be anticipated that a reduction in population mortality attributable to mammographic screening would be heralded by an increasing proportion of breast cancer cases diagnosed at earlier stages and by an improvement in case fatality. Few cancer registers routinely produce incidence or survival data by stage at diagnosis and thus improvement in these will be the harder to assess. By thorough casenote review and follow up, this study has determined the usual presentation and survival of breast cancer in Northern Ireland in 1986 before the introduction of screening. Overall, 85% of cases were Manchester stage I or II, figures which accord with other British studies. Five-year survival ranged from 77.8% for stage I (95% confidence limits 71.7%, 82.7%) to 35.7% for stage IV (95% confidence limits 13.0%, 59.4%). Forty-three per cent of cases treated in non-teaching hospitals could not be pathologically staged, more than twice the figure for teaching hospitals (Chi-squared = 15.7, df = 1, P < 0.001). Since many tumours not detected by screening will be treated outside teaching centres, this difference will reduce the statistical power to detect the true shift in stage distribution and improvement in survival from screening. Comprehensive surgical audit would help to resolve the inadequacies in existing data collection and improve the ability to evaluate the outcome of the screening programme.

Adult↗

NAD+ Metabolism Licenses Zygotic Genome Activation via PARP7-Mediated ADP-Ribosylation of UHRF1 in Mouse Early Embryos.

Zygotic genome activation (ZGA) is a critical developmental milestone whose metabolic regulation remains unclear. This study identifies a pivotal role for Nicotinamide adenine dinucleotide (NAD+) metabolism in regulating ZGA through poly(ADP&#x2011;ribose) polymerase 7(PARP7)-mediated ADP-ribosylation. Using ultra-low input embryo metabolomics, we profiled metabolism from zygote to blastocyst, revealing a significant NAD+ decline at the 2-cell stage. This shift coincided with specific upregulation of the mono-ADP-ribosyltransferase PARP7, confirmed by transcriptomics, quantitative RT-PCR, western blot, and immunofluorescence. Genetic knockdown via trim-away technology or pharmacological inhibition with RBN-2397 caused developmental delay/arrest at the 2-cell stage, impaired blastocyst formation, and defective ZGA. Mechanistically, PARP7 deficiency reduced chromatin accessibility (ATAC-seq), diminished H3K4ac and H3K27ac marks, and impaired RNA polymerase II transcription. Integrated proteomics and ADP-ribosylome analysis of late 2-cell embryos identified UHRF1 as a key PARP7 target, mono-ADP-ribosylated at lysines K30 and K31. This modification stabilized UHRF1 protein (cycloheximide chase), and UHRF1 overexpression partially rescued the transcriptional defects associated with ZGA from PARP7 inhibition. Our findings establish a metabolic-epigenetic axis wherein NAD+ metabolism, via PARP7-mediated ADP-ribosylation of UHRF1, regulates chromatin remodeling and transcriptional activation during ZGA, offering fundamental insights into early development.

Animals↗

Gastric cancer in young patients.

BACKGROUND: Delayed diagnosis, a high rate of histologically undifferentiated types of tumors, and rapid disease progression are frequently cited as the main reasons for the poor prognosis of gastric cancer in young patients. An improved prognosis has been anticipated for young gastric cancer patients because of recent improvements in digestive tract diagnostic techniques. This retrospective study was designed to determine whether these trends have had an impact on young Japanese patients with gastric cancer, and to further elucidate differences in clinicopathologic features between elderly and young patients. METHODS: From 1984 to 1995, 1654 patients with gastric cancer were admitted to our hospital. Of these, 86 patients (5.2%) were less than 40 years of age (young group). The clinicopathologic features of this young group were reviewed retrospectively, using hospital records, and compared with those of older patients (n = 499 [29.4%], 60 to 69 years of age). RESULTS: The young group contained significantly higher percentages of female patients, epigastric pain symptoms, depressed superficial type lesions, mucosal invasion, and poorly differentiated histology; percentages of hepatic metastasis and venous invasion were lower. Survival rates for all patients and for the resected cases were significantly better in the young group (p = 0.035 and 0.017 respectively). The percentage of early stage stomach cancers for the group less than 40 years of age was 49.0% in 1984-89, but had risen to 60.9% by 1990-95. CONCLUSIONS: Early diagnosis has improved the prognosis of young gastric cancer patients. Furthermore, these data show a recent shift in stage distribution; additional prognostic improvement is anticipated for young patients with early gastric cancer.

