Beta glucan induces proliferation and activation of monocytes in peripheral blood of patients with advanced breast cancer.

AIM: Glucans are glucose polymers that constitute a structural part of fungal cell wall. They can stimulate the innate immunity by activation of monocytes/macrophages. In human studies it has been shown that beta glucan has an immunomodulatory effect and can increase the efficacy of the biological therapies in cancer patients. In this prospective clinical trial we assessed in vivo effects of short term oral beta glucan administration on peripheral blood monocytes and their expression of activation markers in patients with advanced breast cancer. METHODS: 23 female patients with advanced breast cancer were included in the study. Median age of the patients was 52 years. Sixteen healthy females with a median age of 48 years served as the control group for comparing the initial blood samples. Peripheral blood samples were drawn on day zero and patients started receiving oral 1-3, 1-6, D-beta glucan daily. Blood samples were recollected on the 15th day. In the initial samples mean lymphocyte count was significantly lower in the patients with breast cancer (1281+/-306/mm(3) versus 1930+/-573/mm(3), p=0.04). In the patients with breast cancer, mean monocyte count which was 326+124/mm(3) at the beginning, was increased to 496+194/mm(3) at the 15th day (p=0.015). Expression of CD95 (Apo1/Fas) on CD14 positive monocytes was 48.17% at the beginning, which was increased to 69.23 % at the 15th day (p=0.002). Expression of CD45RA on CD14 positive monocytes was 49.9% at the beginning; it was increased significantly to 61.52% on day 15 (p=0.001). CONCLUSION: Oral beta glucan administration seems to stimulate proliferation and activation of peripheral blood monocytes in vivo in patients with advanced breast cancer.

Sequential high-dose methotrexate and fluorouracil combined with doxorubicin--a step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group.

In a prospective phase III multicenter trial, 213 patients with advanced measurable or nonmeasurable gastric cancer were randomized to receive methotrexate (MTX), fluorouracil (5-FU), and Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy) (FAMTX) or 5-FU, Adriamycin, and mitomycin (FAM). The results show a significantly superior response rate (41% v 9% [P less than .0001]), and survival (median, 42 weeks v 29 weeks [P = .004]) for FAMTX. There was a cumulative thrombocytopenia in FAM and not in FAMTX. The FAMTX protocol should be the reference treatment in future clinical trials that seek to improve the therapeutic outcome in advanced gastric cancer.

Overdrive pacing in quinidine syncope and other long QT-interval syndromes.

Prolongation of QT interval is associated with repetitive paroxysm of a particular ventricular tachycardia. It is a typical complication of quinidine therapy but may occur in various other conditions. We used endocardial pacing in nine patients with prolongation of the QT interval who suffered from bouts of ventricular tachycardia and fibrillation. In six patients, the syndrome was due to quinidine and in three, to prenylamine. Acceleration of heart rate resulted in immediate suppression of all arrhythmias. Pacing was continued until the condition producing the QT prolongation disappeared. In one case, a permanent pacemaker was implanted, as the QT prolongation was congenital and permanent. The absolute QT interval was shortened by overdrive pacing from a mean value of 0.65 s to 0.50 s. The corrected QT interval remained prolonged (about 0.56 s). Thus, the arrhythmia was associated with the duration of the actual QT interval, and overdrive pacing was able to suppress it without shortening the corrected QT interval.

Treatment of ruptured interventricular septum with afterload reduction.

Two patients with a ruptured interventricular septum complicating acute myocardial infarction were treated with isosorbide dinitrate. The first patient recovered from cardiogenic shock after sublingual administration of 5 mg of isosorbide dinitrate every two hours and was successfully operated on. The second patient recovered from severe pulmonary edema during the acute stage of the infarction with sublingual isosorbide dinitrate. Moreover, she experienced a considerable symptomatic improvement when a 5 mg sublingual dose of isosorbide dinitrate every three hours was added to her long-term treatment. Analysis of hemodynamic data showed that the most striking change following administration of the drug was the substantial reduction of pulmonary wedge pressure. The striking symptomatic and hemodynamic improvement was achieved by the favorable effect of afterload reduction on left ventricular performance and not by reduction in left to right shunt.

