FOLFCIS Treatment and Genomic Correlates of Response in Advanced Anal Squamous Cell Cancer

Background

Treatment of advanced anal squamous cell cancer (SCC) is usually with the combination of cisplatin and 5-fluorouracil, which is associated with heterogeneous responses across patients and significant toxicity. We examined the safety and efficacy of a modified schedule, FOLFCIS (leucovorin, fluorouracil, and cisplatin), and performed an integrated clinical and genomic analysis of anal SCC.

Hemodynamic analysis of descending versus ascending aortomyoplasty, and comparison with intra-aortic balloon pump

Objective: Descending and ascending aortomyoplasty are two surgical procedures intended to induce hemodynamic benefits similar to those of the intra-aortic-balloon-pump (IABP). To date, there have been no studies comparing the two surgical techniques. The objective of this study was to compare coronary blood flow augmentation and afterload reduction as produced by descending and ascending aortomyoplasty counterpulsation Methods: Twenty-two mongrel dogs (18–35 kg) underwent IABP application (n=7), descending (n=8), or ascending (n=7) aortomyoplasty. Left anterior descending (LAD) coronary artery blood flow was measured using a Transonic Doppler flow probe. Left ventricular pressure as well as aortic pressures proximal and distal to either the aortomyoplasty site or the IABP position were monitored continuously. Results: Descending aortomyoplasty induced higher elevation in the LAD blood flow during assisted beats (27% from 10.8±4 to 13.8±6 ml/min, P<0.001) than that induced by either ascending aortomyoplasty (19% from 11.7±5 to 14±5 ml/min, P<0.001) or IABP counterpulsation (18% from 8.6±3 to 10.2±4 ml/min, P<0.001). Conversely, while ascending aortomyoplasty reduced the left ventricular end-diastolic pressure by 16% (from 60±18 to 50±22 mmHg, P<0.001), similar to the 16% after load reduction achieved by the IABP counterpulsation, descending aortomyoplasty failed to induce afterload reduction. Conclusions: Descending aortomyoplasty produces higher coronary blood flow augmentation than either ascending aortomyoplasty or IABP. However, afterload reduction comparable to that achieved by IABP was observed only with ascending aortomyoplasty and not with descending aortomyoplasty.     

DNA probe technology: implications for service planning in Britain

For certain genetic conditions DNA testing identifies carriers and determines the risk status of foetuses, thus helping parents to make more informed prenatal decisions. Data, collected from three genetic centres in England and Wales from August 1986 to July 1990, are used to describe trends in demand for DNA testing, the impact of DNA tests on carrier risk assessment, and the use of DNA tests in relation to pregnancy outcome. Altogether the data include 23,388 subjects and 681 pregnancies in 8738 families divided into five cohorts by year of entry and referral. The most frequent gene disorders referred to the genetic centres are currently being tested or will soon be tested. For these disorders the initial high level of activity has declined and may have reached steady state. Demand for DNA services is high for cystic fibrosis and Duchenne muscular dystrophy, intermediate for Huntington's disease, and low for adult polycystic kidney disease, phenylketonuria and tuberous sclerosis. Based on these findings we suggest that demand for DNA tests will be high in serious, untreatable and slow progressing conditions with early onset; intermediate for conditions affecting intellect and neurological integrity with later onset; and low for treatable, late-onset conditions, or those for which there is evidence of heterogeneity, and variable penetrance. It would be helpful to assess the extent to which this view of demand is confirmed when the new disorders being DNA tested are considered and for the pattern of activity of DNA testing for some types of cancer. Since no DNA centre could offer a fully comprehensive testing service, it is recommended that a structure is created to audit overall activity, assist in policy formulation, and influence supraregional service organisation, in order that the spread of DNA services be planned as effectively as possible. This structure would facilitate monitoring of the evolution of contract specifications agreed by commissioners and providers on a regional basis.     

