Assessment of neurocognitive decline in cancer patients, except brain cancer, under long-term treatment with bevacizumab.

PURPOSE: We performed a cross-sectional study of neurocognitive function in non-brain cancer patients treated with long-term bevacizumab. METHODS/PATIENTS: From 2015 to 2017, we included patients with different types of cancer treated with bevacizumab with or without chemotherapy (BEV; N = 20) or only chemotherapy (ChT; N = 19) for at least 34 weeks, patients who received non-brain radiotherapy (RxT; N = 19), and healthy controls (HC; N = 19) were assessed once at week 34 of treatment (BEV and ChT) or at completion of radiotherapy. Neurocognition was evaluated with the Hopkins Verbal Learning Test-Revised (HVLT-R) total and delayed recall, the Trail Making Test A and B, and the Controlled Oral Word Association Test in the four groups. Non-parametric tests were used to assess differences between groups. RESULTS: The BEV, ChT, and RxT groups scored significantly lower than the HC group on all tests and especially on the HVLT-R total recall. In no case were the mean scores of the BEV group significantly lower than those of the ChT or RxT groups. CONCLUSIONS: Neurocognitive impairment was seen even in patients treated with local non-brain radiotherapy. Treatment with bevacizumab for a long period of time does not seem to worsen neurocognitive function to a greater extent than chemotherapy.

Delay in starting radiotherapy due to neoadjuvant therapy does not worsen survival in unresected glioblastoma patients

Purpose: We retrospectively examined the potential effect on overall survival (OS) of delaying radiotherapy to administer neoadjuvant therapy in unresected glioblastoma patients. Patients and methods: We compared OS in 119 patients receiving neoadjuvant therapy followed by standard treatment (NA group) and 96 patients receiving standard treatment without neoadjuvant therapy (NoNA group). The MaxStat package of R identified the optimal cut-off point for waiting time to radiotherapy. Results: OS was similar in the NA and NoNA groups. Median waiting time to radiotherapy after surgery was 13 weeks for the NA group and 4.2 weeks for the NoNA group. The longest OS was attained by patients who started radiotherapy after 12 weeks and the shortest by patients who started radiotherapy within 4 weeks (12.3 vs 6.6 months) (P = 0.05). OS was 6.6 months for patients who started radiotherapy before the optimal cutoff of 6.43 weeks and 19.1 months for those who started after this time (P = 0.005). Patients who completed radiotherapy had longer OS than those who did not, in all 215 patients and in the NA and NoNA groups (P = 0.000). In several multivariate analyses, completing radiotherapy was a universally favorable prognostic factor, while neoadjuvant therapy was never identified as a negative prognostic factor. Conclusion: In our series of unresected patients receiving neoadjuvant treatment, in spite of the delay in starting radiotherapy, OS was not inferior to that of a similar group of patients with no delay in starting radiotherapy

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Delay in starting radiotherapy due to neoadjuvant therapy does not worsen survival in unresected glioblastoma patients.

PURPOSE: We retrospectively examined the potential effect on overall survival (OS) of delaying radiotherapy to administer neoadjuvant therapy in unresected glioblastoma patients. PATIENTS AND METHODS: We compared OS in 119 patients receiving neoadjuvant therapy followed by standard treatment (NA group) and 96 patients receiving standard treatment without neoadjuvant therapy (NoNA group). The MaxStat package of R identified the optimal cut-off point for waiting time to radiotherapy. RESULTS: OS was similar in the NA and NoNA groups. Median waiting time to radiotherapy after surgery was 13 weeks for the NA group and 4.2 weeks for the NoNA group. The longest OS was attained by patients who started radiotherapy after 12 weeks and the shortest by patients who started radiotherapy within 4 weeks (12.3 vs 6.6 months) (P = 0.05). OS was 6.6 months for patients who started radiotherapy before the optimal cutoff of 6.43 weeks and 19.1 months for those who started after this time (P = 0.005). Patients who completed radiotherapy had longer OS than those who did not, in all 215 patients and in the NA and NoNA groups (P = 0.000). In several multivariate analyses, completing radiotherapy was a universally favorable prognostic factor, while neoadjuvant therapy was never identified as a negative prognostic factor. CONCLUSION: In our series of unresected patients receiving neoadjuvant treatment, in spite of the delay in starting radiotherapy, OS was not inferior to that of a similar group of patients with no delay in starting radiotherapy.

Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps.

BACKGROUND: Increasing evidence implicates both platelets and neutrophils in the formation, stabilization, and growth of peripheral and coronary thrombi. Neutrophil extracellular traps (NETs) play a key role. The early events in the deregulated cross-talk between platelets and neutrophils are poorly characterized. OBJECTIVES: To identify at the molecular level the mechanism through which platelets induce the generation of NETs in sterile conditions. PATIENTS/METHODS: The presence of NETs was determined in 26 thrombi from patients with acute myocardial infarction by immunohistochemistry and immunofluorescence and markers of NETs assessed in the plasma. In vitro NET generation was studied in static and in physiological flow conditions. RESULTS: Coronary thrombi mainly consist of activated platelets, neutrophils, and NETs in close proximity of platelets. Activated platelets commit neutrophils to NET generation. The event abates in the presence of competitive antagonists of the high mobility group box 1 (HMGB1) protein. Hmgb1(-/-) platelets fail to elicit NETs, whereas the HMGB1 alone commits neutrophils to NET generation. Integrity of the HMGB1 receptor, Receptor for Advanced Glycation End products (RAGE), is required for NET formation, as assessed using pharmacologic and genetic tools. Exposure to HMGB1 prevents depletion of mitochondrial potential, induces autophagosome formation, and prolongs neutrophil survival. These metabolic effects are caused by the activation of autophagy. Blockade of the autophagic flux reverts platelet HMGB1-elicited NET generation. CONCLUSIONS: Activated platelets present HMGB1 to neutrophils and commit them to autophagy and NET generation. This chain of events may be responsible for some types of thromboinflammatory lesions and indicates novel paths for molecular intervention.

Effect of high-dose furosemide in refractory congestive heart failure.

High-dose firosemide is considered effective in primary renal sodium retention but is not generally recommended in congestive heart failure. In order to evaluate efficacy and safety of high-dose furosemide (greater than 500 mg/day), the authors studied 20 patients (pts) resistant to therapy (including furosemide less than 500 mg/day) selected from 161 pts admitted for chronic heart failure. All refractory pts (15 men and 5 women, mean age sixty +/- 12 years) were in NYHA class IV and showed hyponatremia (130 +/- 5 mEq/L) and impaired renal function (BUN 31 +/- 14 mg/dL, serum creatinine 1.3 +/- 0.3 mg/dL and BUN/creatinine ratio 23 +/- 7). In addition to digitalis, dopamine, angiotensin-converting enzyme inhibitors, or vasodilators, IV high-dose furosemide (775 +/- 419 mg/day, 500-2000) was given for ten +/- five days under daily clinical and laboratory monitoring. Three pts died of low-output syndrome while 16 pts were upgraded to NYHA class III and 1 pt to class II; a mean weight reduction of 7.3 +/- 2.9 kg in ten + five days (0.80 +/- 0.4 kg/day) and a mean diuresis increase of 88 +/- 57% occurred. The maximal dose of furosemide did not correlate with serum creatinine but did correlate with BUN/creatinine ratio (r = 0.78, p less than .001). Pts were discharged on with chronic heart failure, and 43% in the subgroup in NYHA class IV with hyponatremia. High dose furosemide was effective for rapid removal of excess water and salt in "furosemide-resistant" congestive heart failure. The relationship between renal impairment and maximal furosemide doses seems to confirm the role of renal pharmacokinetics in the appearance of furosemide resistance.

Prognostic value of hyponatremia in patients with severe chronic heart failure.

