Decision tree algorithm in locally advanced rectal cancer: an example of over-interpretation and misuse of a machine learning approach.

PURPOSE: To analyse the classification performances of a decision tree method applied to predictor variables in survival outcome in patients with locally advanced rectal cancer (LARC). The aim was to offer a critical analysis to better apply tree-based approach in clinical practice and improve its interpretation. MATERIALS AND METHODS: Data concerning patients with histological proven LARC between 2007 and 2014 were reviewed. All patients were treated with trimodality approach with a curative intent. The Kaplan-Meier method was used to estimate overall survival (OS). Decision tree methods were was used to select important variables in outcome prediction. RESULTS: A total of 100 patients were included. The 5-year and 7-year OS rates were 76.4% and 71.3%, respectively. Age, co-morbidities, tumor size, clinical tumor classification (cT) and clinical nodes classification (cN) were the important predictor variables to the tree's construction. Overall, 13 distinct groups of patients were defined. Patients aged < 65 years with cT3 disease and elderly patients with a tumor size < 5 cm seemed to have highest rates of survival. But the process over-fitted the data, leading to poor algorithm performance. CONCLUSION: We proposed a decision tree algorithm to identify known and new pre-treatment clinical predictors of survival in LARC. Our analysis confirmed that tree-based machine learning method, especially classification trees, can be easily interpreted even by a non-expert in the field, but controlling cross validation errors is mandatory to capture its statistical power. However, it is necessary to carefully analyze the classification error trend to chose the important predictor variables, especially in little data. Machine learning approach should be considered the new unexplored frontier in LARC. Based on big datasets, decision trees represent an opportunity to improve decision-making process in clinical practice.

Treating lupus patients with antimalarials: analysis of safety profile in a single-center cohort.

This longitudinal retrospective study aims at describing the safety profile and the reasons for discontinuation of antimalarials in patients with systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE), focusing on ocular toxicity. We analyzed the clinical data of 845 SLE and DLE patients; 59% of them were taking antimalarials: 1.4% chloroquine (CQ), 88.5% hydroxychloroquine (HCQ) and 10.1% both. The mean therapy duration was 82.5 ± 77.4 months. At least one side effect was reported by 19.4% of patients, leading to temporary or permanent withdrawal in 9.1% and 10.3% of cases, respectively; 19.3% of patients experienced side effects with HCQ and 8.6% with CQ. In 55.1% of cases, the adverse event was mild or moderate. Ophthalmological alterations were reported by 8.5% but were confirmed by the ophthalmological examination in 5.5% of cases. Retinal alterations were associated with age, disease duration and duration of the antimalarial therapy, but not to drug dose and comorbidities or lupus nephritis. This is the largest monocentric longitudinal study confirming the good safety profile of antimalarials in DLE and SLE patients. The main adverse events during the therapy were mild or moderate, but maculopathy-reported in a low percentage of patients-remains the main cause of treatment withdrawal.

Design and methods of the Raloxifene Use for The Heart (RUTH) study.

Raloxifene is a selective estrogen receptor modulator that lowers total and low-density lipoprotein (LDL) cholesterol, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. The Raloxifene Use for The Heart (RUTH) trial is designed to determine whether raloxifene 60 mg/day compared with placebo: (1) lowers the risk of the coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI); and (2) reduces the risk of invasive breast cancer in women at risk for a major coronary event. RUTH is a double-blind, placebo-controlled, randomized clinical trial of 10,101 postmenopausal women aged > or =55 years from 26 countries. Women are eligible for randomization if they are postmenopausal and have documented coronary heart disease (CHD), peripheral arterial disease, or multiple risk factors for CHD. Use of estrogen within the previous 6 months is an exclusion factor. The study will be terminated after a minimum of 1,670 participants experience a primary coronary end point. Secondary end points include cardiovascular death, myocardial revascularization, noncoronary arterial revascularization, stroke, all-cause hospitalization, all-cause mortality, all breast cancers, clinical fractures, and venous thromboembolic events, in addition to the individual components of the composite primary coronary end point. RUTH will provide important information about the risk-benefit ratio of raloxifene in preventing acute coronary events and invasive breast cancer, as well as information about the natural history of CHD in women at risk of major coronary events.

Hormone and nonhormone therapy for the maintenance of postmenopausal health: the need for randomized controlled trials of estrogen and raloxifene.

