Statistical challenges posed by uncontrolled master protocols: sensitivity analysis of the vemurafenib study.

Within the evidentiary hierarchy of experimental inquiry, randomized trials are the gold standard. Oncology patients enter clinical studies with diverse lifestyles, treatment pathways, host tissue environments, and competing comorbidities. Randomization attempts to balance prognostic characteristics among study arms, thereby enabling statistical inference of 'average benefit' and attribution to the studied therapies. In contrast, interpretations of uncontrolled trials require additional scrutiny to attempt to place the findings in the context of external evidence. Counter-factual reasoning and speculation across trials may be obscured by the disproportionate enrollment of prognostic subpopulations which may be unknown from publications of trial reports. Recent modifications to the regulatory environment (Food and Drug Administration Safety and Innovation Act) have elevated the importance of non-comparative trials. Moreover, the emergence of recent innovations in precision medicine have yielded trial designs that partition potentially heterogeneous subpopulations into 'statistically exchangeable' cohorts by histologies, or genetic alterations, further elevating the importance of single-cohort analyses. As patient cohorts become ever more refined into smaller targeted subsets, consumers of reports of uncontrolled trials should be further empowered with improvements in reporting practices that better describe the enrolled prognostic subpopulations and importantly their association with study end points. This article demonstrates the issue with a sensitivity analysis of the findings reported in a recent trial that was devised to evaluate the preliminary clinical efficacy of vemurafenib in BRAF V600 mutation-positive nonmelanoma cancers.

Optical, Electrical, and Morphologic Characterization of Chromium-Impurified CdS Thin Films Elaborated by the Chemical Bath Deposition.

In this research work, a material system formed of cadmium sulfide combined with chromium atoms was developed to evaluate the influence of chromium concentration on the optical, electrical, structural, and morphological properties of a precursor layer of CdS. It is possible to observe that the transmission spectra increased for all chromium concentrations analyzed. From X-ray diffractograms, we conclude more accurately that CdS presents a mixture of phases, including orthorhombic, hexagonal, and cubic. Furthermore, the impact of adding chromium results in variations in the intensity of two major peaks in the diffractograms and an anomalous shift in the CdS pattern. The calculated resistivities show an invariable behavior of 4.5 × 106 Ω cm. In addition, the bandgap values remain practically constant, with values of approximately 2.43-2.44 eV. The addition of chromium at different concentrations leads to surface morphology changes, as observed in SEM images.

COMT Val158Met polymorphism in relation to activation and de-activation in the prefrontal cortex: A study in patients with schizophrenia and healthy subjects.

The Val158Met polymorphism in the COMT gene has been found to be associated with differences in brain activation in both healthy subjects and patients with schizophrenia. The predominant finding has been increased prefrontal activation associated with the Val allele; however, genotype-related de-activations have not been studied. In this study 42 schizophrenia patients and 31 controls underwent fMRI while performing the n-back task. Brain differences related to presence/absence of disease and presence/absence of the Val/Val genotype were examined. Both disease and Val/Val genotype were associated with failure of de-activation in a cluster centred in the medial prefrontal cortex. There was no interaction between disease and genotype at this location, but clusters where there were significant interactions emerged in the right prefrontal cortex and left temporal/parietal cortex. These findings suggest that Val158Met polymorphism influences task-related de-activations in the default mode network in both healthy subjects and schizophrenia patients to an equivalent extent. However the Val158Met polymorphism also has disease-specific effects on DLPFC activation in schizophrenia.

Increased level of amplification of the c-myc oncogene in tumors induced in nude mice by a human breast carcinoma cell line.

Cell line SW 613-S, derived from a human breast carcinoma, contained double minute chromosomes (DMs) but lost them progressively upon in vitro cultivation. These cells were tumorigenic in nude mice. Cell lines were derived from the tumors and were found to have a high DM content. In three such cell lines, DMs were stably maintained upon in vitro cultivation, whereas in another they were progressively lost. We found that the c-myc oncogene is amplified 5- to 10-fold in SW 613-S and 20- to 90-fold in the different cell lines derived from the tumors. At least part of the additional c-myc copies were found associated with a purified DM fraction. In cell lines which lost the DMs during in vitro passages, the level of amplification was maintained. In situ hybridization experiments indicated that this loss was compensated by the acquisition of copies of the c-myc gene integrated into a chromosome. No major rearrangement of the amplified c-myc gene was detected. The amount of c-myc messenger RNAs is roughly proportional to the level of amplification. Our results indicate that growth of SW 613-S cells as tumors in nude mice selected cells with an increased level of amplification and expression of the c-myc oncogene.