In order to evaluate the incidence and the prognostic value of hyponatremia (hypoNa) in patients (pts) with severe chronic heart failure (SCHF), the authors studied 161 consecutive pts (113M, 48F ages sixty-seven +/- ten) with SCHF in NYHA class III-IV. The cause of SCHF was ischemic in 64 pts, hypertensive in 39, valvular in 14, alcohol-related in 3, and idiopathic in 41. Pretreatment hypoNa (less than 135 mmol/L) was found in 64/161 pts (40%) (Group I); Na+ was less than 125 in 10 pts, 125-130 in 19, and 131-135 mmol/L in 35; 42/64 pts (66%) of Group I were in NYHA class IV at admission. In the pts with pretreatment Na+ less than 125 mmol/L, hypoNa was persistent and refractory to high-dose furosemide (less than 500 mg/day) and water restriction. Cardiovascular mortality of Group I pts was 69% within twenty-four months (34 pts died of low-output syndrom and 10 suddenly). All pts with Na+ less than 130 mmol/L died within six months. The 20 pts who normalized Na+ are alive, and in NYHA class II-III (follow-up: twenty-six +/- fifteen, six to sixty months). Pts without hypoNa were 97/161 (Group II), and 58/97 (60%) are alive (follow-up: thirty +/- eighteen, five to fifty-eight months), whereas 39 pts died (27 suddenly, 9 of low-output syndrome, and 3 of extracardiac disease) within twenty-four months. The mortality rate of Group II was significantly lower (40% vs 69%, p less than 0.001) compared with Group I. The two groups were similar for age, sex, and cause and duration of SCHF.(ABSTRACT TRUNCATED AT 250 WORDS)

Time-related decrease in sensitivity to ergonovine in patients with variant angina.

Eighteen patients with variant angina, a positive ergonovine test, and a favorable response to calcium antagonists were studied by serial ergonovine tests and Holter monitoring to assess the long-term changes in response to ergonovine and the relationship with the spontaneous activity of the disease. The number of patients with a positive test decreased from 18 of 18 in the acute phase to 12 of 18 (66%) at 3 months, 10 of 17 (59%) at 6 months, and five of 17 (29%) at 12 months. The mean dose level of ergonovine associated with a positive response and the percentage of positive tests with ST segment depression increased progressively during follow-up. The results of the ergonovine test were well correlated with the spontaneous activity of the disease in 94%, 83%, 76%, and 71% of the patients at initial observation and at 3, 6 and 12 months, respectively. Thus in patients with variant angina and a favorable response to calcium antagonists, a time-related decrease in sensitivity to ergonovine develops during follow-up. In most patients the response to ergonovine is well correlated with the spontaneous activity of the disease; thus the ergonovine test may be a useful tool in the assessment of the natural evolution of vasospastic angina.

Hyperventilation and ergonovine tests in Prinzmetal's variant angina pectoris in men.

Hyperventilation and ergonovine tests were carried out in a group of 30 patients with variant angina to assess the sensitivity of the 2 tests and to correlate the response with spontaneous disease activity. Hyperventilation produced a positive response in 83% (25 of 30) and ergonovine in 93% (28 of 30) of the patients. After hyperventilation 22 of 25 showed ST-segment elevation, 2 ST depression and 1 T-wave pseudonormalization; after ergonovine ST-segment elevation developed in 23 patients, ST depression in 4 and T-wave pseudonormalization in 1. In all cases the electrocardiographic changes occurred in the same leads as during the spontaneous attacks. The incidence of chest pain and ventricular arrhythmias was similar during both tests; spontaneous remission of ischemia, however, was more frequent (48 vs 14%) after hyperventilation than after ergonovine. Acute ischemia developed at a mean of 218 +/- 112 seconds after the end of hyperventilation in 19 of 25 positive tests; at that time double product was not significantly different from basal values. The sensitivity of hyperventilation was similar (95 vs 100%) to ergonovine in the patients with greater than or equal to 1 daily attack, while in those with less than 1 daily attack the sensitivity of hyperventilation decreased to 55% compared to 77% with ergonovine. Thus, in variant angina the sensitivity of both tests correlates with disease activity. Hyperventilation is a safe provocative test with a sensitivity similar to ergonovine in patients with active disease; however, in patients with sporadic attacks hyperventilation has a lower sensitivity than ergonovine and therefore a limited diagnostic value.

Spontaneous remission of variant angina documented by Holter monitoring and ergonovine testing in patients treated with calcium antagonists.