Multiple health benefits have been postulated for the long-term use of hormone therapy in postmenopausal women, most notably for prevention of osteoporotic fractures and coronary heart disease, as well as several risks, including cancer of the breast and uterus and venous thromboembolism. Cardiovascular disease is the most common cause of death among postmenopausal women. If real, the reduction in risk of coronary heart disease by hormone use suggested by observational studies would likely outweigh the risks. The decision to initiate and maintain hormone therapy is complicated by uncertainties about estrogen's true benefits and risks. Raloxifene, a selective estrogen receptor modulator (SERM), appears to have many of the benefits of estrogen without the cancer risks. It is not known if SERMs can provide significant cardiovascular protection. This article reviews the relation of use of postmenopausal hormones and raloxifene to women's health and addresses the need for large randomized trials to quantify the effect of both postmenopausal estrogen and raloxifene on cardiovascular health.

New method for quantitatively determining aortic regurgitant volume using Doppler color flow imaging: experimental validation study.

We have developed a method to provide the two-dimensional distribution of blood flow velocity and the blood flow volume rate in the ascending aorta from the cross-sectional Doppler color flow image. Regional blood flow velocities were determined by converting color intensities of the cross-sectional Doppler color flow image into the corresponding flow velocities with the correction with the spatial ultrasound beam incident angle. The spatial ultrasound beam incident angle was estimated from the geometric characteristics of the color flow image contour. The method was validated in a steady flow model circuit comparing the calculated flow volume rates by the method with those simultaneously measured by an electromagnetic flowmeter. We performed an open chest dog experiment and calculated the blood flow volume rate at the ascending aorta before and after the aortic regurgitation was made. The calculated ejection flow volume rate and regurgitant volume were validated by the comparison with those simultaneously measured by an electromagnetic flowmeter. Based on these data, we can conclude that the current method provides accurate measurements of regurgitant volume as well as ejection flow volume rate in the ascending aorta.

Hyperventilation-echocardiography test for the diagnosis of myocardial ischaemia at rest.

The purpose of this study was to assess the feasibility, safety, specificity and sensitivity of the hyperventilation test performed under echocardiographic monitoring for the provocation of vasospastic ischaemia. Hyperventilation (approximately 30 cycles.min-1 for 5 min) was performed in 104 hospitalized patients, referred for pain typical of angina at rest, under 2-D echocardiographic and 12-lead electrocardiographic monitoring. All the tests were completed and no significant side effect was observed. In-hospital documentation of spontaneous myocardial ischaemia and/or ergonovine-induced ischaemia was achieved in 38 patients (group I). A positive hyperventilation-echocardiography test (occurrence of new transient asynergies or worsening of basal ones) was obtained in 32/38 patients. Among the group I patients, only 23 had diagnostic ST-T changes and only 16 experienced chest pain during the hyperventilation-echo test. Of the 66 patients without evidence of myocardial ischaemia at rest (negative ECG monitoring during hospitalization and/or negative ergonovine maleate-echo test)--Group II, none showed echocardiographic changes, seven presented ST-T changes and six complained of typical chest pain during the test. Thus, in relation to in-hospital documentation of myocardial ischaemia at rest, both spontaneous and/or ergonovine-induced episodes, the hyperventilation-echo test showed a specificity of 100%, a sensitivity of 84%, a positive predictive value of 100% and a negative predictive value of 92%. In conclusion, hyperventilation performed under echocardiographic monitoring is feasible and safe; it can be proposed as a screening test to unmask vasospastic myocardial ischaemia in patients with angina at rest, in whom documentation of spontaneous episodes is not available.

Efficacy of isosorbide-5-mononitrate versus nifedipine in preventing spontaneous and ergonovine-induced myocardial ischaemia. A double-blind, placebo-controlled study.

This study was designed to assess the efficacy of oral nifedipine as compared to oral isosorbide-5-mononitrate in the prevention of spontaneous and induced vasospastic myocardial ischaemia. Twenty-one patients admitted to the Coronary Care Unit as a result of angina at rest underwent both Holter monitoring and an echo-ergonovine test during placebo and following either isosorbide-5-mononitrate or nifedipine according to a double-blind randomized trial. Both drugs caused a statistically significant reduction in spontaneous (87% and 95%, respectively) and induced ischaemic attacks (66% and 75%, respectively). No significant difference was found between the two drugs.

Monitoring of cardiac output during exercise in coronary patients: a Doppler study.

