Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set.

BACKGROUND: A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool. PATIENTS AND METHODS: This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured. RESULTS: Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%). CONCLUSION: In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests. CLINICAL TRIAL NUMBER: NCT02889978.

Duplex sonography in the planning and evaluation of arteriovenous fistulae for haemodialysis.

This paper describes how to perform duplex sonography in the planning and evaluation of arteriovenous fistulae in haemodialysis patients, discusses its roles in these settings, and presents a review of commonly encountered complications.

Reproducibility of ultrasound blood flow measurement of the superior mesenteric artery before and after exercise.

This study examines the reproducibility of gastro-intestinal blood flow measurements in the superior mesenteric artery (SMA) both before and immediately after exercise with Doppler ultrasound measurements. Twelve well-trained males (mean +/- SD: age 25.9 +/- 3.8 yr; VO2max 4.8 +/- 0.91 x min(-1)) were measured twice (trial 1 and 2) with a 1 week interval before and immediately after 1 hr cycling at 70% VO2max. Duplex scanning was performed with the athletes in supine position immediately after transition from a chair (before exercise) or bicycle (after exercise). The variability of three measurements before exercise was studied within both trials (short-term reproducibility) and the mean pre-exercise values were compared between the trials (long-term reproducibility). In addition, post-exercise measurements were compared in the same way. Reproducibility was tested using the coefficient of variation and Cronbach's alpha. Mean pre-exercise blood flow was 424 +/- 66 ml/min (n = 12) in trial 1 and 375 +/- 38 ml/min (n = 11) in trial 2. Immediately after exercise blood flow had decreased by 49% to 214 +/- 36 ml/min (p <0.01) in trial 1 and by 38% to 234 +/- 36 ml/min (p < 0.01) in trial 2. Blood flow before and after exercise was not significantly different between trials (paired t-test) and therefore reproducible at the group level. Before exercise a good to fair reproducibility was observed both at the short-term (Cronbach's alpha: 0.88 in trial 1, 0.73 in trial 2, n = 11), and at the long-term (alpha = 0.80, n= 11). In contrast, long-term reproducibility immediately after exercise was poor (alpha = -0.99, n = 8 and alpha = 0.36, n = 7 after the first and second cycling period, respectively). In conclusion, duplex scanning of SMA after a sitting-supine transition in well-trained subjects is not a reproducible method at the individual level for intestinal blood flow measurements immediately after exercise.

Metastatic ocular melanoma to the left ventricle inducing near-syncope attacks in an 84-year-old woman.

Cardiac tumors may represent mechanical causes for syncope by limiting left ventricular filling and/or by obstructing the left ventricular outflow tract. Malignant melanoma is known to metastasize to the myocardium or pericardium, but there are only a very limited number of reports describing endocardial involvement by the tumor. We describe herein an 84-year-old woman who presented with daily near-syncope episodes, 9 years after treatment for a choroidal melanoma. The echocardiography and the pathologic examination revealed a metastatic melanoma. This is the first reported case of an ocular melanoma metastasizing to the heart and presenting as a left ventricular intracavitary pedunculated mass.

Pathology of transitional cell carcinoma of the bladder and its clinical implications.

Transitional cell carcinomas are divided into superficial and muscle-invasive tumors. Most of them are superficial tumors, and approximately 15-20% are muscle-invasive carcinomas. Pathologists play a significant role in diagnosing bladder tumors and in reporting features important for determining prognosis. We will review the cytologic and histopathologic features that help determine prognosis, including depth of invasion, tumor grade, multicentricity, tumor size, and the presence of vascular/lymphatic invasion, blood group antigen expression, proliferative indices, and molecular markers. Brief mention will be made of specimen handling, interpretation, reporting, and histologic variants of transitional cell carcinoma.

Pathologic prognostic parameters in bladder urothelial biopsy, transurethral resection, and cystectomy specimens.

Pathologists play an important role not only in diagnosing bladder tumors but also in reporting features important in determining prognosis. In this article, the authors review histopathologic features that may help determine prognosis including depth of invasion, grade of tumor, multicentricity, tumor size, and presence of (1) carcinoma in situ, (2) variant histological patterns, and (3) lymphatic and vascular invasion. The biology of bladder tumors is being extensively studied, and newer prognostic factors based on these molecular studies are emerging, some of which appear to show prognostic significance in limited clinical reports. Such factors as blood group antigen expression, proliferative indices, molecular markers, and new proposed techniques are discussed.

Appendiceal spirochetosis.

Appendiceal spirochetosis is rarely described in the literature. We assessed the incidence of spirochetosis in a series of 109 appendectomies (76 adult and 33 pediatric cases) done for either suspected acute appendicitis or as a concurrent procedure. Appendiceal spirochetosis was identified on hematoxylin-eosin sections and confirmed by Steiner and Steiner stain and ultrastructural study in two women and two men. One of these four patients was found to have HIV infection. The HIV status of the other three patients was unknown. We observed appendiceal spirochetosis to be an uncommon phenomenon that affects both sexes, occurring with or without symptoms of acute appendicitis. None of our four positive cases occurred in the pediatric age group.