The beneficial effects of verapamil in chronic atrial fibrillation.

Digitalis preparations frequently fail to control heart rate in many patients who have chronic atrial fibrillation, particularly during physical exertion. The effects of orally administered verapamil, 160 to 240 mg/day, on the heart rate at rest and during mild exercise were studied in 23 digitalized patients with chronic atrial fibrillation of various causes. Verapamil substantially reduced the excessive heart rate response to exercise in well-digitalized patients who had chronic atrial fibrillation.

High-dose MTX/5-FU and adriamycin for gastric cancer.

In a phase II trial we tried to evaluate the efficacy of a sequential combination of high-dose methotrexate (MTX) and 5-fluorouracil (5-FU) combined with Adriamycin (ADM). In a pilot study we had found high-dose MTX effective as a single agent in gastric cancer. MTX and 5-FU were combined sequentially because Cadman et al had shown synergism for this combination. The therapy protocol consisted of high-dose MTX, 1.5 g/m2 of body surface, and high-dose 5-FU, 1.5 g/m2. MTX was administered 1 hr prior to 5-FU. Both drugs were given as a bolus. Twenty-four hours after MTX administration, citrovorum factor rescue was started, 15 mg/m2, q.6h. X 12, orally. Forty-eight hours after MTX administration, serum concentration of the drug was measured by high performance liquid chromatography (HPLC). Fourteen days after MTX was given, ADM, 30 mg/m2, was injected as a bolus. This protocol was repeated every 28 days. Patients eligible for this treatment should have a creatinine clearance of greater than 60 ml/min. The study included 30 patients with metastasizing gastric cancer and performance status between 40% and 70%. The response rate was 63% (19 of 30 patients). Two of 30 patients had complete remissions, which are still maintained. The median survival for responders is not yet evaluable: 68% are living after 17+ mo. The median survival for nonresponders was only 5 mo. The difference in survival curves is significant at a level of p less than 0.05. Cytostatic treatment was well tolerated. Fifty percent of the patients could be treated on an outpatient basis. Total alopecia was observed in only 10% of the patients. Severe leukopenia, thrombocytopenia, and kidney disorders were not observed.

Inefficacy of digitalis in the control of heart rate in patients with chronic atrial fibrillation: beneficial effect of an added beta adrenergic blocking agent.

The role of digoxin and the new beta adrenergic blocking agent, timolol, in controlling heart rate at rest and during exercise was investigated in 28 patients with chronic atrial fibrillation. Digoxin failed to prevent excessively rapid heart rates during mild to moderate exercise. Increasing digoxin blood levels from a mean of 0.6 to 1.8 ng/ml had no effect on heart rate either at rest or during exercise. The addition of timolol, 20 to 30 mg/day, resulted in a satisfactory and significant attenuation of the rapid heart rates both at rest and during exercise. Heart rates at rest were 91 and 98 beats/min in the patients with low and high digoxin dosage and rose to 135 and 139 beats/min, respectively, during exercise. Timolol reduced the heart rate to 67 at rest and to 92 beats/min during exercise. The effect of beta adrenergic blockade at rest was less pronounced in patients whose initial heart rates were below 90 beats/min. Digoxin alone may not suffice to control excessive heart rate in patients with chronic atrial fibrillation. The additional beta adrenergic blockade actually normalizes the heart rate response in these patients.

Effects of atenolol on exercise capacity in patients with mitral stenosis with sinus rhythm.