The monitoring of aortic blood flow velocities by transcutaneous continuous-wave Doppler was performed in 45 patients to determine, non-invasively, the haemodynamic response to exercise in subsets of coronary patients during a multistage supine exercise tests. Group I consisted of 14 patients with ischaemia on effort (IE); group II, 12 patients with both IE and prior myocardial infarction (MI); group III, 19 patients with MI and no IE; there were also 12 normals. Peak flow velocity (PV) indices of cardiac output (CO), of peripheral resistance (PR) and of stroke work (SW) were measured every min. Resting CO was lower and PR higher in coronary patients than in normals. With exercise, for the same muscular work, CO increased less in IE patients (group I: y = 26.9 + 1.8 x cm sec-1; Group II: y = 21.9 + 1.8 x cm sec-1) than in MI (group III: y = 26.6 + 2.1 x cm s-1) and in normals (y = 35 + 2.7 x cm s-1) and PR decreased less. This suggested a more efficient distribution of CO towards working muscles. A shallower increase in SW was observed in all coronary patients in comparison with normals even if resting SW was significantly lower only in patients with MI (groups II and III). PV increased up to peak exercise only in group III, while it tended to plateau in ischaemic patients even earlier than IE occurred on the ECG.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of platelet function during in vivo infusion of isosorbide mononitrates: relationship between plasma drug concentration and hemodynamic effects.

Isosorbide monitrates (IS-2-MN and IS-5-MN), hepatic metabolites of isosorbide dinitrate, inhibit platelet function in vitro very differently, with IS-2-MN being much more potent than IS-5-MN. To assess their antiplatelet properties in vivo and to compare time and dosage requirements, we infused both IS-2-MN and IS-5-MN for 30 minutes, on 2 separate days, into nine patients with stable coronary artery disease, at rates of 4 mg/hr (n = 4) and 8 mg/hr (n = 5). Two additional patients received IS-5-MN at 16 mg/hr. Platelet aggregation and thromboxane (TX) B2 generation in response to various agonists, drug plasma concentrations, and blood pressure were monitored throughout the study. A significant decrease in platelet aggregation and TXB2 production by adenosine diphosphate and adrenaline occurred in seven of nine patients receiving IS-2-MN and in 7 of 11 patients receiving IS-5-MN. Response was dose related, with more patients responding at 8 mg/hr to IS-2-MN (five of five) than to IS-5-MN (three of five), and was maximum at the end of the infusion time, corresponding to peak plasma levels. Patients responding to drug infusions with an inhibition of platelet function were characterized by a greater vascular responsiveness compared to nonresponders, since the decrease in systolic blood pressure (mean +/- SEM) was significantly greater in the former (15.4 +/- 3.2) than in the latter (2.5 +/- 2.1, p less than 0.05). Therefore both mononitrates, when administered at infusion rates between 8 and 16 mg/hr, are accompanied by a consistent inhibition of adenosine diphosphate- and adrenaline-induced aggregation and TX generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiparametric approach to diagnosis of non-Q-wave acute myocardial infarction.

The present study investigated whether the lack of enzyme increase is reason enough to exclude necrosis in patients with ischemic heart disease who develop electrocardiographic sustained ST-T changes in the absence of Q waves. In 15 consecutive patients with angina who developed sustained ST-T changes during hospitalization, the presence of myocardial necrosis was investigated by a prospective multiparametric approach. Serum enzymes and myoglobin, pyrophosphate uptake, 2-dimensional echocardiography, perfusion scintigraphy, left ventriculography and coronary angiography were evaluated. According to creatine kinase and creatine kinase-MB peak at twice the upper normal value, the diagnosis of acute myocardial infarction applied only to 40% of patients. However, myoglobin was positive in 80% and a perfusion defect could be documented by an electrocardiographic gated microsphere technique in 100% of patients. The positivity of myoglobin increased to 100% and of creatine kinase and creatine kinase-MB to 87 and 60%, respectively, when a peak value twice the individual lowest value was considered for positivity. The 100% presence of perfusion defects associated with the high prevalence of both positive pyrophosphate uptake (87%) and regional dyssynergies (87 and 73%, respectively, by left ventriculography and echocardiography) strongly suggest that sustained (greater than or equal to 7 days) ST-T changes in this population were indicative of myocardial necrosis. Thus, by conventional enzymatic approach, diagnosis of non-Q-wave infarction can be missed in a sizable number of patients and present important clinical implications.

Oral isosorbide 5-mononitrate can protect from myocardial ischemia induced by ergonovine test and by isometric effort. Preliminary results from an echocardiographic acute study in anginal patients.