Colour duplex ultrasonographic imaging and provocation of popliteal artery compression.

OBJECTIVES: Provoked compression of the popliteal artery by active plantar flexion of the foot is still mainstay in the assessment of the popliteal artery entrapment syndrome. In this study, the effects of several provocation manoeuvres of the foot on the flow patterns of the popliteal arteries of normal healthy volunteers were evaluated. DESIGN: Experimental study among healthy volunteers in a vascular laboratory. MATERIALS AND METHODS: The popliteal artery of 16 healthy volunteers was studied with Duplex scanning in rest and during active and passive plantar and dorsal flexion of the foot. RESULTS: Active plantar flexion was the only movement that influenced popliteal artery flow patterns. Changes were found in 27 arteries (85%), consisting of either a complete occlusion (n = 19, 59%), a significant lumen reduction (n = 4, 13%) or a low flow state (n = 4, 13%). CONCLUSION: Compression of the popliteal artery by active plantar flexion of the foot is a physiologic phenomenon and its value in the assessment of patients suspected of the popliteal artery entrapment syndrome is limited.

An audit of the quality of cancer registration data.

The accuracy of cancer registration data in the East of Scotland (Tayside) Cancer Registry was audited by comparing 200 consecutive registrations (about 10% of the annual total) with the 'gold standard' of the Histopathology records. ICD codes were independently generated by a pathologist by examining final pathology reports and then compared to those codes given by the local cancer registrar. Discrepancies were graded by the pathologist and the epidemiologist according to severity. Major errors of coding were few. Minor and moderate differences in coding occurred because of the nature and structure of the coding system and the manner in which data are retrieved. The level of detail required by the Cancer Registry needs to be evaluated.

Personality assessment of the prelingual, profoundly deaf child or adolescent.

Personality assessment of children and adolescents experiencing an early, profound hearing loss is hampered by the lack of instruments standardized and/or developed primarily for use with deaf clients. Further compounding the problem are the relatively few psychologists trained in and/or experienced with deaf personality assessment. This article reviews the rudimentary requirements for personality assessment with the deaf and critiques the available personality tests that are either used or useable in assessing the deaf.

Contraceptive prevalence: the influence of organized family planning programs.

Estimates of contraceptive prevalence for the period 1977-1983 are presented for 73 less developed countries. Socioeconomic conditions are associated with much of the variance in prevalence, but organized family planning programs strengthened this association significantly. The average percent of couples in the reproductive ages practicing fertility regulation is 26, with the range from 4 to 55 percent between the low and high socioeconomic groups of countries, and from 7 to 59 percent between groups of countries with very weak (if any) to strong family planning program effort.

Family planning program: world review 1974. Introduction.

PIP: The 1974 Population Conference at Bucharest was marked with controversy between developed and developing countries, with the latter strongly critical of aid for population control but less for social and economic development. The Plan of Action which was finally approved emphasized the importance of social and economic factors in relation to population growth while recommending that couples in all nations should have access to family planning information. Different regions of the world, however, have widely divergent population policies and goals. The Asia-Pacific region of the developing world, which has 3/4 of the population of the developing world, has articulated a strong stance in favor of reducing birth rates at Post-Bucharest Consultation. Government-supported family planning programs are seen as a high priority item to reduce rapid population growth. Rapid population growth is not seen as a high-priority problem in most African, Arab, and Latin American countries. Population problems will be solved with economic and social advancement. There is more concern in Latin America for family planning as a "human right" issue than to promote demographic goals. Latin America was also concerned with migration/urbanization issues. All of the Regional Consultations after Bucharest favored a greater emphasis on population in development planning, concern for the problems caused by migration and urbanization, improvement in the status of women, and support for the reduction of mortality levels. Some 74 countries containing 93% of the population of the developing world, supported family planning, with only 4 populous countries -- Burma, Ethiopia, Peru, and North Korea not in support. More than 98% of the population of Asia lives in countries which support family planning; the figures are 94% for Latin America, 90% for the Middle East and North Africa and 64% for Sub-Saharan Africa. The governments of 39 countries with a combined population of 2.3 billion have stated that rapid population growth is detrimental to the rapid attainment of social and economic development; 35 additional developing countries favor family planning as a basic human right, to improve the status of women, and for health reasons. There is a wide range of acceptance rates for contraceptives among the developing countries with gains shown for most countries between 1972 and 1974. There is a strong pattern of fertility decline in 11 East Asian and Latin American countries plus Mauritius. Induced abortion countries to be a major means of birth control even in countries where it is illegal. Legal access to abortion on broad grounds is available in China, North Vietnam, Tunisia, Singapore, India, Zambia, and Hong Kong. It seems likely that liberalization of abortion laws will occur in more developing countries in the near future for health reasons as well as for demographic reasons.^ieng

Fertility reduction in an MCH/family planning program: a model for projection.