Exercise capacity is frequently impaired in patients with mitral stenosis (MS) and sinus rhythm (SR). The resulting increased heart rate, which shortens the diastolic filling period, and the increased cardiac output lead to further elevations of left atrial pressure and subsequent pulmonary congestion. The effect of the beta-receptor blocking agent atenolol, 100 mg/day, was assessed in 13 patients with MS and SR. Exercise performance was assessed using a modified multistage Bruce protocol after 2 weeks of placebo and after 2 weeks therapy with atenolol in a single-blind, crossover, placebo-controlled, randomized study. Atenolol resulted in significant decreases in mean heart rates at rest and during exercise (p = 0.0015) and a significant increase in total exercise time (p = 0.0015). Maximal exercise capacity was also significantly improved (p = 0.0015). All patients were both objectively and subjectively improved by atenolol. Thus, beta-blockade with atenolol improves exercise capacity in patients with MS and SR and may be of benefit to most such patients. The improved effort tolerance is attributed to reduction of the exercise-associated sinus tachycardia by beta-blockade, allowing a longer diastolic filling period and better left atrial decompression.

Prolonged hemodynamic effect of a slow-release nitroglycerin ointment.

Nitroglycerin (NTG) ointment has been shown to be effective in the treatment of angina pectoris and congestive heart failure. Its duration of action is usually 4 to 6 hours. This study presents data that show that a new slow-release NTG ointment produces hemodynamic improvement over at least 24 hours. Twenty patients with coronary artery disease were tested with serial gated equilibrium radionuclide ventriculography before and at various stages of continuous, once-a-day use of slow-release NTG ointment and 4 days after cessation of therapy. NTG ointment significantly (p less than 0.005) decreased left ventricular end-diastolic and end-systolic volumes both at rest (23% and 33%) and during handgrip exercise (22% and 32%) when examined after continuous usage of at least 24 hours. Ejection fraction increased 21% at rest, from 0.42 +/- 0.15 to 0.51 +/- -0.18, p less than 0.0005). The ratio of peak systolic pressure to end-systolic volume increased 85% at rest (p less than 0.05) and 54% during exercise (p less than 0.01). All values had returned to baseline 4 days after cessation of treatment. Thus, slow-release NTG ointment may be useful in the treatment of angina pectoris and congestive heart failure on a once-a-day basis.

Contribution of echocardiography and immediate surgery to the management of severe aortic regurgitation from active infective endocarditis.

The timing of surgery in patients with severe aortic regurgitation and left ventricular (LV) failure, particularly when associated with active infective endocarditis (IE), is of the utmost importance. From July 1982 to May 1984, 34 patients, aged 15 to 60 years, with severe aortic regurgitation underwent immediate (within 24 hours of diagnosis) aortic valve surgery. All patients were in New York Heart Association class IV for LV failure. Eighteen patients had right-sided heart failure. Decision for immediate surgery was based on the echocardiographic demonstration of diastolic closure of the mitral valve or of vegetations on the aortic valve. Premature closure of the mitral valve was demonstrated echocardiographically in 17 patients, 13 of whom had diastolic crossover of LV and left atrial pressure tracings recorded at surgery. IE of the aortic valve was confirmed at surgery in 29 patients, 27 of whom had vegetations on echocardiography. Seven patients required replacement of both aortic and mitral valves. Antibiotic therapy for IE was started immediately after blood cultures were taken and continued for 4 to 6 weeks postoperatively. The mortality rate within 30 days of surgery was 6% for the group as a whole and 7% for those with IE. Mean follow-up period for the 32 survivors was 10.6 months. There were 2 late deaths. No patient had periprosthetic regurgitation or persistence of endocarditis. Procrastination in referral for surgery of these extremely ill patients is not justified and is likely to be associated with higher risks of morbidity and mortality.

Effects of the dipyridamole test on left ventricular function in coronary artery disease.

The dipyridamole stress test is used with thallium-201 to detect areas of inhomogeneity of blood flow that point to coronary artery disease (CAD). It is unclear whether dipyridamole produces inhomogeneous perfusion only or whether it actually decreases net flow in the obstructed vessels and produces true ischemia. It is also unclear what effect dipyridamole has on global and segmental left ventricular function. Therefore, ejection fraction, segmental wall motion and ventricular volume equivalents were measured before and after dipyridamole in 113 patients and 32 normal subjects. Ejection fraction responded in an abnormal fashion in 98 patients (87%), decreasing from 49 +/- 11% to 43 +/- 13% (p less than 0.0001), whereas it increased in 29 normal subjects (90%) from 57 +/- 6% to 64 +/- 10% (p less than 0.0001). Wall motion worsened distinctly in 75 patients (66%), and pressure/volume ratio deteriorated in 72%. The effect of dipyridamole lasted between 10 and 25 minutes, but was promptly reversed by aminophylline. These findings indicate that dipyridamole generally induces true ischemia in CAD. Furthermore, the degree of dysfunction is related to the angiographically assessed severity of CAD. The shortness of breath (seen in 10% of patients) may be partially explained by the findings, and it seems advisable to give aminophylline to every patient in order to promptly correct left ventricular dysfunction.