Adult↗

Prevention and management of early esophageal cancer.

Early esophageal cancer is defined by its limitation to the esophageal mucosa and submucosa. It has become a curable malignant disease, in sharp contrast to the dismal prognosis of esophageal cancer at advanced stages, which still represents the majority of patients. Understanding the risk factors, establishing surveillance programs for patients at risk, and developing preventative interventions such as dietary and lifestyle changes or pharmacologic interventions hold the potential of reducing the incidence of the disease and of shifting the stage distribution toward early cancer. Endoscopic ultrasound examination is pivotal for distinguishing early from advanced stages of the disease because it allows for accurate assessment of tumor infiltration and regional lymph node involvement. The therapeutic mainstay for early esophageal cancer remains surgery. New, less invasive surgical techniques are being tested that are associated with less morbidity and mortality than standard radical esophagectomies. For patients who are not candidates for surgery, definitive chemoradiation is a viable alternative. New endoscopic ablation techniques, such as endoscopic mucosa resection and photodynamic therapy, are potential alternatives to surgery in patients with cancers limited to the mucosa. For patients with adenocarcinoma of the gastroesophageal junction with submucosal involvement, adjuvant chemoradiation should be considered because of its potential to increase survival.

Adenocarcinoma↗

[Lactate dehydrogenase and creatine kinase activity in nerve compression and myodystrophic syndromes of lumbar osteochondrosis].

The blood serum lactate dehydrogenase (LDH), creatine kinase (CK), and LDH isoforms activities have been measured in 103 patients with the compression neural and myodystrophic syndromes of lumbar osteochondrosis. The studies have revealed a relationship between the myodystrophic process severity and the intensity of LDH and CK ejection from the muscle into the blood, particularly in the trigger stage. The shift of LDH activity towards the predominance of slowly migrating isoforms augments and the total blood serum LDH and CK activities grow as the muscular syndrome progresses. These data permit a differentiation between the compression neural and the myodystrophic syndromes, as well as between the algic and the trigger stages of muscle involvement. Such a differentiation does not involve biopsy in many cases.

Adult↗

National trends in the epidemiology of prostate cancer, 1973 to 1994: evidence for the effectiveness of prostate-specific antigen screening.

OBJECTIVES: The use of prostate-specific antigen (PSA) to screen for prostate cancer remains controversial. Although it is still too early to measure directly the effects of PSA screening on mortality, we examined changes in the epidemiology of prostate cancer to determine if there is other evidence of the effectiveness of PSA as a screening tool. METHODS: We examined trends in age at diagnosis, and age-adjusted trends in stage and grade at diagnosis, for 140,936 white and 15,662 African American men diagnosed with prostate cancer from 1973 to 1994 in the National Cancer Institute's Surveillance Epidemiology and End Results data base. RESULTS: We found a significant downward trend in age at diagnosis, concomitant with a downward shift in stage of disease at diagnosis, starting with the advent of the PSA era in the late 1980s. We noted most cancers detected since the PSA era to be moderately well differentiated (International Classification of Diseases of the World Health Organization grade 2; Gleason score 5, 6, 7) and organ confined. Although findings were similar for both whites and African Americans, African Americans experienced a greater increase in poorly differentiated disease than did whites. CONCLUSIONS: Changes in the epidemiology of prostate cancer since the advent of the PSA era are consistent with the introduction of an effective screening test. This is evidenced by an increase in detection of significant prostate cancer in individuals who will likely benefit from treatment.

Aged↗

The rate of phase shift of plasma corticosterone circadian rhythm during early developmental stages in neonatally blinded rats.

The phase shift of circadian periodicity of pituitary-adrenocortical activity was studied in neonatally blinded infant rats. The phase shift of the rhythm was surprisingly rapid during the early stage of prepubertal period, while changes in the rhythm pattern were rather small after puberty, as indicated by a slight shift of the acrophase. Low amplitude was observed in the group data of blinded rats after puberty.

Age Factors↗

Stage, age, comorbidity, and direct costs of colon, prostate, and breast cancer care.