Early dipyridamole (99m)Tc-sestamibi single photon emission computed tomographic imaging 2 to 4 days after acute myocardial infarction predicts in-hospital and postdischarge cardiac events: comparison with submaximal exercise imaging.

BACKGROUND: Because of its brief hemodynamic effects and minor effect on determinants of myocardial oxygen demand, vasodilator stress myocardial perfusion imaging (MPI) can be applied very early after acute myocardial infarction (AMI) for risk stratification, allowing management decisions to be made earlier and thus potentially shortening hospitalization stays, reducing costs, and preventing early cardiac events. This multicenter randomized trial compared the prognostic value of early dipyridamole MPI and standard predischarge submaximal exercise MPI in patients who presented with AMI. METHODS AND RESULTS: Patients who presented with their first AMI (n=451) were randomized in a 3:1 ratio to undergo either both an early (day 2 to 4) dipyridamole (99m)Tc-sestamibi MPI study and a predischarge (day 6 to 12) submaximal exercise (99m)Tc-sestamibi MPI study or only the predischarge study. Multivariate predictors of in-hospital cardiac events included nuclear imaging summed stress and summed reversibility scores and peak creatine kinase. For postdischarge cardiac events, multivariate predictors in patients undergoing dipyridamole MPI included only the summed stress, reversibility, and rest imaging scores and anterior MI. For a given summed stress score, the interaction of reversibility score further improved the predictive value. Dipyridamole MPI showed better risk stratification than submaximal exercise MPI. CONCLUSIONS: Dipyridamole MPI very early after MI predicts early and late cardiac events, with superior prognostic value compared with submaximal exercise imaging. The extent and severity of the stress defect and reversibility of the defect were the most important predictors of cardiac death and recurrent MI. This technique can allow management decisions to be made earlier with regard to AMI patients and could have important economic impact if applied widely.

Emergency percutaneous transluminal coronary angioplasty in acute myocardial infarction: a 3 year experience.

In 151 patients experiencing acute myocardial infarction, emergency coronary angioplasty was performed as primary therapy. Overall, angioplasty was successful in 132 patients (87%); it was successful in 91 (85%) of 107 patients with a totally occluded infarct-related artery and in 41 (93%) of 44 patients with a subtotally occluded infarct-related artery. After successful angioplasty, mean residual stenosis was 29% (range 0 to 70). Eighteen patients were in cardiogenic shock (12%) including four patients receiving cardiopulmonary resuscitation during the angioplasty procedure. Hospital mortality was 9%, with 7 of 13 deaths occurring in patients presenting with cardiogenic shock or intractable ventricular arrhythmia. Hospital mortality was 5% in patients with successful angioplasty versus 37% in those with unsuccessful angioplasty (p less than 0.001). In the immediate period after angioplasty, left ventricular ejection fraction was significantly lower for patients with lesions of the left anterior descending artery (34 +/- 10%) than for patients with lesions of the left circumflex or right coronary artery (43 +/- 11%). In patients with successful angioplasty, significant improvement in left ventricular ejection fraction averaged 13 +/- 12% (p less than 0.001) for those with lesions of the left anterior descending artery and 10 +/- 12% (p less than 0.001) for those with lesions of the left circumflex or right coronary artery. Repeat coronary angiography was performed in 85 (70%) of 121 patients who had successful angioplasty and survived hospitalization without requiring bypass surgery; restenosis was found in 26 (31%), and angioplasty was repeated in 22 patients, successfully in each.(ABSTRACT TRUNCATED AT 250 WORDS)

Transfer ribonucleic acid methylase activity in adult and foetal rat liver.

Foetal rat liver extracts were found to have higher tRNA methylene activities than corresponding extracts of adult liver. When the specific activities were expressed per mg of liver or per mg of protein, the foetal tRNA methylating enzymes were respectively 2.5 and 6 times higher than those of adult livers. The presence of an inhibitor in adult liver can be excluded, since the same recoveries of total tRNA methylase activity were obtained after partial purification of both adult and foetal liver extracts: yields were close to 100%. The apparent Km's for the substrates in the methylating reactions were the same when tRNA methylases from either adult or foetal liver were used: values were 0.2 muM for Escherichia coli tRNA and 2.1 muM for S-adenosyl-L-methionine. After T1-T2 ribonuclease digestion of an in vitro methylated tRNA, similar methyl nucleotide patterns were observed in foetal and adult enzymatic extracts. It is concluded that the same tRNA methylase pool is present in adult and foetal liver. In addition, it is hypothesized that the different reaction rates exhibited by these enzymes might be due to the tRNA functional requirements rather than to the presence of a tRNA methylase inhibitor.