One of the important questions in an integrated maternal and child health/family planning program is the likely effects on fertility rates if given proportions of a stated target population can be reached and provided with family planning services. The question is easy, but the process of obtaining viable estimates of potential fertility decline from this type of program is complicated. First of all, the number of women in the target population must be estimated. Next, it is necessary to make various assumptions and estimates concering the types of contraceptives accepted, the age distribution of acceptors, the sets of continuation rates that go with each age/method specific group of women, and a variety of other factors. This article describes and illustrates a procedure for estimating potential fertility declines with an integrated maternal and child health/family planning program.

A program for family planning based on maternal-child health services.

PIP: The Population Council set up as a reference framework for a study an organizational model postulating the number of doctors, midwives, and field workers, the type and number of Maternal/Child Health (MCH) centers needed for given units of population. An extrapolation cost of providing MCH services with family planning was about 1 billion dollars for the women in the developing world. Six projects have been developed in a number of countries. Principles of operation for the delivery of family planning from an MCH base include: 1) integration of family planning with MCH; 2) size and location of project areas; 3) the target population; 4) subdivisions of target groups; 5) replicability; 6) evaluation. Evaluation of the project should provide answers to: 1) success of the program in delivering specified services, 2) results of the program in terms of health and fertility, 3) effectiveness of the program as a family planning delivery service. Programs are proposed for Indonesia (Java), Turkey (Yozgat), the Philippines (Bohol), Egypt (Behlira Governorate), Brazil (Rio Grande do Norte), and Bangladesh.^ieng

Family planning in Tunisia and Morocco: a summary and evaluation of the recent record.

PIP: Family planning activity during 1969-1970 in Morocco and Tunisia is discussed in terms of 12 criteria (such as leadership, educational services, availability) used to evaluate the programs in the 2 countries. Significant differences between family planning activity in the 2 countries can be seen in the nature of involvement of their governments through the open and public endorsement of family planning by Tunisia's president compared to the reserve of Morocco's king. Although family planning programs in both countries are organized within the Ministries of Health, the Tunisian program is conducted by a separate division, the Department of Family Planning and Maternal and Child Health, while Morocco's program is completely integrated within existing health services, a fusion which seems to create financial problems for the Moroccan family planning efforts. The Tunisian program, when compared to that of Morocco, is also characterized by a greater availability of contraceptives, more postpartum education and information activity, available induced-abortion and sterilization services, more widespread use of mass media and communication techniques and greater success in program evaluation. On a population basis, Tunisia (population of 5.2 million in 1970) has about 3 times the number of acceptors as Morocco (population of 15.4 million). Both programs have record-keeping systems which improved considerably during 1969 and 1970, but neither program has an effective field worker network. While Tunisia's program has demonstrated more success in meeting the criteria than Morocco's program and a slight decline has occurred in the crude birth rate in Tunisia in recent years, much of this decline can be attributed to a rising age at marriage resulting from the government's policies of social development. Evaluation indicated that both countries will have to increase availability of contraceptives and encourage effective use if substantial decreases in the crude birth rate are to be achieved.^ieng

Population policies in the Maghreb.

PIP: The population policies of 3 North African countries are reviewed: Morocco, Algeria, and Tunisia. There are about 15.5 million persons in Morocco, 14.2 million in Algeria, and 5.2 million in Tunisia, with current growth rates over 3% in the 2 larger nations, and probably 2.7% in Tunisia. The population policies of the 3 countries are quite different. In Tunisia there has been considerable social progress for women plus a vigorous and open concern with population growth. There exists a definite and expanding family planning program. In Morocco there is government policy to reduce population growth via family planning, but the efforts to fulfill this policy are weak. In Algeria research and study are being carried out to obtain more and better data on population growth and related subjects. There is also an avowed policy of economic development as the solution to lower fertility. None of the countries proclaims as policy that it does not have enough people and should seek to increase fertility or in-migration. The author believes that the organized family planning effort began in Tunisia at about the right time. Morocco, however, may have started its family planning program too early, with the result that not only is there very slow program development, but maybe the long-term goal of reduced fertility is pushed a bit further into the future by what might be termed a semi-false start. The author suggests that it would be unwise for the Algerian government to begin an organized family planning program now and even more unwise for outside agencies and organizations to urge it to do so. In the Maghreb, the 2 countries with organized family planning programs want them, and the 1 country without does not want one. The author ends with the question of what and whose criteria are to be utilized in cases in which external agencies are asked for population program assistance once a government decides that it wants a program for its people.^ieng