PURPOSE: This study was conducted to evaluate the effect of stage at diagnosis, age, and level of comorbidity (presence of other illness) on the costs of treating three types of cancer among members of a health maintenance organization. METHODS: Among 388,000 members enrolled anytime during 1990 and 1991 in Group Health Cooperative (GHC) of Puget Sound (Washington State), we estimated the total and net direct costs of medical care for colon, prostate, and breast cancers, including both incident (290, 554, and 645 patients, respectively) and prevalent (1046, 1295, and 2299 patients, respectively) cases. We summarized costs for initial, continuing, and terminal phases of care. Net costs were the difference between the costs of the care of each case subject and the average costs of the care for all enrollees without the cancer of interest who were of the same sex and in the same 5-year age group. Differences in estimated total and net costs by stage at diagnosis, age, and comorbidity were separately evaluated using multivariate regression modeling. All P values were two-sided. Comorbidity was based on a score calculated from 1988 pharmacy data. RESULTS: Total costs of initial care increased with stage at diagnosis for colon (P = .0013) and breast (P < .0001) cancer cases, but not for prostate cancer cases. Total initial costs decreased with age for prostate (P = .0225) and breast (P = .0002) cancers but did not change with degree of comorbidity for any of the three cancers. Total continuing medical care costs increased with stage at diagnosis for colon (P < .0001) and breast (P < .0001) cancer cases but not for prostate cancer cases. Total terminal care costs were similar by stage for all three cancers. Net initial costs differed with stage for all three cancers (P < .05). Net continuing care costs increased with stage (P < .0001) and decreased with age (P < .001) for colon and breast cancers but not for prostate cancer. Net continuing care costs decreased with comorbidity for all three cancers (P = .004, P = .011, and P < .0001 for colon, prostate, and breast cancers, respectively). Among regional stage cancers, continuing care costs decreased with age for colon (P < .0017) and breast (P = .033) cancers but not for prostate cancers. CONCLUSIONS: The results show that total costs vary by stage at diagnosis and age, but the patterns of variation differ for each cancer. Costs of cancer are not simply additive to costs of other conditions. IMPLICATIONS: More needs to be done to explore the reasons and implications of age-related cost differences. Cost-effectiveness analyses of cancer control interventions that shift cancer stage distributions may need to consider both the age and comorbidity of the target populations.

Adult↗

Detection of expanded T cell clones in skin biopsy samples of patients with lichen sclerosus et atrophicus by T cell receptor-gamma polymerase chain reaction assays.

Lichen sclerosus et atrophicus is a chronic dermatosis of unknown etiology and pathogenesis. Lichen sclerosus et atrophicus associated skin lesions show T cell enriched infiltrates, sometimes resembling the histologic picture of early mycosis fungoides. It is supposed that the infiltrating T cells participate in the pathogenesis of atrophy and sclerosis. We investigated skin biopsies from 39 lichen sclerosus et atrophicus patients by histology, immunohistochemistry and, in order to establish the status of T cell clonality, by polymerase chain reaction amplifying the T cell receptor-gamma rearrangements. A stage-dependent shift of the CD3-positive T cells was observed from a predominantly CD4-positive to a predominantly CD8-positive phenotype. The increase of CD8-positive cells was associated with more pronounced epidermotropism and basal degeneration. Nearly all CD8-positive cells expressed cytotoxic granules (TIA1), possibly causing the basal destruction. In the late fibrotic stage of the disease, only a weak or no infiltrate was found. Regarding the T cell receptor-gamma polymerase chain reaction, the presence of clonally expanded T cells was demonstrated in 19 of 39 patients (49%) by at least one of two different high resolution electrophoresis techniques applied to separate the amplification products. Thus, for the first time clonally expanded infiltrating T cells were detected in lichen sclerosus et atrophicus. Furthermore, this is one of the first reports on the detection of clonally expanded infiltrating T cells in an inflammatory skin disease. The clonal T cells could not be assigned to the CD4 or CD8 subtype. Most likely, their presence is not the result of a malignant transformation but a response to an as yet unknown lichen sclerosus et atrophicus associated antigen.

Adult↗

Paroxysmal atrial fibrillation in sleep.