Twenty-four patients with Prinzmetal's variant angina showing a favorable initial response to calcium antagonist treatment were studied to assess the evolution of the disease and the frequency and time course of spontaneous remission. At 3, 6 and 12 months from the acute phase, patients underwent in-hospital control studies, with 48-hour Holter monitoring and ergonovine testing carried out during treatment and after its interruption. During calcium antagonist therapy complete protection from spontaneous attacks was documented in 22 of 24 patients at 3 months, in 19 of 21 at 6 months and in all 21 at 12 months; ergonovine test results were negative in 16 of 23 patients at 3 months, in 16 of 20 at 6 months and in all 20 studied at 12 months. After stopping treatment spontaneous attacks did not reappear in 7 of 24 patients (29%), 14 of 21 (66%) and 16 of 21 (76%) at 3, 6 and 12 months respectively, while the ergonovine test response remained negative in 6 of 21 (28%), 7 of 18 (39%) and 13 of 20 (65%) of the patients controlled at 3, 6 and 12 months. Thus, complete remission of angina documented by both Holter recording and ergonovine testing occurred in 5 of 24 patients (21%) at 3 months, in 7 of 21 (33%) at 6 months and in 12 of 21 (57%) at 12 months. Patients with remission of angina had a shorter duration of symptoms and more often showed normal or not critically diseased coronary arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

[The Italian Group for the Study of Streptokinase in Myocardial Infarct: Changes in surface cardiac potentials. Study with chest electromaps]. / G.I.S.S.I.: Variazioni dei potenziali cardiaci di superficie. Studio con elettromappe toraciche.

The electrocardiographic changes during and after the thrombolytic treatment with streptokinase (SK) were assessed by means of body surface potential mapping. The aim of the study was to identify potential patterns suggesting reperfusion and revealing possible short-term effects on the infarct size of the recanalization. We studied 23 patients enrolled in the G.I.S.S.I. trial; 11 had an anterior and 12 had an inferior myocardial infarction; 14 were treated with SK and 9 were controls. Body surface maps were recorded from 105 lead points located on the anterior thoracic surface using an automated instrument. The maps were obtained immediately before the SK infusion (or at the time of randomization in the control patients), 30, 60, 120 minutes thereafter and then 24 hours and 7 days after the onset of the infarct symptoms. In each patient the surface potential distribution at 100 msec after the end of QRS was considered and the sum of all the positive potential values was calculated (sigma ST). In addition, the potential time integrals relating to two intervals of the cardiac cycle (first 100 msec of ST and first 40 msec of QRS) were calculated at each lead point and transferred to diagrams representing the chest surface explored (isointegral map). With respect to Q-40 maps, deviation index maps were calculated as follows: the mean Q-40 map (obtained from 30 normal subjects) was subtracted from the map of each patient; the value obtained at each lead point was then divided by the standard deviation of the normal values for that point. An area where the integral values were at least 2 SD lower than normal was considered a reliable index of infarct. By considering as index of reperfusion an early peak of CPK (less than 12 hours from the onset of infarct symptoms), we divided the patients into 2 subsets: reperfused (R) and not reperfused (NR). The mean values of sigma ST at 100 msec progressively decreased in all patients from the baseline to the subsequent recordings in both control and SK groups, without significant differences; nevertheless, the highest percent reductions of sigma ST were observed only in some R patients. The maximum on the ST-100 isointegral maps also showed a similar behaviour.(ABSTRACT TRUNCATED AT 250 WORDS)

[Usefulness and limitations of the ergonovine maleate test in the evaluation of calcium-antagonist therapy in Prinzmetal variant angina]. / Utilità e limiti del test con ergonovina maleato nella valutazione della terapia calcio-antagonista nell'angina variante di Prinzmetal.

Ergonovine testing was carried out in a selected group of 25 patients with Prinzmetal's variant angina treated with calcium-antagonists in order to: define its usefulness in the evaluation of the short-term effectiveness of calcium-antagonist treatment; compare the results of the test with those of Holter monitoring; verify if the results of the test during the acute phase are correlated with the long-term response to treatment. In all patients a control period lasting 2-6 days was carried out, after which a treatment period with calcium-antagonists (nifedipine, diltiazem, verapamil), lasting 2-8 days, was instituted. In 20 patients only 1 calcium-antagonist was evaluated, in 1 patient 2 calcium-antagonists and in 4 all of them. Scalar ergonovine test was carried out in control conditions and repeated during each calcium-antagonist treatment period. During both control and treatment periods all patients underwent Holter monitoring for evaluation of frequency of the spontaneous attacks. After the acute phase 21 of the 25 patients were discharged on calcium-antagonist treatment and followed-up for a mean period of 11 +/- 7 months. In control conditions ergonovine test was positive in 24 patients at a mean dose of 0.11 +/- 0.09 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

When are arrhythmias and conduction disturbances markers of myocardial ischemia at rest?