Isosorbide 5-mononitrate (IS 5-MN) has favourable pharmacodynamic properties, such as the specific half-life (close to 5 h) and the bioavailability (100% after oral ingestion). The efficacy of IS 5-MN (20 mg t.i.d.) in the treatment of stable angina has been documented in previous studies. In the present acute study, two subsets of patients were evaluated: the first group consisted of 10 patients with coronary vasospasm in whom oral IS 5-MN was effective in preventing myocardial ischaemia due to an abrupt reduction in coronary blood flow; the second group regarded 8 patients with a mixed form of angina, where the responsible mechanism for ischaemia can be considered a combination of increased myocardial oxygen demand and reduction of coronary blood flow due to vasoconstriction of large vessels. In all these patients, IS 5-MN was able to protect against transient myocardial ischaemia induced by isometric test. In conclusion, from the data available in our studies, IS 5-MN appears to be a useful drug in anginal patients: the beneficial effect is likely based on its capability both to prevent the abnormal vasoconstriction of diseased coronary vessels and to reduce myocardial oxygen demand.

Echocardiography in the study of myocardial ischemia in man: the clinical model of Prinzmetal's angina.

Standard echocardiography was employed to study the clinical model of myocardial ischemia with ST-segment elevation, well known as Prinzmetal's angina. Ultrasonic monitoring was performed during the appearance of ST-segment elevation, from onset of pain, during an ergonovine maleate test, hemodynamic monitoring, radioisotopic studies and, occasionally, during routine examinations, when spontaneous episodes occurred. Reliability of findings was supported by two important conditions: each patient acted as his own control, since recording was carried out from basal state to basal state, throughout ischemia, or from ischemia to basal state; behaviour of ischemic walls was compared with that of non-ischemic ones. Echocardiographic findings in acute myocardial ischemia were similar both in spontaneous and in induced episodes and were mainly characterized by: decrease in contractility indices of the ischemic segment, such as wall motion and percent systolic thickening; increase in left ventricular end-systolic and end-diastolic diameter, with a decrease in percent fractional shortening; distorted shape of ventricular cavity, transiently deformed as in a "functional" aneurysm; a sharp demarcation between ischemic and non-ischemic adjacent segment, "step sign", was present only in severe cases. Taking ST-segment elevation as a reference the time sequence of events was studied, correlating mechanical, electric and clinical markers of ischemia. At least three different echocardiographic phases were identified in the evolution of ischemic attacks: Pre-electrocardiographic phase, when mechanical impairment is detected by ultrasounds in the absence of both ST-segment changes and pain; Electrocardiographic phase, when echocardiographic signs of ischemia co-exist with obvious electrocardiographic signs.(ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiographic documentation of myocardial ischemia in presence of angina pectoris without ST-T changes.

A frequent clinical problem is to document the elusive entity of electrocardiographically silent myocardial ischemia. Since echocardiography offers a practical tool to detect reversible mechanical changes due to ischemia, 32 patients with angina on effort, and coronary artery disease, and 15 patients with angina at rest were studied. In all 47 patients electrocardiographic changes during effort or rest pain were inconclusive. Combined 12 lead electrocardiographic and 2-Dimensional echocardiographic monitoring were performed: during ergonovine testing in the 15 patients with angina at rest; during dipyridamole testing in the 32 patients with effort angina and a non diagnostic stress test. Interpretable echocardiograms were obtained in all the patients studied. Positivity of both the Ergonovine-Echocardiographic test and the Dipyridamole-Echocardiographic test was based upon the detection of regional transient asynergy. Of the 15 patients who had chest pain at rest in the absence of diagnostic electrocardiographic changes, Ergonovine-Echocardiographic test was positive in 6 (40%). Of the 32 patients who had chest pain in absence of diagnostic electrocardiographic changes during exercise stress testing, the Dipyridamole-Echocardiographic test was positive in 18 (56%). Echocardiographic monitoring in combination with provocative testing (ergonovine and dipyridamole) may be a practical, non invasive, inexpensive tool which is feasible in all patients with good basal echocardiograms and is able to unmask electrocardiographically silent myocardial ischemia by providing objective mechanical evidence of the ischemic event.

Dipyridamole-echocardiography test in angina at rest: noninvasive assessment of coronary stenosis underlying spasm.