Thirty-eight patients with lone paroxysmal atrial fibrillation (PAF) were monitored during spontaneous sleep. The starts of 111 episodes of atrial fibrillation (AF) occurred in 12 patients. Statistical analysis failed to disclose significant differences in the number of starts per hour between wakefulness and the different sleep stages. Heart rate (HR) in the 60 seconds prior to a PAF episode did not show significant changes with respect to fragments of recording taken away from PAF episodes. As expected, spectral analysis of HR variability during sleep (basal values) showed a reduction of low frequency/high frequency (LF/HF) ratio during slow sleep, while the ratio returned to values similar to wake levels during REM sleep. In the 2 minutes preceding a PAF episode the LF/HF ratio of the spectral power was more unstable with a clear-cut prevalence of sympathetic activity both in wake and in different sleep stages. A shift toward parasympathetic activation was never seen before the start of any of the 17 PAF episodes recorded during sleep.

Adult↗

Cytokines and cutaneous T-cell lymphomas.

Cytokines are considered to be of major importance for the pathogenesis of cutaneous T-cell lymphomas (CTCL). Their impact may result from autocrine, paracrine or endocrine effects. Several investigations demonstrated the overexpression of different cytokines in different CTCL entities. Interestingly, stage-dependent shifts in the cytokine pattern have been observed in mycosis fungoides (MF). There is evidence that the abnormal cytokine expression in CTCL might be responsible for tumor progression, resulting from an enhanced proliferation of the malignant cells and/or the depression of the anti-tumor immune response. Moreover, cytokine loops might explain phenomena like the epidermotropism of malignant cells or eosinophilia and increased plasma levels of IgE, which are present in advanced stages of CTCL. Analysis of the cytokine pattern in CTCL might give the basis for direct therapeutic intervention into the cytokine network as a new therapeutic approach. In this review, the current knowledge regarding cytokines in CTCL is summarized.

Cytokines↗

A comparison of staging systems for squamous cell carcinoma of the vulva.

A review of 172 patients with squamous cell cancer of the vulva treated at the University of Michigan Medical Center from 1975-1989 was performed to compare the 1988 FIGO Staging System to the 1970 FIGO Staging System. The stage distribution according to the 1970 FIGO Staging System was stage I, 65; stage II, 44; stage III, 50; and stage IV, 13. The cumulative 5-year survival under the old system was stage I, 94%; stage II, 91%; stage III, 36%; and stage IV, 26%. The distribution changed under the 1988 FIGO system to stage I, 58; stage II, 36; stage III, 49; stage IVA, 16; and stage IVB, 13. The cumulative survival also changed to stage I, 94%; stage II, 89%; stage III, 71%; stage IVA, 19%; and stage IVB, 8%. The new FIGO stage distribution shifted for the worse due to the influence of positive lymph nodes found at the time of surgery. The survival was then analyzed for death from all causes. This was markedly decreased when compared to the cumulative corrected survival. This relates to the high number of other primary malignancies and the age of the patients. Among these 172 patients, other primary malignancies included squamous cell cancer of the cervix (11), squamous cell cancer of the vagina (2), endometrial cancer (3), squamous cell cancer of the lung (2), colon cancer (3), and others (6). An additional 5 patients died from myocardial infarction within 2 years of diagnosis. The new 1988 FIGO Staging System provides for better discrimination of survival between stages than the 1970 FIGO Staging System.

Carcinoma, Squamous Cell↗

Computer expert systems for African-American smokers in physicians offices: a feasibility study.

BACKGROUND: Stage-based computer expert systems (CES), delivered in physician offices, may offer unique opportunities to combine high participation and high efficacy, resulting in a high public health impact. Applying this technology in settings serving low-income African-American smokers, with the addition of practical tools for stress reduction, may help to reduce disparities in morbidity and mortality from smoking-related diseases. METHODS: Ninety-eight African-American smokers were recruited from a publicly funded, continuity care clinic waiting room to a study of computer interactive feedback and stress reduction audiotapes. The study was designed to assess: participation and retention rates; acceptability of both the computer expert system and the audiotapes; the fit of the transtheoretical model for the target population; and the 6-month shift in stages of change. RESULTS: Overall, 55.6% of invited smokers participated, 75.5% were seen at all three observation points. The CES and the audiotape were rated as highly interesting, relevant, and new, and most participants tried them. The predictable relationship between stage and decisional balance was reproduced in this low income African-American population. Significant stage progression occurred from baseline to 3 months (P = 0.011), from 3 to 6 months (P = 0.0001), and from baseline to 6 months (P = 0.0001). CONCLUSIONS: These data support the feasibility, acceptability and potential efficacy of stage-tailored computer interactive feedback plus stress reduction intervention delivered at the point of service to low-income African-Americans.