Myocardial ischemia, particularly when transmural as in variant angina pectoris, may be associated with ventricular tachycardia, ventricular fibrillation and paroxysmal atrioventricular block (15%). Syncope (7%) and sudden death (3%) due to these malignant arrhythmias are sometimes a unique marker of myocardial ischemia. Two-hundred fifty-four patients (220 males and 34 females), aged 5 +/- 9 years with transmural myocardial ischemia related to coronary artery spasm, were studied. Particular attention was paid to the role of syncopal attacks as unique clinical manifestation of silent ischemia. Patients examined were divided into 3 Groups. Group 1 includes 5/254 (2%) patients with atrial fibrillation during acute ischemia. Group 2 was divided into four subgroups: subgroup A includes 17/254 (7%) patients with syncopal attacks due to malignant arrhythmias (ventricular tachycardia and advanced A-V block); subgroup B, 15/254 (6%) patients with documented malignant arrhythmias, without syncopal attacks; subgroup C, 7/254 (3%) with ventricular fibrillation during acute ischemia and subgroup D, 18/254 (7%) patients with history of syncopal attacks without documented arrhythmias during hospital observation. Group 3 includes 17/254 (7%) patients with left anterior hemiblock in basal condition, 7/254 (3%) patients with left anterior hemiblock and one left posterior hemiblock during acute ischemia and one patient with right bundle branch block during acute ischemia. Syncopal symptoms are present in many of these cases of angina pectoris; paroxysmal A-V block is documented in nearly half of the cases with syncope (65%); ventricular tachycardia is frequently demonstrated during ischemia but leads to syncope in only a few cases; patients with syncope do not present specific clinical features.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventricular arrhythmias during acute myocardial ischaemia in man. The role and significance of R-ST-T alternans and the prevention of ischaemic sudden death by medical treatment.

Malignant ventricular arrhythmias appearing during acute myocardial ischaemia, are the most frequent mechanism of sudden death. ST-T alternans is the result of an intraischaemic conduction delay and is frequently associated with those potentially lethal arrhythmias. In fact, such a phenomenon was seen in 35% of 46/86 patients with Prinzmetal's variant angina who showed ventricular arrhythmias during ischaemia, while it was never observed in the remaining 40 patients without arrhythmias during ischaemia. Therefore ST-segment alternans should be considered a reliable marker of the possible occurrence of ventricular arrhythmias during myocardial ischaemia. ST-T-segment alternans is associated with R alternans, as clearly demonstrated by thoracic maps, and this phenomenon is due to a 2:1 intraischaemic block. The patients with Prinzmetal's variant angina who present ventricular arrhythmias during ischaemia, show a more prominent increase of the positive area of the QRS (411.75 +/- 102.5 vs 294.05 +/- 80.3 mu volts ms), that is, a more relevant intraischaemic conduction delay. The effects of different pretreatments (lidocaine, propranolol and diltiazem) on arrhythmias related to vasospastic myocardial ischaemia induced by ergonovine maleate, were evaluated in four patients with Prinzmetal's variant angina. As in experimental observations, neither a 'pure' antiarrhythmic agent like lidocaine, nor a betablocking agent like propranolol, prevented acute ischaemic ventricular arrhythmias. Only the calcium antagonist, diltiazem, seemed to prevent such arrhythmias. However, these findings necessitate further confirmation.

Analgesic treatment in acute myocardial infarction: a comparison between indoprofen and morphine by a double-blind randomized pilot study.