In a previous study performed in patients with effort angina pectoris, we showed that the dipyridamole-echocardiography test (DET) is feasible and useful for the detection of coronary artery disease. The positivity of the test (consisting of two-dimensional echocardiography [2 DE] combined with dipyridamole infusion [0.14 mg/kg/min for 4 minutes]) is linked to the appearance of regional asynergy. In the present study, DET and exercise stress test (EST) were performed in 62 patients with angina at rest in the active phase. The overall sensitivity of DET and EST for the detection of coronary artery disease was 62% and 83%, respectively (p less than 0.05); the specificity of DET and EST was 100% and 64%, respectively (p less than 0.05). In 10 DET-positive patients, a spontaneous attack was also monitored by 2DE; the myocardial wall involved by ischemia was invariably the same both in patients with spontaneous and in those with dipyridamole-induced ischemia. Thus, in our population of patients with angina at rest (in whom an important functional component is also likely to be present during exercise), DET was significantly less sensitive but significantly more specific than EST in detecting coronary artery disease.

The therapeutic role of isosorbide-5-mononitrate+ in stable and unstable angina pectoris.

Various studies on the pharmacodynamic and clinical properties of isosorbide-5-mononitrate (IS-5-MN) indicate that this drug is effective in the treatment of stable angina pectoris. Acute and chronic studies, in fact, show an improved performance and an amelioration of the clinical status in patients under treatment. On the other hand, acute studies on vasospastic and mixed angina, two common clinical manifestations of coronary artery disease, have demonstrated the capability of IS-5-MN in preventing episodes of transient myocardial ischemia. In analogy with other forms of nitrates, it is clear that IS-5-MN has a positive effect both on the coronary tree (preventing vasoconstriction) and on those hemodynamic parameters which influence the myocardial oxygen demand (reducing myocardial oxygen consumption). Further information is needed, however, to clarify the issue of tolerance development after chronic administration; so far it appears that tolerance may develop when patients are treated with doses of IS-5-MN greater than 20 mg t.i.d.. On the basis of the clinical studies carried out with IS-5-MN, and its favourable pharmacological profile, it is foreseeable that this drug will have an increasing role in the treatment of angina pectoris.

Echocardiographic versus hemodynamic monitoring during attacks of variant angina pectoris.

Six attacks of variant angina (2 spontaneous, 4 induced by ergonovine) were studied in 6 patients by combined echocardiographic and hemodynamic monitoring. A decrease of percent systolic thickening of the ischemic wall, which occurred as early as the decrease in peak dP/dt of contraction, was detected before the onset of ST-segment elevation ("pre-electrocardiographic phase"). At this stage, no significant change in left ventricular (LV) end-diastolic pressure or end-diastolic diameter was observed. Subsequently, in the presence of clear-cut ST-segment elevation ("electrocardiographic phase"), percent systolic thickening (an index of regional function) reached its nadir, while dP/dt of contraction (an index of global function) was almost back to preischemic values. In this phase, a significant increase in LV end-diastolic diameter and end-diastolic pressure could be also detected. In the recovery phase, when the ST segment had returned to the isoelectric line ("post-electrocardiographic phase"), percent systolic thickening and dP/dt of contraction showed supernormal values, while LV end-diastolic pressure and end-diastolic diameter decreased below basal values. Thus, echocardiographic signs of impairment in LV mechanics are as early and sensitive as hemodynamic indexes during attacks of variant angina. Furthermore, information on morphologic characteristics and regional LV function, not available with hemodynamic monitoring, can be obtained by echocardiography.

Transient myocardial ischemia with minimal electrocardiographic changes: an echocardiographic study in patients with Prinzmetal's angina.

Kn patients with Prinzmetal's angina, episodes of transient T wave abnormalities (T abn) are often documented in addition to the typical episodes of ST segment elevation (ST). As the interpretation of these minor ECG changes is still uncertain, we investigated if transient T abn are associated with reversible ventricular asynergies, similar to episodes with ST. For this purpose an ECG lead and a two-dimensional echocardiographic projection, which showed clear-cut changes during previous episodes of ST, were simultaneously monitored in five patients with Prinzmetal's angina for a total of 13 hours and 20 minutes. In all patients, the 30 episodes of ST recorded were all accompanied by reversible ventricular asynergies. Furthermore, in four of these patients, 14 episodes of T abn (peaking, flattening, or the appearance of a diphasic T wave) were recorded. All T abn were associated with reversible asynergies, as detected by three independent observers. The mechanical impairment occurred in the same ventricular wall both during ST and during T abn. During T abn the degree of mechanical impairment appeared less severe (hypokinesia in 12 and akinesia in two episodes) than during ST (hypokinesia in one, akinesia in 25, and dyskinesia in four episodes) (p less than 0.001). The duration of asynergies was less during T abn (107 +/- 76 seconds) than during ST (169 +/- 83 seconds) (p less than 0.05). Chest pain was reported in 5 of 14 episodes of T abn (36%) and in 20 of 30 (66%) episodes of ST (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)