Familial homozygous hypercholesterolemia: clinical and cardiovascular features in 18 patients

Homozygous familial hypercholesterolemia (HFH) is a very rare autosomal dominant disease characterized by accelerated severe atherosclerosis. We examined 18 patients from 9 families with HFH. The age range was 6-30 years (mean = 16 years). Male to female ratio was equal. All patients had huge, multiple tuberous xanthomas on the skin and tendons. Mean +/- standard deviation of plasma cholesterol, triglycerides, low-density lipoproteins (LDL), and high-density lipoproteins (HDL) cholesterol levels were 608 +/- 89, 122 +/- 39, 550 +/- 88, and 26 +/- 8 mg/dl, respectively. Five patients (28%) had angina pectoris, two sustained a myocardial infarction, and one died at the age of 15 years. Two-dimensional echocardiography demonstrated supravalvular aortic stenosis in 3 of the 13 patients (23%). Coronary arteriography performed in 11 patients demonstrated significant obstruction in 6 patients, 2 each with single-, double-, and triple-vessel disease. Left main stenosis was present in 3 patients (27%). Supravalvular aortic narrowing was demonstrated in 6 patients (54%) and was associated with a gradient in 2 (25 and 35 mmHg, respectively). Segmental contraction abnormalities were detected in 2 of the 11 patients (18%). It is concluded that coronary artery disease is prevalent in patients with HFH and, based on the data presented, we recommend the performance of noninvasive technique, coronary arteriography and supravalvular aortography at an early age to detect and to follow the progression of the disease.     

The Relationship Between Daily Life Stress and Gastrointestinal Symptoms in Women with Irritable Bowel Syndrome

Research on irritable bowel syndrome (IBS), a functional disorder of the gastrointestinal (GI) system, has linked GI symptoms to stress. This study examined the relationship between daily stress and GI symptoms across women and within woman in IBS patients (n = 26), IBS nonpatients (IBS-NP; n = 23), and controls (n = 26), controlling for menstrual cycle phase. Women (ages 20–45) completed daily health diaries for two cycles in which they monitored daily GI symptoms and stress levels. The Life Event Survey (LES) was used as a retrospective measure of self-reported stress. The across-women analyses showed higher mean GI symptoms and stress in the IBS and IBS-NP groups relative to controls but no group differences in LES scores. The within-woman analyses found a significant and positive relationship between daily stress and daily symptoms in both the IBS-NP and the IBS groups. Controlling for menstrual cycle had no substantial impact on the results.     

Integrated plasma cortisol concentration in children with asthma receiving long-term inhaled corticosteroids.

We assessed the effect of long-term therapy with inhaled beclomethasone dipropionate (BDP) on the pituitary-adrenal axis, by measuring the integrated concentration (IC) of plasma cortisol in eight children with asthma (age, 6-16 years) who regularly used inhaled BDP in doses ranging from 8 to 26.5 micrograms/kg (200-450 micrograms/day) for 6 months to 4 years. The control group included six children (age, 6-16 years) who had the IC of plasma cortisol measured as part of an endocrinological evaluation and were found to be healthy. Cortisol concentration was measured in blood samples collected continuously over a 24-hr period. Mean IC of plasma cortisol in the study group was significantly lower than in the healthy controls (mean +/- SD, 4.9 +/- 3.3 vs 9.1 +/- 1.9 micrograms/mL; P less than 0.02). Cortisol response to 0.25 mg ACTH (iv) was abnormal in one of the eight BDP-treated patients. No correlation was found between IC of plasma cortisol and the BDP dose, severity of asthma, height percentile, or the Tanner stage. We conclude that long-term therapy, even with relatively conventional doses of inhaled BDP may cause reduction in the normal physiological secretion of cortisol. The clinical relevance of low IC of plasma cortisol is not clear, but it may reflect partial suppression of the pituitary-adrenal axis.     