On the basis of the results of an earlier study, showing that i.v. indoprofen induced no clinically significant changes in hemodynamic parameters of patients with acute myocardial infarction (AMI), a double-blind randomized trial was carried out in 40 AMI patients to evaluate the analgesic activity of 400 mg i.v. indoprofen in comparison with 10 mg i.m. morphine hydrochloride. Pain severity was recorded before and at several intervals within 24 h after drug administration. The average analgesic response was prompt and progressive up to the 6th hour in both treatment groups, with no significant difference between drugs in various pain descriptors. However, the proportion of responding patients in indoprofen group was greater than in morphine group at all observation times, indicating a significant difference (p less than 0.05) in favor of indoprofen. In view of its good tolerability, i.v. indoprofen is worth considering in early AMI as an alternative to morphine in those patients in whom non-opiate analgesia might be preferable.

Dihydroquinidine versus disopyramide: efficacy in patients with chronic stable ventricular ectopy.

Dihydroquinidine (DQ) is contained in substantial amounts in quinidine salts, but its direct antiarrhythmic action has not been studied. The efficacy of oral DQ (300 mg t. i. d.) compared to disopyramide (D) (200 mg t.i.d.) was thus investigated using a double-blind crossover placebo-controlled protocol in 12 patients, aged 13 to 67 years, with chronic stable high frequency premature ventricular beats (PVB), defined as greater than 100 PVB/h during 48-72-h control Holter monitoring. The protocol included three 72-h treatment periods: DQ, D, and placebo at random. On days 2 and 3 of each period a 24-h Holter recording was carried out; drug blood levels were determined at peak (days 2 and 3) and trough time (day 3). No significant difference in the mean PVB/h was found between control (735 +/- 400) and placebo periods (564 +/- 388), or between the two Holter recordings of each period. Compared to placebo both DQ (106 +/- 113, p less than 0.005) and D (240 +/- 263, p less than 0.05) reduced the mean PVB/h, but the decrease was significantly higher with DQ (78 versus 53%, p less than 0.02). Nine patients (75%) on DQ and 5 (42%) on D had a greater than 70% decrease in mean PVB/h; complex PVBs were abolished in 3 of 6 patients on both treatments. On day 3, DQ plasma levels were 1.31 +/- 0.44 (peak) and 0.92 +/- 0.45 (trough) mg/l; D plasma levels were 2.88 +/- 0.64 (peak) and 2.02 +/- 0.31 (trough) mg/l; no significant difference was found between day 2 and day 3 samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventricular tachyarrhythmias in Prinzmetal's variant angina: clinical significance and relation to the degree and time course of S-T segment elevation.

Fifty-six patients with active Prinzmetal's variant angina were studied to determine the incidence and clinical significance of ventricular tachyarrhythmias and the correlation between arrhythmias and degree and time course of S-T segment changes during the ischemic attacks. Twenty-nine patients (Group I) had no ventricular arrhythmias in any of the 1,083 recorded episodes, while 27 patients (Group II) developed arrhythmias in 18% of the attacks. No significant differences in clinical, electrocardiographic, angiographic, or hemodynamic findings could be found between the 2 groups. In 23 of the 27 Group II patients, ventricular arrhythmias developed during maximal S-T segment elevation (occlusion arrhythmias), while in 10 they occurred during resolution of S-T segment changes (reperfusion arrhythmias); 6 of the latter patients also had occlusion arrhythmias. Eight of the 23 patients with occlusion arrhythmias and 6 of the 10 with reperfusion arrhythmias had ventricular fibrillation or ventricular tachycardia. Maximal S-T segment elevation was significantly greater (p less than 0.001) in patients with occlusion arrhythmias than in those without arrhythmias. The episodes with reperfusion arrhythmias were significantly longer (p less than 0.001) and showed a significantly greater S-T segment elevation (p less than 0.001) than those without arrhythmias in Group I patients. This study shows that significant ventricular tachyarrhythmias develop during ischemic attacks in about 50% of patients with active variant angina; clinical and angiographic features are not useful in distinguishing patients with arrhythmias from the others. Our findings suggest that in variant angina ventricular arrhythmias may be due to the effects of both coronary artery occlusion and reperfusion; both types of arrhythmias are correlated with the severity of ischemia, as measured by the degree of S-T segment elevation. Reperfusion arrhythmias also appear to be correlated with the duration of ischemia.