Purification and properties of the major tRNAHis from sheep liver.

The major isoacceptor of tRNAHis from sheep liver was purified. Two different methods were described which both took advantage of the presence of the hypermodified Q nucleotide in this tRNA. In the first procedure, CNBr treatment of tRNA which was previously enriched in tRNAHis greatly increased the efficiency of the subsequent chromatographic steps. The tRNAHis obtained by this technique showed a specific activity of 1,690 picomoles of histidine per A260 unit. In the second one, a twenty-fold enrichment in tRNAHis was obtained by fractionation of crude tRNA on acetylated DBAE-cellulose columns. The nucleotide composition of the tRNA obtained by the CNBr procedure was determined. No thymine ribotide could be detected. When this tRNA was submitted to periodate oxidation and tritium borohydride reduction, a radioactive label was introduced in this molecule which was assumed to be located in the Q nucleotide.

The human breast carcinoma cell line SW 613-S: an experimental system to study tumor heterogeneity in relation to c-myc amplification, growth factor production and other markers (review).

Amplification of the c-myc gene has been frequently reported in breast carcinomas. However the precise function of the c-myc protein is still unknown and the nature of the selective advantage offered to a cell by an overexpression of such a protein is unclear. We are addressing this question using the SW 613-S human breast carcinoma cell line as a model system. This cell line harbours an amplified c-myc gene and a mutated c-Ki-ras gene. By various criteria the amplified c-myc gene of SW613-S cells appears undistinguishable from a normal human c-myc gene. The SW613-S cell line is heterogeneous: it contains cells with a high level of amplification and carrying the extra copies of the c-myc gene in double minute chromosomes (DMs) and cells with few c-myc genes integrated into chromosomes. DM-containing cells are progressively lost upon in vitro cultivation but are selected for during in vivo growth, as tumors in nude mice, or by cultivating the cells in a chemically defined, serum-free medium or under conditions preventing anchorage. Clones with different levels of amplification and different chromosomal localization of the c-myc copies were isolated from the SW 613-S cell population. Those with a high level of amplification and expression of the c-myc gene are tumorigenic in nude mice, whereas those with a low level are not. Introduction of c-myc gene copies by transfection confers tumorigenicity to the nontumorigenic clones, indicating that a high level of amplification of the c-myc gene contributes to the tumorigenic phenotype of SW 613-S cells. Tumorigenic clones grow unattached, are able to proliferate in a chemically defined medium, and produce high levels of several growth factors (e.g. TGF-alpha, IGF2). Nontumorigenic clones are more dependent upon anchorage for growth, show a restricted growth in defined medium, and produce low or undetectable level of the growth factors tested. We have identified several genes, besides c-myc, the expression level of which is markedly different in the two types of clones. TGF-alpha, IGF2, PDGF-A, int-2, cytokeratins K8 and K18 and ferritin H chain are overexpressed in tumorigenic clones. In contrast, c-erbB1 (EGF receptor), c-jun, vimentin and p53 are expressed at a higher level in the nontumorigenic clones. Finally the major histocompatibility class I antigens, ferritin L chain, TGF-beta and c-Ki-ras, are examples of genes expressed at the same level in both types of clones.(ABSTRACT TRUNCATED AT 400 WORDS)

Percutaneous transluminal coronary angioplasty for acute myocardial infarction.