Black or African American↗

Can varicocelectomy significantly change the way couples use assisted reproductive technologies?

PURPOSE: We assessed how varicocelectomy alters semen quality in a large cohort of infertile men and determined whether it can change patient candidacy for assisted reproductive technology procedures. MATERIALS AND METHODS: A cohort of 540 infertile men with clinical palpable varicocele underwent microsurgical varicocelectomy and were followed more than 1 and 2 years postoperatively for alterations in semen quality and conception, respectively. Preoperatively and postoperatively the total motile sperm count was calculated in all semen analyses. Based on total motile sperm count values patients were divided into 4 groups according to the type of assisted reproductive technology for which they qualified, including 0 to 1.5 million or less (intracytoplasmic sperm injection candidates), 1.5 to 5 million or less (in vitro fertilization candidates), 5 to less than 20 million (intrauterine insemination candidates) and 20 million or greater sperm (spontaneous pregnancy candidates). Preoperative and postoperative semen quality was compared among individuals in these cohorts to determine the shifts in assisted reproductive technology care that are possible after varicolectomy. RESULTS: Mean patient age was 29.5 years (range 18 to 58). Microsurgical varicocelectomy was bilateral in 393 patients (73%), on the left side in 146 (27%) and on the right side in 1 (0.2%). A positive response to varicocelectomy, defined as a greater than 50% increase in total motile sperm count, was observed in 271 patients (50%). An overall spontaneous pregnancy rate of 36.6% was achieved after varicocelectomy with a mean time to conception of 7 months (range 1 to 19). Of preoperative in vitro fertilization and intracytoplasmic sperm injection candidates 31% became intrauterine insemination or spontaneous pregnancy candidates after varicolectomy. Of intrauterine insemination candidates 42% gained the potential for spontaneous pregnancy. CONCLUSIONS: Varicocelectomy has significant potential not only to obviate the need for assisted reproductive technology, but also to down stage or shift the level of assisted reproductive technology needed to bypass male factor infertility.

Adolescent↗

Changes in students' moral development during medical school: a cohort study.

INTRODUCTION: The requirements of professionalism and the expected qualities of medical staff, including high moral character, motivate institutions to care about the ethical development of students during their medical education. We assessed progress in moral reasoning in a cohort of medical students over the first 3 years of their education. METHODS: We invited all 92 medical students enrolled at the University of Sherbrooke, Que., to complete a questionnaire on moral reasoning at the start of their first year of medical school and at the end of their third year. We used the French version of Kohlberg's Moral Judgment Interview. Responses to the questionnaire were coded by stage of moral development, and weighted average scores were assigned according to frequency of use of each stage. RESULTS: Of the 92 medical students, 54 completed the questionnaire in the fall of the first year and again at the end of their third year. The average age of the students at the end of the third year was 21 years, and 79% of the students included in the study were women. Over the 3-year period, the stage of moral development did not change substantially (i.e., by more than half a stage) for 39 (72%) of the students, shifted to a lower stage for 7 (13%) and shifted to a higher stage for 8 (15%). The overall mean change in stage was not significant (from mean 3.46 in year 1 to 3.48 in year 3, p = 0.86); however, the overall mean change in weighted average scores showed a significant decline in moral development (p = 0.028). INTERPRETATION: Temporal variations in students' scores show a levelling process of their moral reasoning. This finding prompts us to ask whether a hidden curriculum exists in the structure of medical education that inhibits rather than facilitates the development of moral reasoning.

Adult↗

Cancer trends in Sweden until 2010.