Oxidized low-density lipoprotein reduces plasma coagulation in vitro

Oxidation of low-density lipoprotein (LDL) was shown to occur in vivo and involved lipid peroxidation and apolipoprotein modification. We studied the effect of oxidized-LDL (Ox-LDL) on plasma coagulation by measuring prothrombin time (PT) and partial thromboplastin time (PTT) following the addition of Ox-LDL to normal plasma. Ox-LDL, but not native LDL, caused prolongation of PT and PTT by 30% in a dose- and time-dependent pattern. This effect was also shown to be present following lipoprotein delipidation, suggesting that it was the apolipoprotein fraction of Ox-LDL, but not its lipid fraction, that was responsible for the prolongation of PT and PTT. This was further substantiated since similar effect could be obtained by adding LDL treated with trinitrobenzenesulphonic acid to block the lysine groups, as occurs in oxidized LDL. Ox-LDL, unlike LDL, was found to reduce plasma ionized calcium by 33%. Moreover, adding calcium ions to Ox-LDL negated its effect on PT and PTT, suggesting that Ox-LDL apolipoprotein may influence coagulation by binding calcium ions.     

Respiratory illness and home environment of ethnic groups

Factors contributing to differences in the prevalences of respiratory symptoms and diseases among ethnic groups were studied in primary schoolchildren living in 20 inner city areas of England in 1983. The raised prevalences of respiratory symptoms in these groups were compared with results from a national representative sample of children studied in 1982. Data on age, sex, respiratory illness, and social and environmental variables were obtained by questionnaire for 4815 children living in inner cities. The children were classified as white, Afro-Caribbean, Urdu, Gujarati, Punjabi, other Asian, or "other." Significant differences in the prevalence of respiratory conditions were found among the ethnic groups after allowance was made for the effects of interfering variables. Except for asthma all conditions were most prevalent in Afro-Caribbeans and whites. In these two ethnic groups respiratory illness was significantly associated with belonging to a one parent family and the combined use of gas cookers and paraffin heaters at home. Respiratory illness was found to vary in prevalence among ethnic groups but may be perceived differently by different groups. Further studies, measuring lung function, are necessary.     

Genetic services in the context of DNA probes: what do they cost?

We describe results from the first year of a three year economic evaluation of genetic services in the context of DNA probes provided at three genetic centres in Great Britain. The analysis so far has concentrated on the costs of providing DNA diagnostic services. Estimates are given of the total costs of providing DNA probe services at each of the three centres, together with information for assessing the cost implications of future developments in these services. DNA probe services are likely to be funded as a Regional specialty. This paper concludes that relative to other developing medical technologies and as an investment by Regions, DNA probe services are inexpensive. An appraisal of the benefits to be derived from DNA probe services is still to be undertaken.     

The influence of genetic counselling in the era of DNA testing on knowledge, reproductive intentions and psychological wellbeing

Subjects of reproductive age at risk of having an affected child with a severe single gene disorder such as Duchenne muscular dystrophy (DMD) or cystic fibrosis (CF) were surveyed to ascertain: their views on genetic counselling and antenatal testing; their knowledge of their risk of having an affected child; and their psychological wellbeing. Questionnaires were posted to 209 individuals at 130 addresses; a 65% response rate was achieved. The majority of those surveyed were under 40 years of age (91%), half of them had received genetic counselling only once and for 47% the first encounter was after the diagnosis of their affected child. Most patients expressed their intention to use prenatal testing. However, less than 50% of those counselled knew their risk of having an affected child. Knowledge of risk was associated with the type of disease in the family (p<0.001) (inheritance of DMD was poorly understood by relevant subjects) and was positively associated with the participant's level of education (p<0.05). We did not detect a significant association between the number of intended children and the risk of having an affected child. In terms of family relations, genetic counselling appears to be beneficial for the nuclear family, the couple and their children, but some counsellees reported a detericration in relations with other relatives. The results indicate that couples at risk of having a child with a severe genetic disorder value the counselling provided, but many of them do not remember important facts in relation to their risk status.