Q-T prolongation and polymorphous ("torsade de pointes") ventricular arrhythmias associated with organophosphorus insecticide poisoning.

It is not generally appreciated in the Western world that organophosphorus poisoning may be associated with a serious and often fatal cardiac complication: Q-T interval prolongation with malignant ventricular arrhythmias of the "torsade de pointes" type. This insidious complication may lead to delayed, sudden death after the patients appears to be well on the way to recovery from the other, more dramatic respiratory and neurologic symptoms. In this study 15 patients with organophosphorus poisoning are described. Q-T prolongation was observed in 14 and malignant tachyarrhythmias in 6. In view of the dismal prognosis of these patients, ventricular pacing, previously used with success in other conditions associated with this syndrome, was tried in four patients and successfully shortened the Q-T interval and eliminated the arrhythmias. Isoproterenol did the same in a fifth patient. Awareness of this lethal, but preventable complication of organophosphorus poisoning is called for. Careful electrocardiographic monitoring is necessary until the Q-T interval returns to normal. Electrical pacing appears to be the treatment of choice for the tachyarrhythmias.

Rate-dependent premature beats in man.

Ventricular premature beats (VPBs) appeared in a patient after pacemaker insertion for complete heart block secondary to acute myocardial infarction. Contrary to expectations, the frequency of VPBs was directly related to the basic pacemaker rate. The VPBs are either reentrant beats or represent VPBs arising from pacemaker cells with "slow-response" characteristics, which have been shown to become more automatic with increasing rates of electrical stimulation. This case documents the phenomenon of rate dependency of VPBs in man and discusses its practical importance.

Paradoxic acceleration of ventricular rate after therapy with lidocaine and ajmaline. Findings in two patients with supraventricular tachyarrhythmia.

In two patients with supraventricular tachyarrhythmias with atrioventricular block, therapy with lidocaine and ajmaline decreased the atrioventricular block and caused paradoxic acceleration of the ventricular rate. Appropriate treatment of this hazardous result of therapy with antiarrhythmic drug is reviewed.

Procainamide-induced left anterior hemiblock of the 2:1 type (pseudoelectrical alternans).

A selective defect in cardiac conduction in the anterior division of the left bundle branch was induced in a patient by therapy with procainamide hydrochloride. The defect in conduction, when intermittent, resulted in 2:1 Wencklebach sequences and produced a pattern similar to classic electrical alternans. The prognosis in drug-induced alternans is good, and it is important to differentiate it from true electrical alternans.

Color Doppler echocardiography of isolated cleft mitral valve. Roles of the cleft and the accessory chordae.

To study the mechanism of altered mitral function in the presence of an isolated cleft mitral valve (ICMV) with regard to the relative roles of the cleft and of the accessory chordae, seven patients with ICMV were studied with color Doppler echocardiography. Mitral insufficiency ranging from mild to severe was demonstrated in six cases. The regurgitant jet originated in each case from the site of the cleft: in five patients the regurgitant jet had a narrow base originating exactly from the cleft; in the sixth patient, the regurgitant flow presented as a broad-based jet suggesting that accessory chordae restricted the motion of the anterior mitral leaflet. Turbulent flow in the left ventricular outflow tract, starting at the level of the accessory chordae, was found in one patient in whom a pressure drop of 44 mm Hg was detected with continuous-wave Doppler imaging. The altered function of the mitral valve cleft stems from two elements, the cleft itself and the accessory chordae. Color Doppler flow imaging showed that the cleft was the main factor causing mitral insufficiency. The accessory chordae played an additional pathogenetic role in two patients by causing restricted mitral motion or left ventricular outflow tract obstruction.