To arrive at a reasonable estimate of the total need for radiotherapy, the various descriptions of population trends and measures of cancer trends must be studied concurrently. Incidence and mortality are well documented by official statistics. All prognoses are based on these measures, the official population statistics, and the 1989 population prognosis from Statistics Sweden. Incidence, mortality, and prevalence may be considered either individually or together as indirect measures of the need for radiotherapy at different stages for different types of cancer. Incidence, ie, the number of cases of disease onset during a given period, shows the indirect need for curative radiotherapy, eg, for breast cancer, laryngeal cancer, gynecological tumor types, and head and neck cancer. The projected average annual mean increase in total incidence is 1.0%. Mortality may be used as an indirect measure of the need for palliative treatment for recurring cancer, eg, for bone metastases, prostate cancer, lung cancer, or breast cancer. The mean increase is estimated at 0.9% per year. Likewise, prevalence can be an indirect measure of the need for palliative treatment for cancer diseases of a chronic nature, eg, prostate cancer and multiple myeloma. The total mean increase per year has been estimated at 2.0%. The total need for radiotherapy in the future should be viewed against the background of all these descriptive measures. Assessment must also consider numerous other factors that directly influence need. A change in the indications for treatment can quickly increase the need for radiotherapy, eg, the benefits of radiotherapy for noninvasive breast cancer are currently being studied. Even a change in the indications for surgical intervention for small tumors in the breast influence the need for primary curative radiotherapy in this large group of patients. Likewise, a shift in staging the primary diagnosis, eg, in head and neck cancer, and changes in fractionation (hyperfractionation) may substantially influence need. This is addressed further in another section of the report. The largest single group of cancer patients who receive radiotherapy are those with bone metastases (25% of the total). The size of this group, and thereby the potential unsatisfied need, is largely unknown since no statistics show the prevalence of metastases in the population. This group is comprised mainly of patients that were primarily diagnosed with prostate cancer, breast cancer, and lung cancer. Concerning lung cancer, incidence trends probably provide the best measure of changes in the number of bone metastases over time. The annual increase in incidence has been estimated at 1.5%. As for breast cancer and prostate cancer, mortality trends provide more information about trends in the number of bone metastases. Both types of cancer increased by 1.9% per year. Chapter 6 presents the types of cancer for which radiotherapy is usually given. The projected trends show that each of these cancer diagnoses, except lung cancer in men and cervical cancer in women, are expected to increase in number until the year 2010. Prevalence is expected to increase even more, particularly cancer in the rectum, breast, and prostate. Also, the number of cases of non-Hodgkin's lymphoma is expected to nearly double by 2010.

Adult↗

Prostate cancer facts and fiction.

1. The observed increase in prostate cancer incidence followed by a decrease, was not an epidemic, but the result of generalized prostate cancer screening in the United States. 2. The increase showed a shift in stage, to mainly early disease in grade 2 (Gleason's 4-6) clinically significant cancers with a decrease in advanced disease. 3. There was an increase in the use of radical prostatectomy, mainly in men 40 to 75 years of age with a 10-year relative survival rate of 100%. It appears that 15% were grade 1 cancers and in the absence of more information may have been clinically unimportant. 4. There was a 20% increase in the overall relative survival rate for prostate cancer. 5. There was a decrease in the incidence of advanced disease followed by a 6.3% decrease in the United States mortality rate for prostate cancer. 6. It appears that an annual PSA blood test and a DRE on all men over 50 years of age followed by appropriate treatment has decreased deaths from prostate cancer.

Adult↗

Improvements in the treatment and prognosis of colorectal carcinoma.

In a survey of the surgical results in 709 patients with colorectal carcinoma (CRC) treated between 1976 and 1985 a favourable shift of stage distribution was observed. The tumour was localized (Dukes' classification A or B) in 61 per cent of patients, as compared with 47 per cent in the previous 10-year period. This change was, in part, due to different interpretation of stage definitions. Clear improvements of the results were, however, also noted. Radical surgery was possible in 76 per cent of patients and the primary tumour was removed in 93 per cent. Surgical mortality was 4.4 per cent and complication rate 15 per cent, significantly less than earlier (6.5 and 38 per cent, respectively). Increasing numbers of sphincter-saving operations were performed in rectal cancers (47 per cent as compared with 24 per cent in the previous 10-year period). The overall 5-year survival rate improved from 40.5 to 52.5 per cent. Premalignant conditions were identified in 12.6 per cent of patients: previous CRC 4.8 per cent, cancer family syndrome 4.1 per cent, ulcerative colitis 1.7 per cent and familial adenomatosis 0.6 per cent. In order to sustain the favourable trend of improving survival prospects, more emphasis must be directed to the detection of early stage cancers.

Adult↗