Studies have suggested that intracoronary and intravenous thrombolysis and emergency PTCA result in decreased infarct size, improved left ventricular function, and decreased in-hospital mortality. Significant problems remain with all three treatment modalities. Thrombolysis is associated with significant bleeding, especially if acute catheterization also is performed. The intracoronary method of thrombolysis requires cardiac catheterization facilities and entails a significant delay in reperfusion. Lower rates of reperfusion initially were found with intravenous than intracoronary streptokinase, but the intravenous administration of t-PA has been associated with a reperfusion rate (75 per cent) similar to that of intracoronary streptokinase. Significant bleeding complications occur with t-PA just as with streptokinase. Furthermore, there are patients in whom thrombolysis is contraindicated because of the high risk of life-threatening hemorrhagic complications. Once thrombolysis is achieved, an underlying significant coronary artery lesion usually is present so that a significant risk of recurrent ischemia and/or reinfarction still exists. In controlled studies, the addition of cardiac catheterization and angioplasty after thrombolytic therapy is associated with a further increase in significant bleeding episodes. Also, in low-risk subgroups of patients randomized to emergency angioplasty versus elective angioplasty or noninvasive treatment after thrombolytic therapy, the complications of angioplasty may outweigh the benefits of further reduction in lesion severity. Potential problems of emergency angioplasty following thrombolytic therapy include: (1) hemorrhage into ischemic myocardium, which may have a deleterious effect on ultimate muscle recovery; (2) hemorrhage at the angioplasty site caused by thrombolytic therapy, with a resultant increased chance of occlusion of the vessel post-angioplasty, and (3) production of reperfusion arrhythmias and hypotension, predisposing to vessel reclosure and infarct extension. With primary angioplasty therapy, the reperfusion success rate is 85 to 90 per cent. This is higher than the approximately 75 per cent success rate with thrombolytic therapy alone. If angioplasty can be performed expeditiously, within 6 hours of the onset of ischemia, potential advantages of this technique include: (1) rapid reperfusion, possibly comparable to thrombolytic therapy alone; (2) higher success rate for reperfusion than thrombolytic therapy; (3) alleviation of underlying stenosis usually present after thrombolytic therapy alone; (4) avoidance of systemic thrombolysis, with a concomitant decrease in hemorrhagic risk; (5) possible avoidance of hemorrhagic infarction, which may have a deleterious effect on ultimate muscle recovery; and (6) applicability to patients in cardiogenic shock, who presently respond poorly to thrombolytic therapy alone. No large controlled randomized study exists comparing primary angioplasty with thr

Percutaneous laser-assisted thermal coronary angioplasty in native coronary arteries and saphenous vein grafts: initial results and angiographic follow-up.

Percutaneous laser-assisted thermal coronary angioplasty was attempted in 29 vessels (27 patients): 10 left anterior descending, 2 left circumflex and 17 mid-shaft (non-anastomotic) saphenous vein grafts. Argon or YAG laser thermal energy was applied via a 1.3, 1.6 or 1.9 mm metal capped probe followed by conventional balloon angioplasty in 27 vessels and sole thermal laser therapy in two vessels. The laser probe successfully crossed 83% (24/29) of vessels and subsequent balloon dilatation increased the success rate to 93% (25/27). Perforation occurred in a vein graft resulting in one in-hospital death post repeat emergency coronary artery bypass graft surgery. Angiographic follow-up was obtained in 85% (24/28) of vessels. Angiographic restenosis ( greater than 50% reduction in lumen diameter) occurred in 27% (3/11) of native coronary arteries and 62% (8/13) of saphenous vein grafts. Therefore, despite high initial success rates, the application of laser thermal energy with small laser probes relative to vessel size, followed by conventional balloon angioplasty, does not appear to alter restenosis. Further evaluation of coronary laser systems should be continued only with catheters that are capable of creating channels closer to the size of the vessel treated.

Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant?

BACKGROUND: Ibudilast is a phosphodiesterase inhibitor influencing inflammation and neurodegeneration in multiple sclerosis (MS). This study evaluated the safety, tolerability, and effects on MRI parameters of 2 different doses of ibudilast in relapsing forms of MS. METHODS: In this multicenter, double-blind, phase 2 trial, patients with relapsing MS and gadolinium-enhancing lesions were randomly assigned 1:1:1 to receive 30 or 60 mg ibudilast or placebo every day for 12 months. The primary endpoint was the cumulative number of newly active lesions on bimonthly brain MRI over 12 months. Secondary endpoints included relapse rate, change in Expanded Disability Status Scale (EDSS) score, T2-hyperintense and T1-hypointense lesion volumes, and percent brain volume change (PBVC). RESULTS: A total of 297 patients were randomized in 19 centers. During the first 12 months, the mean number of active lesions and relapse rate did not differ between treatment arms. A reduction in PBVC (p = 0.04) was found in the 60-mg group (0.8%) compared with placebo (1.2%). Post hoc analysis showed a reduction in the proportion active lesions that evolved into persistent black holes for the 60-mg (0.14; p = 0.004) and 30-mg (0.17; p = 0.036) groups compared with the placebo group (0.24). Over 2 years, there were fewer patients (p = 0.026) with confirmed progression on the EDSS. Treatment with ibudilast was generally safe and well tolerated. CONCLUSION: Ibudilast showed no beneficial effect on the rate of newly active lesions and relapses. However, preliminary evidence suggests that ibudilast seems to act in a neuroprotective fashion as measured by 2 independent MRI outcomes, with a possible beneficial clinical effect on disability progression. CLASSIFICATION OF EVIDENCE: This interventional study provides Class III evidence on the effect of ibudilast on disease activity.