Beta-adrenergic blockade as adjunctive oral therapy in patients with chronic atrial fibrillation.

In many patients with chronic atrial fibrillation, it is difficult to prevent an excessive ventricular rate under stress, even with high levels of digoxin in the blood. The effect of adding beta-adrenergic blockade with practolol to digoxin on the heart rate at rest and during low-grade controlled exercise was investigated in 28 patients with chronic atrial fibrillation and in ten normal control subjects who were receiving maintenance dosages (0.25 to 0.75 mg) of digoxin. In atrial fibrillation, therapy with practolol decreased the mean heart rate at rest from 99.8 beats per minute to 77.5 beats per minute (23 percent reduction; P less than 0.01) and during mild exercise from 148.9 beats per minute to 105.4 beats per minute (29 percent) reduction (P less than 0.001). Fifteen patients had clinically significant heart failure; therapy with practolol did not worsen it. Reversible side effects were detected in two patients. When therapy with digoxin is not sufficient to control atrial fibrillation, the addition of a beta-adrenergic blocking agent is recommended as adjunctive treatment in selected patients.

Unsuspected cerebral perfusion. A complication of the use of a central venous pressure catheter.

Cardiac resuscitation is accompained by rapidly performed life-saving procedures. Central venous pressure catheters may be inadvertently inserted into the internal jugular vein, and infusion of pharmacologic agents through such a catheter may lead to potentially serious complications. Rapid detection of these iatrogenic complications is required.

Pronus angina (angina pectoris induced by stooping or crouching). A proposed mechanism.

Patients with severe coronary artery disease (CAD) sometimes complain of chest pressure upon crouching or bending-forward (pronus angina). The factors that trigger pronus angina are not clear. We therefore investigated 28 patients with CAD and 26 normal subjects in the sitting, knee-chest, stooping, and squatting positions. Systolic and diastolic blood pressures were found to increase by 13.5 and 19.5 percent (p < 0.005) in the stooping position. In addition, left ventricular (LV) ejection time index (LVETI) also increased (p < 0.005). Despite the acute rise in aortic pressure, which is expected to lengthen the pre-ejection period index (PEPI), the latter shortened slightly in 10 of 14 (71 percent) patients tested, suggesting augmentation in contractile force during the isovolumic phase. Finally, left atrial size increased (p < 0.005) during the knee-chest maneuver, suggesting that the LV size also increases upon bending forward. The effect of stooping on blood pressure was similar in magnitude to that of squatting. It is concluded that the triggering factor for "pronus angina" in severe CAD may be explained as a combination of hemodynamic events which acutely increase myocardial oxygen requirements.

Increased intensity of the murmur of hypertrophic obstructive cardiomyopathy with carotid sinus pressure.

In a prospective study murmurs increased in intensity with carotid sinus pressure in 18 of 26 patients with hypertrophic obstructive cardiomyopathy (HOCM) (sensitivity, 69.2 percent for the 26 patients, 85.7 percent for the 21 patients in whom heart rate and blood pressure decreased with carotid sinus pressure). On the other hand, the murmur remained constant or decreased in all but one of 104 patients with valvular aortic stenosis, mitral insufficiency, hypertrophic nonobstructive cardiomyopathy, and systolic murmurs of miscellaneous origins (specificity, 99 percent; positive predictive value, 94.7 percent). Catheterization, indirect arterial pressure tracings, and echocardiographic studies indicated that carotid sinus pressure-induced bradycardia was associated with increased left ventricular outflow tract obstruction. The carotid sinus pressure-induced increase in the murmur is probably multifactorial: decreased aortic pressure and impedance; increased contractility immediately on sudden slowing of heart rate; further increase in obstruction as the mitral valve systolic anterior movement is enhanced; and delayed vasodilatation maintaining the obstruction even after return of heart rate to precarotid sinus pressure values. An increase in a systolic murmur with carotid sinus pressure is characteristic of HOCM.