Modifications du renouvellement de l'amp final du tRNA dans le foie de rat sous l'influence de divers inhibiteurs de synthese.

The turnover of terminal AMP of rat liver tRNA relative to that of internal AMP was studied in presence of various inhibitors. Actinomycin D and aflatoxin B(1), which strongly depress transcription in liver, lead to an increase of the specific radioactivity of external AMP/specific radioactivity of internal AMP ratio. On the contrary, drugs which inhibit the in vivo incorporation of aminoacids determine a significant decrease of this ratio.

Adjusting for time trends when estimating the relationship between dietary intake obtained from a food frequency questionnaire and true average intake.

In measuring food intake, three common methods are used: 24-hour recalls, food frequency questionnaires and food records. Food records or 24-hour recalls are often thought to be the most reliable, but they are difficult and expensive to obtain. The question of interest to us is to use the food records or 24-hour recalls to examine possible systematic biases in questionnaires as a measure of usual food intake. In Freedman, et al. (1991), this problem is addressed through a linear errors in variables analysis. Their model assumes that all measurements on a given individual have the same mean and variance. However, such assumptions may be violated in at least two circumstances, as in for example the Women's Health Trial Vanguard Study and in the Finnish Smokers' Study. First, some studies occur over a period of years, and diets may change over the course of the study. Second, measurements might be taken at different times of the year, and it is known that diets differ on the basis of seasonal factors. In this paper, we will suggest new models incorporating mean and variance offsets, i.e., changes in the population mean and variance for observations taken at different time points. The parameters in the model are estimated by simple methods, and the theory of unbiased estimating equations (M-estimates) is used to derive asymptotic covariance matrix estimates. The methods are illustrated with data from the Women's Health Trial Vanguard Study.

Correlation between the presence of tRNA His GUG and the erythropoietic function in foetal sheep liver.

Histidyl-tRNAs from foetal and adult sheep liver were compared to their reticulocyte counterparts. The combination of various techniques revealed the existence of two histidyl-tRNA species in reticulocytes, one of which was not retained on acetylated DBAE-cellulose columns and was guanylatable. Three histidyl-tRNA isoacceptors were identified in foetal liver. Two of these species were not adsorbed on acetylated DBAE-cellulose but only one was found to be guanylatable. An identical chromatographic behaviour on RPC-5 columns was observed for guanylated histidyl-tRNAs from both origins. These results suggest the occurrence of a GUG anticodon in these guanine-accepting tRNAs. In foetal liver the amount of guanylatable histidyl-tRNA was estimated to be 7% of the total tRNA population. This observation is in agreement with the erythropoietic function of liver during the foetal life.

A c-ras-Ki oncogene is activated, amplified and overexpressed in a human osteosarcoma cell line.

We present a characterization of an activated oncogene which we found to be present in DNA of the OHA osteosarcoma cell line. We identify this tumor oncogene which transforms Swiss mouse 3T3-cells, with c-ras-Ki 2, one of two known members of the Kirsten ras family of human proto-oncogenes. Its structural outlines are given and we show that: 1) a single point mutation causing a substitution of valine for glycine in codon 12 was found by DNA sequencing; 2) the c-ras-Ki gene is amplified and overexpressed in the original OHA tumor cells and its transformants and 3) the gene product is an abnormal form of the p21 protein.

The impact of restrictive entry criterion during the placebo lead-in period.

In the study of depression, most randomized clinical trials have design features that attempt to sample from a stable patient population. One commonly used design feature is to require patients to maintain some minimum baseline symptom severity score during a placebo lead-in period. One intent of this design feature is to evaluate the behavior of patients prior to administration of active medication. If, during the lead-in period, patients do not maintain minimum symptom severity, the patients are excluded from the remainder of the study, the theory being that the excluded patients are not part of a stable patient population and hence are not likely to demonstrate efficacy of a truly effective treatment. This presentation investigates the effectiveness of a restrictive entry criterion and proposes an alternative explanation for what is usually defined as placebo response.

Safety of early intravenous dipyridamole technetium 99m sestamibi SPECT myocardial perfusion imaging after uncomplicated first myocardial infarction. Early Post MI IV Dipyridamole Study (EPIDS).

We assessed the safety of early (2 to 4 days) intravenous dipyridamole infusion in conjunction with technetium 99m sestamibi tomographic myocardial perfusion imaging in patients with first myocardial infarction (MI). Early risk stratification with myocardial perfusion imaging of patients after acute MI may be useful to identify patients who either require further evaluation or may be safely discharged. Because of minimal hemodynamic effects, intravenous dipyridamole may be a safe means of producing hyperemia for myocardial perfusion imaging. Stable patients with first acute MI who met entry criteria were randomized (3:1) to either intravenous dipyridamole infusion (0.56 mg/kg over a 4-minute period) 48 to 96 hours after onset of symptoms or a control (no test) group. Adverse cardiac events (unstable angina, recurrent MI, or cardiac death) were evaluated during and 24 hours after the dipyridamole infusion and during the corresponding 24 hours for the control group. Two hundred eighty-four patients received dipyridamole infusion a mean time of 3.3 +/- 0.7 days after MI. There were no adverse clinical events either during or immediately after the infusion. During the 24 hours after infusion, three patients had symptoms of unstable angina pectoris, one patient had a recurrent MI, and no patients died. The earliest event occurred 4.2 hours after the dipyridamole infusion. Three patients had unstable angina pectoris, whereas no patients had either recurrent MI or died in the control group. There were no statistically significant differences between the two groups. In a multicenter trial, dipyridamole infusion administered early after the first acute MI resulted in no increased evidence of cardiac events either immediately or 24 hours after the procedure compared with a control group. Therefore intravenous dipyridamole can be safely used as a pharmacologic vasodilator for myocardial perfusion imaging soon after uncomplicated MI.

Exercise testing and training of the elderly patient.

As an invariable accompaniment of the aging process, cardiac function declines, that is, cardiac output, stroke volume, heart rate, and maximum oxygen consumption all decrease. The vital capacity declines as residual volume increases, and ventilation-perfusion imbalance increases. Muscles atrophy and weaken, joints stiffen, and bones are demineralized. Certainly the aging process per se explains a portion of this functional deterioration. Disease states also account for some deterioration. However, inasmuch as approximately one half of the deterioration in function can be prevented or reversed by an exercise training program, it would seem that disuse or inactivity is responsible for at least a portion of the functional decline characteristic of aging. Special considerations in prescribing exercise training for the elderly include careful cardiovascular assessment; evaluation of orthopedic problems; consideration of heat intolerance; and careful attention to motivation. The exercise prescription should be specific and tailored to the subject's individual cardiovascular status, musculoskeletal limitations, and personal goals. Walking, stretching calisthenics, and other aerobic activities, if of reasonable intensity and duration, and when preceded and followed by an appropriate warm-up and cool-down period, respectively, can result in a substantial, positive training effect in the elderly. In response to such a training program, elderly subjects demonstrate an increase in stroke volume, cardiac output, and maximum heart rate. Respiratory function changes little, yet maximal oxygen consumption is increased. Fat may be replaced by lean muscle mass as muscle strength and endurance improve. Flexibility is improved and bone demineralization retarded or even reversed. Exercise has a tranquilizing effect on elderly subjects so that anxiety and depression may be prevented. The subject develops self-respect as effort tolerance improves. An excessively conservative attitude on the part of physicians, families, and elderly subjects has resulted in inappropriate activity limitations with a consequent decrement in effort tolerance. Elderly individuals can maintain a reasonable level of effort tolerance or can be rehabilitated to this level of activity with an appropriate exercise program. The decline in overall function expected with age can be substantially retarded. Consequently, physicians, families, and the subjects themselves should consider the potential advantages of an exercise program.

Successful excimer laser angioplasty following unsuccessful primary balloon angioplasty.

We report five patients where excimer laser coronary angioplasty facilitated successful balloon dilatation of heavily calcified lesions that could not be dilated by conventional angioplasty techniques alone. In each case, the lesion was crossed successfully with a guide wire. Conventional angioplasty failed because of inability to cross the lesion with a balloon (four lesions) or inability to dilate the lesion with balloon inflation (two lesions). These cases illustrate an indication for excimer laser coronary angioplasty as an adjunctive procedure in heavily calcified coronary stenoses.